In Vivo Bioconcentration of 10 Anionic Surfactants in Rainbow Trout Explained by In Vitro Data on Partitioning and S9 Clearance.

Bioconcentration factors (BCFs) in rainbow trout were measured for 10 anionic surfactants with a range of alkyl chain lengths and different polar head groups. The BCFs ranged from 0.04 L kg-1 ww (for C10SO3) to 1370 L kg-1 ww (C16SO3). There was a strong correlation between the log BCF and log membrane lipid-water distribution ratio (DMLW, r2 = 0.96), and biotransformation was identified as the dominant elimination mechanism. The strong positive influence of DMLW on BCF was attributed to two phenomena: (i) increased partitioning from water into the epithelial membrane of the gill, leading to more rapid diffusion across this barrier and more rapid uptake, and (ii) increased sequestration of the surfactant body burden into membranes and other body tissues, resulting in lower freely dissolved concentrations available for biotransformation. Estimated whole-body in vivo biotransformation rate constants kB-BCF are within a factor three of rate constants estimated from S9 in vitro assays for six of the eight test chemicals for which kB-BCF could be determined. A model-based assessment indicated that the hepatic clearance rate of freely dissolved chemicals was similar for the studied surfactants. The dataset will be useful for evaluation of in silico and in vitro methods to assess bioaccumulation.

Bioconcentration of Several Series of Cationic Surfactants in Rainbow Trout.

Cationic surfactants have a strong affinity to sorb to phospholipid membranes and thus possess an inherent potential to bioaccumulate, but there are few measurements of bioconcentration in fish. We measured the bioconcentration of 10 alkylamines plus two quaternary ammonium compounds in juvenile rainbow trout at pH 7.6, and repeated the measurements at pH 6.2 for 6 of these surfactants. The BCF of the amines with chain lengths ≤ C14 was positively correlated with chain length, increasing ∼0.5 log units per carbon. Their BCF was also pH dependent and approximately proportional to the neutral fraction of the amine in the water. The BCFs of the quaternary ammonium compounds showed no pH dependence and were >2 orders of magnitude less than for amines of the same chain length at pH 7.6. This indicates that systemic uptake of permanently charged cationic surfactants is limited. The behavior of the quaternary ammonium compounds and the two C16 amines studied was consistent with previous observations that these surfactants accumulate primarily to the gills and external surfaces of the fish. At pH 7.6 the BCF exceeded 2000 L kg-1 for 4 amines with chains ≥ C13, showing that bioconcentration can be considerable for some longer chained cationic surfactants.

Tissue Distribution of Several Series of Cationic Surfactants in Rainbow Trout (Oncorhynchus mykiss) Following Exposure via Water.

Bioaccumulation assessment is important for cationic surfactants in light of their use in a wide variety of consumer products and industrial processes. Because they sorb strongly to natural surfaces and to cell membranes, their bioaccumulation behavior is expected to differ from other classes of chemicals. Divided over two mixtures, we exposed rainbow trout to water containing 10 alkyl amines and 2 quaternary alkylammonium surfactants for 7 days, analyzed different fish tissues for surfactant residues, and calculated the tissues' contribution to fish body burden. Mucus, skin, gills, liver, and muscle each contributed at least 10% of body burden for the majority of the test chemicals. This indicates that both sorption to external surfaces and systemic uptake contribute to bioaccumulation. In contrast to the analogue alkylamine bases, the permanently charged quaternary ammonium compounds accumulated mostly in the gills and were nearly absent in internal tissues, indicating that systemic uptake of the charged form of cationic surfactants is very slow. Muscle-blood distribution coefficients were close to 1 for all alkyl amines, whereas liver-blood distribution coefficients ranged from 13 to 90, suggesting that the dominant considerations for sorption in liver are different from those in blood and muscle. The significant fraction of body burden on external surfaces can have consequences for bioaccumulation assessment.

Development and Evaluation of a Combined Bioenergetics and Organic Chemical Mass-Balance Bioaccumulation Model for Fish.

This study describes the development and evaluation of a new bioenergetically balanced bioaccumulation (3B) model for organic chemicals in fish. The 3B model is developed from a large database of routine metabolic (oxygen consumption) rates composed of a range of species, body mass, and temperatures. The chemical uptake and elimination rates of the 3B model are compared against those from three existing bioaccumulation models. A time-variant version of the 3B model is evaluated against measured concentrations of five polychlorinated biphenyls in different-size fish depurated over the course of a year, during which water temperature changed by 22 °C. The "generic" species 3B model predicts fish concentrations to within a factor of 3 of the measured data for the majority of observations ( n = 438) and outperforms a previously published "species-specific" bioenergetics model. Bioenergetics aspects of the 3B model are further evaluated by comparing predicted feeding rates and growth rates to measured rates obtained from diverse laboratory conditions ( n 572). While bioenergetics performance is acceptable, the 3B model seems to generally perform better when ingestion rates are calculated from growth rates rather than vice versa. For field applications, parametrization of the activity multiplier remains a key uncertainty underlying the bioenergetics calculations.

A Model for Risk-Based Screening and Prioritization of Human Exposure to Chemicals from Near-Field Sources.

Exposure- and risk-based assessments for chemicals used indoors or applied to humans (i.e., in near-field environments) necessitate an aggregate exposure pathway framework that aligns chemical exposure information from use sources to internal dose and eventually to their potential for health effects. Such a source-to-effect continuum is advocated to balance the complexity of human exposure and the insufficiency of relevant data for thousands of existing and emerging chemicals. Here, we introduce the Risk Assessment, IDentification And Ranking-Indoor and Consumer Exposure (RAIDAR-ICE) model, which establishes an integrated framework to evaluate human exposure due to indoor use and direct application of chemicals to humans. As a model evaluation, RAIDAR-ICE faithfully reproduces exposure estimates inferred from biomonitoring data for 37 chemicals with direct and indirect near-field sources. RAIDAR-ICE generates different rankings for 131 chemicals based on different exposure- and risk-based assessment metrics, demonstrating its versatility for diverse chemical screening goals. When coupled with a far-field RAIDAR model, the near-field RAIDAR-ICE model enables assessment of aggregate human exposure. Overall, RAIDAR-ICE is a powerful tool for high-throughput screening and prioritization of human exposure to neutral organic chemicals used indoors.

Unravelling the Relationship between Body Mass Index and Polychlorinated Biphenyl Concentrations Using a Mechanistic Model.

Human biomonitoring (HBM) often reveals statistical associations between persistent organic pollutant (POP) concentrations and body mass index (BMI). Both negative and positive associations have been observed, which has been hypothesized to reflect variable toxicokinetics in lean and obese individuals during times of increasing and decreasing exposure. We examined this hypothesis and assessed the influence of the obesity epidemic on time trends in human exposure to polychlorinated biphenyls (PCB) at the population level using a mechanistic modeling approach and data from the National Health and Nutrition Examination Survey (NHANES) 1999-2004. Using model results for PCB-153, we simulated cross-sectional body burden versus BMI trends (CBBTs), as well as population level body burden versus time trends. Negative associations between PCB-153 concentrations and BMI are predicted for all birth cohorts in HBM studies conducted in the 1990s, while for future cross-sectional studies, we predict negative or positive relationships depending on the age group sampled. At the population level, demographic changes such as the obesity epidemic and population aging had only marginal influence on the simulated rate of decline in PCB-153 concentrations between 1980 and 2010. Mechanistic bioaccumulation models can help unravel relationships between age, BMI, and POP concentrations, informing efforts to understand potential obesogenic effects of POPs.

Tracking the Global Distribution of Persistent Organic Pollutants Accounting for E-Waste Exports to Developing Regions.

Elevated concentrations of various industrial-use Persistent Organic Pollutants (POPs), such as polychlorinated biphenyls (PCBs), have been reported in some developing areas in subtropical and tropical regions known to be destinations of e-waste. We used a recent inventory of the global generation and exports of e-waste to develop various global scale emission scenarios for industrial-use organic contaminants (IUOCs). For representative IUOCs (RIUOCs), only hypothetical emissions via passive volatilization from e-waste were considered whereas for PCBs, historical emissions throughout the chemical life-cycle (i.e., manufacturing, use, disposal) were included. The environmental transport and fate of RIUOCs and PCBs were then simulated using the BETR Global 2.0 model. Export of e-waste is expected to increase and sustain global emissions beyond the baseline scenario, which assumes no export. A comparison between model predictions and observations for PCBs in selected recipient regions generally suggests a better agreement when exports are accounted for. This study may be the first to integrate the global transport of IUOCs in waste with their long-range transport in air and water. The results call for integrated chemical management strategies on a global scale.

Which Molecular Features Affect the Intrinsic Hepatic Clearance Rate of Ionizable Organic Chemicals in Fish?

Greater knowledge of biotransformation rates for ionizable organic compounds (IOCs) in fish is required to properly assess the bioaccumulation potential of many environmentally relevant contaminants. In this study, we measured in vitro hepatic clearance rates for 50 IOCs using a pooled batch of liver S9 fractions isolated from rainbow trout (Oncorhynchus mykiss). The IOCs included four types of strongly ionized acids (carboxylates, phenolates, sulfonates, and sulfates), three types of strongly ionized bases (primary, secondary, tertiary amines), and a pair of quaternary ammonium compounds (QACs). Included in this test set were several surfactants and a series of beta-blockers. For linear alkyl chain IOC analogues, biotransformation enzymes appeared to act directly on the charged terminal group, with the highest clearance rates for tertiary amines and sulfates and no clearance of QACs. Clearance rates for C12-IOCs were higher than those for C8-IOC analogues. Several analogue series with multiple alkyl chains, branched alkyl chains, aromatic rings, and nonaromatic rings were evaluated. The likelihood of multiple reaction pathways made it difficult to relate all differences in clearance to specific molecular features the tested IOCs. Future analysis of primary metabolites in the S9 assay is recommended to further elucidate biotransformation pathways for IOCs in fish.

Application of mass balance models and the chemical activity concept to facilitate the use of in vitro toxicity data for risk assessment.

Practical, financial, and ethical considerations related to conducting extensive animal testing have resulted in various initiatives to promote and expand the use of in vitro testing data for chemical evaluations. Nominal concentrations in the aqueous phase corresponding to an effect (or biological activity) are commonly reported and used to characterize toxicity (or biological response). However, the true concentration in the aqueous phase can be substantially different from the nominal. To support in vitro test design and aid the interpretation of in vitro toxicity data, we developed a mass balance model that can be parametrized and applied to represent typical in vitro test systems. The model calculates the mass distribution, freely dissolved concentrations, and cell/tissue concentrations corresponding to the initial nominal concentration and experimental conditions specified by the user. Chemical activity, a metric which can be used to assess the potential for baseline toxicity to occur, is also calculated. The model is first applied to a set of hypothetical chemicals to illustrate the degree to which test conditions (e.g., presence or absence of serum) influence the distribution of the chemical in the test system. The model is then applied to set of 1194 real substances (predominantly from the ToxCast chemical database) to calculate the potential range of concentrations and chemical activities under assumed test conditions. The model demonstrates how both concentrations and chemical activities can vary by orders of magnitude for the same nominal concentration.

Tracking the global generation and exports of e-waste. Do existing estimates add up?

The transport of discarded electronic and electrical appliances (e-waste) to developing regions has received considerable attention, but it is difficult to assess the significance of this issue without a quantitative understanding of the amounts involved. The main objective of this study is to track the global transport of e-wastes by compiling and constraining existing estimates of the amount of e-waste generated domestically in each country MGEN, exported from countries belonging to the Organization for Economic Cooperation and Development (OECD) MEXP, and imported in countries outside of the OECD MIMP. Reference year is 2005 and all estimates are given with an uncertainty range. Estimates of MGEN obtained by apportioning a global total of ∼ 35,000 kt (range 20,000-50,000 kt) based on a nation's gross domestic product agree well with independent estimates of MGEN for individual countries. Import estimates MIMP to the countries believed to be the major recipients of e-waste exports from the OECD globally (China, India, and five West African countries) suggests that ∼ 5,000 kt (3,600 kt-7,300 kt) may have been imported annually to these non-OECD countries alone, which represents ∼ 23% (17%-34%) of the amounts of e-waste generated domestically within the OECD. MEXP for each OECD country is then estimated by applying this fraction of 23% to its MGEN. By allocating each country's MGEN, MIMP, MEXP and MNET = MGEN + MIMP - MEXP, we can map the global generation and flows of e-waste from OECD to non-OECD countries. While significant uncertainties remain, we note that estimated import into seven non-OECD countries alone are often at the higher end of estimates of exports from OECD countries.

Modeling the uptake of neutral organic chemicals on XAD passive air samplers under variable temperatures, external wind speeds and ambient air concentrations (PAS-SIM).

The main objective of this study was to evaluate the performance and demonstrate the utility of a fugacity-based model of XAD passive air samplers (XAD-PAS) designed to simulate the uptake of neutral organic chemicals under variable temperatures, external wind speeds and ambient air concentrations. The model (PAS-SIM) simulates the transport of the chemical across the air-side boundary layer and within the sampler medium, which is segmented into a user-defined number of thin layers. Model performance was evaluated using data for polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs) from a field calibration study (i.e., active and XAD-PAS data) conducted in Egbert, Ontario, Canada. With some exceptions, modeled PAS uptake curves are in good agreement with the empirical PAS data. The results are highly encouraging, given the uncertainty in the active air sampler data used as input and other uncertainties related to model parametrization (e.g., sampler-air partition coefficients, the influence of wind speed on sampling rates). The study supports the further development and evaluation of the PAS-SIM model as a diagnostic (e.g., to aid interpretation of calibration studies and monitoring data) and prognostic (e.g., to inform design of future passive air sampling campaigns) tool.

Exploring the role of shelf sediments in the Arctic Ocean in determining the Arctic contamination potential of neutral organic contaminants.

The main objective of this study was to model the contribution of shelf sediments in the Arctic Ocean to the total mass of neutral organic contaminants accumulated in the Arctic environment using a standardized emission scenario for sets of hypothetical chemicals and realistic emission estimates (1930-2100) for polychlorinated biphenyl congener 153 (PCB-153). Shelf sediments in the Arctic Ocean are shown to be important reservoirs for neutral organic chemicals across a wide range of partitioning properties, increasing the total mass in the surface compartments of the Arctic environment by up to 3.5-fold compared to simulations excluding this compartment. The relative change in total mass for hydrophobic organic chemicals with log air-water partition coefficients ≥0 was greater than for chemicals with properties similar to typical POPs. The long-term simulation of PCB-153 generated modeled concentrations in shelf sediments in reasonable agreement with available monitoring data and illustrate that the relative importance of shelf sediments in the Arctic Ocean for influencing surface ocean concentrations (and therefore exposure via the pelagic food web) is most pronounced once primary emissions are exhausted and secondary sources dominate. Additional monitoring and modeling work to better characterize the role of shelf sediments for contaminant fate is recommended.

A weight of evidence approach for bioaccumulation assessment.

Bioaccumulation assessments conducted by regulatory agencies worldwide use a variety of methods, types of data, metrics, and categorization criteria. Lines of evidence (LoE) for bioaccumulation assessment can include bioaccumulation metrics such as in vivo bioconcentration factor (BCF) and biomagnification factor (BMF) data measured from standardized laboratory experiments, and field (monitoring) data such as BMFs, bioaccumulation factors (BAFs), and trophic magnification factors (TMFs). In silico predictions from mass-balance models and quantitative structure-activity relationships (QSARs) and a combination of in vitro biotransformation rates and in vitro-in vivo extrapolation (IVIVE) models can also be used. The myriad bioaccumulation metrics and categorization criteria and underlying uncertainty in measured or modeled data can make decision-making challenging. A weight of evidence (WoE) approach is recommended to address uncertainty. The Bioaccumulation Assessment Tool (BAT) guides a user through the process of collecting and generating various LoE required for assessing the bioaccumulation of neutral and ionizable organic chemicals in aquatic (water-respiring) and air-breathing organisms. The BAT includes data evaluation templates (DETs) to critically evaluate the reliability of the LoE used in the assessment. The DETs were developed from standardized testing guidance. The approach used in the BAT is consistent with OECD and SETAC WoE principles and facilitates the implementation of chemical policy objectives in chemical assessment and management. The recommended methods are also iterative and tiered, providing pragmatic methods to reduce unnecessary animal testing. General concepts of the BAT are presented and case study applications of the tool for hexachlorobenzene (HCB) and ß-hexachlorocyclohexane (ß-HCH) are demonstrated. The BAT provides a consistent and transparent WoE framework to address uncertainty in bioaccumulation assessment and is envisaged to evolve with scientific and regulatory developments. Integr Environ Assess Manag 2023;19:1235-1253. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

An amended in vitro-in vivo extrapolation model that accounts for first pass clearance effects on chemical bioaccumulation in fish.

Measured rates of in vitro intrinsic clearance for fish may be extrapolated to the whole animal as a means of estimating a whole-body biotransformation rate constant (kB; d-1). This estimate of kB can then be used as an input to existing bioaccumulation prediction models. Most in vitro-in vivo extrapolation/bioaccumulation (IVIVE/B) modeling efforts to date have focused on predicting the chemical bioconcentration in fish (aqueous only exposure), with less attention paid to dietary exposures. Following dietary uptake, biotransformation in the gut lumen, intestinal epithelia, and liver can reduce chemical accumulation; however, current IVIVE/B models do not consider these first pass clearance effects on dietary uptake. Here we present an amended IVIVE/B model that accounts for first pass clearance. The model is then used to examine how biotransformation in the liver and intestinal epithelia (alone or combined) may impact chemical accumulation that occurs during dietary exposure. First pass clearance by the liver can greatly reduce dietary uptake of contaminants, but these effects are only apparent at rapid rates of in vitro biotransformation (first order depletion rate constant kDEP ≥ 10 h-1). The impact of first pass clearance becomes more pronounced when biotransformation in the intestinal epithelia is included in the model. Modelled results suggest that biotransformation in the liver and intestinal epithelia cannot entirely explain reduced dietary uptake reported in several in vivo bioaccumulation tests. This unexplained reduction in dietary uptake is attributed to chemical degradation in the gut lumen. These findings underscore the need for research to directly investigate luminal biotransformation in fish.

A framework for understanding the bioconcentration of surfactants in fish.

Surfactants are a class of chemicals released in large quantities to water, and therefore bioconcentration in fish is an important component of their safety assessment. Their structural diversity, which encompasses nonionic, anionic, cationic and zwitterionic molecules with a broad range of lipophilicity, makes their evaluation challenging. A strong influence of environmental pH adds a further layer of complexity to their bioconcentration assessment. Here we present a framework that penetrates this complexity. Using simple equations derived from current understanding of the relevant underlying processes, we plot the key bioconcentration parameters (uptake rate constant, elimination rate constant and bioconcentration factor) as a function of its membrane lipid/water distribution ratio and the neutral fraction of the chemical in water at pH 8.1 and at pH 6.1. On this chemical space plot, we indicate boundaries at which four resistance terms (perfusion with water, transcellular, paracellular, and perfusion with blood) limit transport of surfactants across the gills. We then show that the bioconcentration parameters predicted by this framework align well with in vivo measurements of anionic, cationic and nonionic surfactants in fish. In doing so, we demonstrate how the framework can be used to explore expected differences in bioconcentration behavior within a given sub-class of surfactants, to assess how pH will influence bioconcentration, to identify the underlying processes governing bioconcentration of a particular surfactant, and to discover knowledge gaps that require further research. This framework for amphiphilic chemicals may function as a template for improved understanding of the accumulation potential of other ionizable chemicals of environmental concern, such as pharmaceuticals or dyes.

Graphical tools for the planning and interpretation of polyurethane foam based passive air sampling campaigns.

Due to low cost and easy handling during sampling and extraction, passive air samplers (PASs) using polyurethane foam (PUF) as a sorbent have become the most commonly deployed PASs for semi-volatile organic compounds (SVOCs). However, depending on the scenario, PUF-PAS may not always be operating in the linear uptake phase, which implies the need to consider how temperature, wind speed, deployment length and chemical properties interact to determine the amount of a target chemical taken up and the fraction of a depuration compound (DC) being lost during deployment. Guidance is, therefore, necessary to quantitatively interpret curvi-linear uptake in the PUF-PAS and avoid selection of DCs unsuited to the deployment conditions. In this study, the PAS-SIM model is used to generate graphical tools that aid in addressing important questions frequently arising during the use of PUF-PASs. Specifically, we generated five charts that display (i) the inherent sampling rate as a function of wind speed and a chemical's molecular diffusivity, (ii) the length of the linear uptake period as a function of chemical properties, temperature and the acceptable deviation from linearity, (iii) the time to 95% equilibrium as influenced by chemical properties, temperature and wind speed, (iv) the dependence of the fractional loss of DCs on chemical properties, temperature, wind speed and deployment length, and (v) the influence of chemical properties, temperature and the total suspended particle concentration on the extent of sorption to atmospheric particles. The charts also facilitate the assessment of the influence of parameter uncertainty. It is hoped that these charts assist with planning and interpreting sampling campaigns based on a mechanistic and quantitative understanding of uptake in PUF-based PASs.

Predicting the Accumulation of Ionizable Pharmaceuticals and Personal Care Products in Aquatic and Terrestrial Organisms.

The extent to which chemicals bioaccumulate in aquatic and terrestrial organisms represents a fundamental consideration for chemicals management efforts intended to protect public health and the environment from pollution and waste. Many chemicals, including most pharmaceuticals and personal care products (PPCPs), are ionizable across environmentally relevant pH gradients, which can affect their fate in aquatic and terrestrial systems. Existing mathematical models describe the accumulation of neutral organic chemicals and weak acids and bases in both fish and plants. Further model development is hampered, however, by a lack of mechanistic insights for PPCPs that are predominantly or permanently ionized. Targeted experiments across environmentally realistic conditions are needed to address the following questions: (1) What are the partitioning and sorption behaviors of strongly ionizing chemicals among species? (2) How does membrane permeability of ions influence bioaccumulation of PPCPs? (3) To what extent are salts and associated complexes with PPCPs influencing bioaccumulation? (4) How do biotransformation and other elimination processes vary within and among species? (5) Are bioaccumulation modeling efforts currently focused on chemicals and species with key data gaps and risk profiles? Answering these questions promises to address key sources of uncertainty for bioaccumulation modeling of ionizable PPCPs and related contaminants. Environ Toxicol Chem 2022;00:1-11. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Dynamic Mass Balance Modeling for Chemical Distribution Over Time in In Vitro Systems With Repeated Dosing.

As toxicologists and risk assessors move away from animal testing and more toward using in vitro models and biological modeling, it is necessary to produce tools to quantify the chemical distribution within the in vitro environment prior to extrapolating in vitro concentrations to human equivalent doses. Although models predicting chemical distribution in vitro have been developed, very little has been done for repeated dosing scenarios, which are common in prolonged experiments where the medium needs to be refreshed. Failure to account for repeated dosing may lead to inaccurate estimations of exposure and introduce bias into subsequent in vitro to in vivo extrapolations. Our objectives were to develop a dynamic mass balance model for repeated dosing in in vitro systems; to evaluate model accuracy against experimental data; and to perform illustrative simulations to assess the impact of repeated doses on predicted cellular concentrations. A novel dynamic in vitro partitioning mass balance model (IV-MBM DP v1.0) was created based on the well-established fugacity approach. We parameterized and applied the dynamic mass balance model to single dose and repeat dosing scenarios, and evaluated the predicted medium and cellular concentrations against available empirical data. We also simulated repeated dosing scenarios for organic chemicals with a range of partitioning properties and compared the in vitro distributions over time. In single dose scenarios, for which only medium concentrations were available, simulated concentrations predicted measured concentrations with coefficients of determination (R 2) of 0.85-0.89, mean absolute error within a factor of two and model bias of nearly one. Repeat dose scenario simulations displayed model bias <2 within the cell lysate, and ∼1.5-3 in the medium. The concordance between simulated and available experimental data supports the predictive capacity of the IV-MBM DP v1.0 tool, but further evaluation as empirical data becomes available is warranted, especially for cellular concentrations.

Developing an internal threshold of toxicological concern (iTTC).

BACKGROUND: Threshold of Toxicological Concern (TTC) approaches are used for chemical safety assessment and risk-based priority setting for data poor chemicals. TTCs are derived from in vivo No Observed Effect Level (NOEL) datasets involving an external administered dose from a single exposure route, e.g., oral intake rate. Thus, a route-specific TTC can only be compared to a route-specific exposure estimate and such TTCs cannot be used for other exposure scenarios such as aggregate exposures. OBJECTIVE: Develop and apply a method for deriving internal TTCs (iTTCs) that can be used in chemical assessments for multiple route-specific exposures (e.g., oral, inhalation or dermal) or aggregate exposures. METHODS: Chemical-specific toxicokinetics (TK) data and models are applied to calculate internal concentrations (whole-body and blood) from the reported administered oral dose NOELs used to derive the Munro TTCs. The new iTTCs are calculated from the 5th percentile of cumulative distributions of internal NOELs and the commonly applied uncertainty factor of 100 to extrapolate animal testing data for applications in human health assessment. RESULTS: The new iTTCs for whole-body and blood are 0.5 nmol/kg and 0.1 nmol/L, respectively. Because the iTTCs are expressed on a molar basis they are readily converted to chemical mass iTTCs using the molar mass of the chemical of interest. For example, the median molar mass in the dataset is 220 g/mol corresponding to an iTTC of 22 ng/L-blood (22 pg/mL-blood). The iTTCs are considered broadly applicable for many organic chemicals except those that are genotoxic or acetylcholinesterase inhibitors. The new iTTCs can be compared with measured or estimated whole-body or blood exposure concentrations for chemical safety screening and priority-setting. SIGNIFICANCE: Existing Threshold of Toxicological Concern (TTC) approaches are limited in their applications for route-specific exposure scenarios only and are not suitable for chemical risk and safety assessments under conditions of aggregate exposure. New internal Threshold of Toxicological Concern (iTTC) values are developed to address data gaps in chemical safety estimation for multi-route and aggregate exposures.

Hexabromocyclododecane: current understanding of chemistry, environmental fate and toxicology and implications for global management.

Hexabromocyclododecane (HBCD) is a globally produced brominated flame retardant (BFR) used primarily as an additive FR in polystyrene and textile products and has been the subject of intensified research, monitoring and regulatory interest over the past decade. HBCD is currently being evaluated under the Stockholm Convention on Persistent Organic Pollutants. HBCD is hydrophobic (i.e., has low water solubility) and thus partitions to organic phases in the aquatic environment (e.g., lipids, suspended solids). It is ubiquitous in the global environment with monitoring data generally exhibiting the expected relationship between proximity to known sources and levels; however, temporal trends are not consistent. Estimated degradation half-lives, together with data in abiotic compartments and long-range transport potential indicate HBCD may be sufficiently persistent and distributed to be of global concern. The detection of HBCD in biota in the Arctic and in source regions and available bioaccumulation data also support the case for regulatory scrutiny. Toxicity testing has detected reproductive, developmental and behavioral effects in animals where exposures are sufficient. Recent toxicological advances include a better mechanistic understanding of how HBCD can interfere with the hypothalamic-pituitary-thyroid axis, affect normal development, and impact the central nervous system; however, levels in biota in remote locations are below known effects thresholds. For many regulatory criteria, there are substantial uncertainties that reduce confidence in evaluations and thereby confound management decision-making based on currently available information.