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.

Background: Large numbers of chemicals require evaluation to determine if their production and use pose potential risks to ecological and human health. For most chemicals, the inadequacy and uncertainty of chemical-specific data severely limit the application of exposure- and risk-based methods for screening-level assessments, priority setting, and effective management. Objective: We developed and evaluated a holistic, mechanistic modeling framework for ecological and human health assessments to support the safe and sustainable production, use, and disposal of organic chemicals. Methods: We consolidated various models for simulating the PROduction-To-EXposure (PROTEX) continuum with empirical data sets and models for predicting chemical property and use function information to enable high-throughput (HT) exposure and risk estimation. The new PROTEX-HT framework calculates exposure and risk by integrating mechanistic computational modules describing chemical behavior and fate in the socioeconomic system (i.e., life cycle emissions), natural and indoor environments, various ecological receptors, and humans. PROTEX-HT requires only molecular structure and chemical tonnage (i.e., annual production or consumption volume) as input information. We evaluated the PROTEX-HT framework using 95 organic chemicals commercialized in the United States and demonstrated its application in various exposure and risk assessment contexts. Results: Seventy-nine percent and 97% of the PROTEX-HT human exposure predictions were within one and two orders of magnitude, respectively, of independent human exposure estimates inferred from biomonitoring data. PROTEX-HT supported screening and ranking chemicals based on various exposure and risk metrics, setting chemical-specific maximum allowable tonnage based on user-defined toxicological thresholds, and identifying the most relevant emission sources, environmental media, and exposure routes of concern in the PROTEX continuum. The case study shows that high chemical tonnage did not necessarily result in high exposure or health risks. Conclusion: Requiring only two chemical-specific pieces of information, PROTEX-HT enables efficient screening-level evaluations of existing and premanufacture chemicals in various exposure- and risk-based contexts. https://doi.org/10.1289/EHP9372

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 β‐hexachlorocyclohexane (β‐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 2022;00:1–19. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Bioaccumulation (B) assessment is challenging because there are various B‐metrics from laboratory and field studies, multiple criteria and thresholds for classifying bioaccumulative (B), very bioaccumulative (vB), and not bioaccumulative (nB) chemicals, as well as inherent variability and uncertainty in the data. These challenges can be met using a weight of evidence (WoE) approach. The Bioaccumulation Assessment Tool (BAT) provides a transparent WoE assessment framework that follows Organisation for Economic Co‐operation and Development (OECD) principles for performing a WoE analysis. The BAT guides an evaluator through the process of data collection, generation, evaluation, and integration of various lines of evidence (LoE) (i.e., B‐metrics) to inform decision‐making. Phenanthrene (PHE) is a naturally occurring chemical for which extensive B and toxicokinetics data are available. A B assessment for PHE using the BAT is described that includes a critical evaluation of 74 measured in vivo LoE for fish and invertebrate species from laboratory and field studies. The number of LoE are reasonably well balanced across taxa (i.e., fish and invertebrates) and the different B‐metrics. Additionally, in silico and in vitro biotransformation rate estimates and corresponding model‐predicted B‐metrics are included as corroborating evidence. Application of the BAT provides a consistent, coherent, and scientifically defensible WoE evaluation to conclude that PHE is not bioaccumulative (nB) because the overwhelming majority of the bioconcentration, bioaccumulation, and biomagnification metrics for both fish and invertebrates are below regulatory thresholds. An analysis of the relevant data using fugacity ratios is also provided, showing that PHE does not biomagnify in aquatic food webs. The critical review identifies recommendations to increase the consistency of B assessments, such as improved standardization of B testing guidelines, data reporting requirements for invertebrate studies, and consideration of temperature and salinity effects on certain B‐metrics. Integr Environ Assess Manag 2021;17:911–925. © 2021 Concawe. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC)

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.