FutureTox IV Workshop Summary: Predictive Toxicology for Healthy Children

Abstract

FutureTox IV, a Society of Toxicology (SOT) Contemporary Concepts in Toxicology (CCT) workshop, was held in November 2018. Building upon FutureTox I, II, and III, this conference focused on the latest science and technology for in vitro profiling and in silico modeling as it relates to predictive developmental and reproductive toxicity (DART). Publicly available high throughput screening data sets are now available for broad in vitro profiling of bioactivities across large inventories of chemicals. Coupling this vast amount of mechanistic data with a deeper understanding of molecular embryology and post-natal development lays the groundwork for using new approach methodologies (NAMs) to evaluate chemical toxicity, drug efficacy, and safety assessment for embryo-fetal development. NAM is a term recently adopted in reference to any technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment to avoid the use of intact animals (USEPA, 2018). There are challenges to implementing NAMs to evaluate chemicals for developmental toxicity compared with adult toxicity. This forum article reviews the 2018 workshop activities, highlighting challenges and opportunities for applying NAMs for adverse pregnancy outcomes (e.g., preterm labor, malformations, low birth weight) as well as disorders manifesting postnatally (e.g., neurodevelopmental impairment, breast cancer, cardiovascular disease, fertility). DART is an important concern for different regulatory statutes and test guidelines. Leveraging advancements in such approaches and the accompanying efficiencies to detecting potential hazards to human development are the unifying concepts toward implementing NAMs in DART testing. Although use of NAMs for higher level regulatory decision making is still on the horizon, the conference highlighted novel testing platforms and computational models that cover multiple levels of biological organization, with the unique temporal dynamics of embryonic development, and novel approaches for estimating toxicokinetic parameters essential in supporting in vitro to in vivo extrapolation.

Conducting evaluations of evidence that are transparent, timely and can lead to health-protective actions

“…These limitations include lack of biological coverage for complex developmental processes such as neurodevelopment, human genetic diversity, growth processes, and metabolic activity. Thus, complex and multi-system effects such as chronic and systemic health endpoints like developmental neurotoxicity, immunotoxicity, and endocrine effects may be missed with NAMs tests [ 78 – 80 ]. For this reason, expedited timelines to replace mammalian tests with high-throughput assays that are not capable of providing necessary information about health endpoints of critical concern, particularly for highly exposed and/or susceptible populations like workers, frontline community members, children, and pregnant women, would not be consistent with providing health protections for these populations.…”

Toxic Substances Control Act (TSCA) Implementation: How the Amended Law Has Failed to Protect Vulnerable Populations from Toxic Chemicals in the United States

“…94 , 95 While there is potential for these tools to provide more timely information on hazards of concern, thus reducing the time between potential human exposure and action to mitigate these harms, NAMs also have well established limitations, including limits to their ability to identify chronic and systemic health end points such as immunotoxicity, endocrine effects and developmental neurotoxicity. 96 − 98 …”

“…Third, the application of “New Approach Methods” (NAMs) has been proposed to facilitate the number of hazard evaluations EPA can complete, while replacing the need for animal testing and reducing costs. , While there is potential for these tools to provide more timely information on hazards of concern, thus reducing the time between potential human exposure and action to mitigate these harms, NAMs also have well established limitations, including limits to their ability to identify chronic and systemic health end points such as immunotoxicity, endocrine effects and developmental neurotoxicity. − …”

TISBE: A Public Web Platform for the Consensus-Based Explainable Prediction of Developmental Toxicity

“…Developmental toxicity (Dev Tox) is one of the most relevant human health endpoints whose investigation is required by the European Union’s REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) and the United States Environmental Protection Agency (US EPA) . Dev Tox is explicitly reported in different regulatory statutes and test guidelines . Despite its scientific and regulatory importance, the investigation of this end point is hampered by the lack of high-quality experimental data, and thus, novel approaches are needed to fully exploit the limited amount of available in vivo toxicity data as widely reported elsewhere. , Hence, several initiatives, like those promoted by the US EPA, U.S. Food and Drug Administration (FDA), and the Center for Drug Evaluation and Research (CDER), investigate protocols and guidelines to integrate in vivo experimental data with nonclinical data, support research activities, and minimize the use of animal testing for studying specific adverse effects. − …”