Resource Summary:Scientific confidence frameworks (SCFs) are alternatives to traditional validation for new approach methodologies (NAMs). The SCFs adapted by the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) and the American Chemistry Council (ACC) both address inference performance—the ability of NAMs to predict or inform the biological effect of interest. Inference performance is a distinct evaluation procedure in ACC’s SCF but is blended into several steps of ICCVAM’s SCF. Here, we first reproduce the previously derived human relevant potency threshold (HRPT) for the estrogen receptor alpha (ERα) agonism of Borgert et al. (2018) using guideline and guideline-like studies; we found that a HRPT of 1 to 10–1 positively and consistently predicted clinical endometrial and endocervical effects. We next mapped inference performance to ICCVAM’s SCF and found that it can be used as an effective initial screen prior to performing more detailed characterizations in their SCF. We first conclude that a HRPT for ERα agonism of 10–2 to 10–4 is a health-protective NAM based on an established mode of action that could potentially be used in early screening, much like the threshold of toxicological concern. We then conclude that inference performance is a core requirement for SCFs.

Resource Summary:A flexible approach is described for incorporating a weight‐of‐evidence (WoE) methodology into a tiered ecological risk assessment (ERA)/management framework for chemicals. The approach is oriented toward informing decisions about chemicals. Communication is regarded as a critical component of the risk assessment process. The paper resulted from insights gained from seven ERA workshops held by SETAC (Society of Environmental Toxicology and Chemistry, www.setac. org) in the Asia‐Pacific, African, and Latin American regions. Formal ERA methods are not fully developed or applied in many of these countries and assessments often begin with tables of risk values and test methods from countries where ERA is already implemented. While appropriate and sometimes necessary, workshop participants had questions about the reliability and relevance of using this information for regionally specific ecosystems with different receptors, fate processes, and exposure characteristics. The idea that an assessment of reliability and relevance of available information and the need for additional information was necessary at an early stage of the assessment process was considered. The judgment of reliability and relevance is central to WoE approaches along with the identification of information needs and the integration of such information. The need to engage in WoE considerations early and throughout the assessment process indicates that a tiered approach is appropriate for unifying the evaluation process in a consistent way from early screening‐level steps to later more involved evaluations. The approach outlined in this article is complementary to WoE guidance developed by the Organization for Economic Co‐operation and Development and many national guidance documents. To link assessments of risk to management decisions, emphasis is given to communications at each tier between the risk assessor (technical side) and the decision‐makers (policy and regulatory side). Tools and information sources are suggested for each tier and suggestions are meant to be illustrative and not prescriptive.

Resource Summary:The weight of evidence (WoE) approach conflates the aspects of quality, reliability, relevance, and consistency of data and information to systematically strengthen the body of evidence and enable credible communication and decision‐making on chemical risk assessment. Between 2015 and 2019, the Society of Environmental Toxicology and Chemistry (SETAC) held several workshops in all the geographical units with scientists and managers from academia, government, and business sectors focusing on the chemical risk‐assessment approach. This article summarizes the knowledge that informs the needs concerning application of WoE, especially in the context of developing countries. This effort supports the use of existing data and test strategies for assessing chemical toxicity, exposure, and risk, and highlights the critical process for risk assessors to convey and discuss information sufficiency and uncertainty mitigation strategy with risk managers. This article complements the four articles in the special series that provide a critical review of existing frameworks for chemical risk screening and management, and applications of the WoE approach for assessing exposure in the aquatic environment, prediction of fish toxicity, and bioaccumulation. Collectively, the articles exemplify the use of WoE approaches to evaluate chemicals that are data rich and/or data poor for decision‐making. They integrate the WoE concepts and approaches into practical considerations and guidance, and help to scale the value of WoE in supporting sound chemical risk assessment and science‐based policy implementation.

Resource Summary:Despite the evolution over the last half century of regulatory programs and frameworks developed for the evaluation of safety and management of risks associated with chemicals and materials, new and emerging contaminant issues continue to be identified. These recurring issues suggest a need for review and reflection on current approaches and strategies for ensuring the safety of chemicals and materials. Twelve existing frameworks relating to the evaluation and management of chemical or material risk were reviewed to identify potential process improvements for facilitating early identification of potentially problematic substances and better inform risk management strategies (e.g., prohibition, restricted use, or selection of safer alternatives). The frameworks were selected to represent a broad spectrum of regional, national, and international authorities and purposes, including preproduction evaluation of new substances, classification and hazard communication, identification of persistent pollutants, and identification of safer alternatives. Elements common to the frameworks were identified, as well as features unique to select frameworks. A comparative evaluation was performed, and potential new strategies and approaches were identified to inform process improvement recommendations. These recommendations include requiring validated analytical procedures to enable measurement in environmental media, improved data transparency and accessibility, flexibility to incorporate advances into the state of the practice (e.g., new approach methodologies and high‐throughput assessment tools), and incorporation of monitoring and adaptive management strategies to enable more timely intervention. Process improvement recommendations are discussed and summarized in a conceptual risk management framework.

Resource Summary:Weight of evidence (WoE) is a useful approach to quantifying the relative relevance, strength, reliability, and uncertainty associated with estimates of exposure concentrations. WoE is often used in exposure assessments but rarely explored or discussed in detail. In this article, the utility of a WoE approach in aquatic exposure assessments is illustrated via two case studies using a tiered approach and the chemical triclosan. Each case study evaluates the same chemical and pathway to the environment but with substantially different data strength, reliability, and uncertainty. The collection and qualitative evaluation of relevant lines of evidence (LoE) using a three‐tiered approach are discussed. Our results demonstrate how a higher tiered WoE approach can reduce uncertainty and improve decision‐making based on predicted exposure concentrations. We also identify LoE that played a significant role in the final exposure determinations and describe a framework for conducting exposure assessments using WoE.

Resource Summary:Acute fish toxicity (AFT) is a key endpoint in nearly all regulatory implementations of environmental hazard assessments of chemicals globally. Although it is an early tier assay, the AFT assay is complex and uses many juvenile fish each year for the registration and assessment of chemicals. Thus, it is imperative to seek animal alternative approaches to replace or reduce animal use for environmental hazard assessments. A Bayesian Network (BN) model has been developed that brings together a suite of lines of evidence (LoEs) to produce a probabilistic estimate of AFT without the testing of additional juvenile fish. Lines of evidence include chemical descriptors, mode of action (MoA) assignment, knowledge of algal and daphnid acute toxicity, and animal alternative assays such as fish embryo tests and in vitro fish assays (e.g., gill cytotoxicity). The effort also includes retrieval, assessment, and curation of quality acute fish toxicity data because these act as the baseline of comparison with model outputs. An ideal outcome of this effort would be to have global applicability, acceptance and uptake, relevance to predominant fish species used in chemical assessments, be expandable to allow incorporation of future knowledge, and data to be publicly available. The BN model can be conceived as having incorporated principles of tiered assessment and whose outcomes will be directed by the available evidence in combination with prior information. We demonstrate that, as additional evidence is included in the prediction of a given chemical's ecotoxicity profile, both the accuracy and the precision of the predicted AFT can increase. Ultimately an improved environmental hazard assessment will be achieved.

Resource Summary: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 transparentWoE framework to address uncertainty in bioaccumulation assessment and is envisaged to evolve with scientific and regulatory developments

Resource Summary:IARC has begun using ToxCast/Tox21 data in efforts to represent key characteristics of carcinogens to organize and weigh mechanistic evidence in cancer hazard determinations and this implicit inference approach also is being considered by USEPA. To determine how well ToxCast/Tox21 data can explicitly predict cancer hazard, this approach was evaluated with statistical analyses and machine learning prediction algorithms. Substances USEPA previously classified as having cancer hazard potential were designated as positives and substances not posing a carcinogenic hazard were designated as negatives. Then ToxCast/Tox21 data were analyzed both with and without adjusting for the cytotoxicity burst effect commonly observed in such assays. Using the same assignments as IARC of ToxCast/Tox21 assays to the seven key characteristics of carcinogens, the ability to predict cancer hazard for each key characteristic, alone or in combination, was found to be no better than chance. Hence, we have little scientific confidence in IARC's inference models derived from current ToxCast/Tox21 assays for key characteristics to predict cancer. This finding supports the need for a more rigorous mode-of-action pathway-based framework to organize, evaluate, and integrate mechanistic evidence with animal toxicity, epidemiological investigations, and knowledge of exposure and dosimetry to evaluate potential carcinogenic hazards and risks to humans.

Resource Summary:The kinetically-derived maximal dose (KMD) is the maximum external dose where kinetics remain unchanged relative to lower doses. Toxicity may differ qualitatively above versus below the KMD. This evaluation tests whether high-dose toxic effects of octamethylcyclotetrasiloxane (D4), a lipophilic silicone monomer, stem from kinetic overload. Chronic rat inhalation at doses 10,000-fold above human exposures causes mild respiratory, hepatic, renal, uterine, and fertility effects, mostly lacking human relevance due to rodent-specific mechanisms. Bayesian analysis with differential equations was applied to information from kinetic studies on D4 to build statistical distributions of plausible values of the Km and Vmax for D4 elimination. A set of Michaelis–Menten equations were generated to represent the slope function for the relationship between D4 exposure and blood concentration. The resulting Michaelis–Menten functions were investigated using a change-point methodology known as the “kneedle” algorithm to identify the probable KMD range. Analysis of the Michaelis–Menten elimination curve generated from those Vmax and Km values indicates a KMD with an interquartile range of 230.0–488.0 ppm, which is consistent with prior work indicating saturation of D4 metabolism at approximately 300 ppm. The results support the hypothesis that many adverse effects of D4 arise secondary to high-dose-dependent events, likely due to mechanisms of action that cannot occur at concentrations below the KMD. Regulatory methods to evaluate D4 for human health protection should avoid endpoint data from rodents exposed to D4 above the KMD range and future toxicological testing should focus on doses below the KMD range.

Resource Summary:The endocrine system operates via ligand-receptor interactions, where ligand potency (affinity × efficacy) and concentration dictate physiological effects, governed by mass action laws relating affinity to receptor occupancy. Previously, we established a Human-Relevant Potency Threshold (HRPT) for ERα agonists at 1/10,000 the potency of 17β-estradiol (E2), as weak ligands (e.g., from botanicals) lack clinically observable estrogenic effects. Here, we hypothesize the HRPT stems from competition with the endogenous metabolic milieu (hormone precursors, metabolites). Fractional ERα occupancy calculations, incorporating normal circulating E2 and other endogenous ligands, show that exogenous ligands with potencies greater than 1/1,000 relative to 17β-estradiol may compete effectively against individual or mixed milieu components; those with relative potencies less than 1/1,000 cannot. Thus, the HRPT proposed originally (1/10,000 of E2) is conservative, arguing against estrogenic disruption potential. For potencies above 1/1,000 of E2, disruption is equivocal, requiring corroboration. Critically, the endogenous milieu drives the HRPT for both agonists and antagonists, providing a kinetics-based mechanistic rationale using established metabolic properties.