New Toxicology Tools and the Emerging Paradigm Shift in Environmental Health Decision-Making.

BACKGROUND: Numerous types of rapid toxicity or exposure assays and platforms are providing information relevant to human hazard and exposure identification. They offer the promise of aiding decision-making in a variety of contexts including the regulatory management of chemicals, evaluation of products and environmental media, and emergency response. There is a need to consider both the scientific validity of the new methods and the values applied to a given decision using this new information to ensure that the new methods are employed in ways that enhance public health and environmental protection. In 2018, a National Academies of Sciences, Engineering, and Medicine (NASEM) workshop examined both the toxicological and societal aspects of this challenge. OBJECTIVES: Our objectives were to explore the challenges of adopting new data streams into regulatory decision-making and highlight the need to align new methods with the information and confidence needs of the decision contexts in which the data may be applied. METHODS: We go beyond the NASEM workshop to further explore the requirements of different decision contexts. We also call for the new methods to be applied in a manner consistent with the core values of public health and environmental protection. We use the case examples presented in the NASEM workshop to illustrate a range of decision contexts that have applied or could benefit from these new data streams. Organizers of the NASEM workshop came together to further evaluate the main themes from the workshop and develop a joint assessment of the critical needs for improved use of emerging toxicology tools in decision-making. We have drawn from our own experience and individual decision or research contexts as well as from the case studies and panel discussions from the workshop to inform our assessment. DISCUSSION: Many of the statutes that regulate chemicals in the environment place a high priority on the protection of public health and the environment. Moving away from the sole reliance on traditional approaches and information sources used in hazard, exposure, and risk assessment, toward the more expansive use of rapidly acquired chemical information via in vitro, in silico, and targeted testing strategies will require careful consideration of the information needed and values considerations associated with a particular decision. In this commentary, we explore the ability and feasibility of using emerging data streams, particularly those that allow for the rapid testing of a large number of chemicals across numerous biological targets, to shift the chemical testing paradigm to one in which potentially harmful chemicals are more rapidly identified, prioritized, and addressed. Such a paradigm shift could ultimately save financial and natural resources while ensuring and preserving the protection of public health. https://doi.org/10.1289/EHP4745.

Evaluating Chemicals for Thyroid Disruption: Opportunities and Challenges with in Vitro Testing and Adverse Outcome Pathway Approaches.

BACKGROUND: Extensive clinical and experimental research documents the potential for chemical disruption of thyroid hormone (TH) signaling through multiple molecular targets. Perturbation of TH signaling can lead to abnormal brain development, cognitive impairments, and other adverse outcomes in humans and wildlife. To increase chemical safety screening efficiency and reduce vertebrate animal testing, in vitro assays that identify chemical interactions with molecular targets of the thyroid system have been developed and implemented. OBJECTIVES: We present an adverse outcome pathway (AOP) network to link data derived from in vitro assays that measure chemical interactions with thyroid molecular targets to downstream events and adverse outcomes traditionally derived from in vivo testing. We examine the role of new in vitro technologies, in the context of the AOP network, in facilitating consideration of several important regulatory and biological challenges in characterizing chemicals that exert effects through a thyroid mechanism. DISCUSSION: There is a substantial body of knowledge describing chemical effects on molecular and physiological regulation of TH signaling and associated adverse outcomes. Until recently, few alternative nonanimal assays were available to interrogate chemical effects on TH signaling. With the development of these new tools, screening large libraries of chemicals for interactions with molecular targets of the thyroid is now possible. Measuring early chemical interactions with targets in the thyroid pathway provides a means of linking adverse outcomes, which may be influenced by many biological processes, to a thyroid mechanism. However, the use of in vitro assays beyond chemical screening is complicated by continuing limits in our knowledge of TH signaling in important life stages and tissues, such as during fetal brain development. Nonetheless, the thyroid AOP network provides an ideal tool for defining causal linkages of a chemical exerting thyroid-dependent effects and identifying research needs to quantify these effects in support of regulatory decision making. https://doi.org/10.1289/EHP5297.

A review of potential neurotoxic mechanisms among three chlorinated organic solvents.

The potential for central nervous system depressant effects from three widely used chlorinated solvents, trichloroethylene (TCE), perchloroethylene (PERC), and dichloromethane (DCM), has been shown in human and animal studies. Commonalities of neurobehavioral and neurophysiological changes for the chlorinated solvents in in vivo studies suggest that there is a common mechanism(s) of action in producing resultant neurotoxicological consequences. The purpose of this review is to examine the mechanistic studies conducted with these chlorinated solvents and to propose potential mechanisms of action for the different neurological effects observed. Mechanistic studies indicate that this solvent class has several molecular targets in the brain. Additionally, there are several pieces of evidence from animal studies indicating this solvent class alters neurochemical functions in the brain. Although earlier evidence indicated that these three chlorinated solvents perturb the lipid bilayer, more recent data suggest an interaction between several specific neuronal receptors produces the resultant neurobehavioral effects. Collectively, TCE, PERC, and DCM have been reported to interact directly with several different classes of neuronal receptors by generally inhibiting excitatory receptors/channels and potentiating the function of inhibitory receptors/channels. Given this mechanistic information and available studies for TCE, DCM, and PERC, we provide hypotheses on primary targets (e.g. ion channel targets) that appear to be most influential in producing the resultant neurological effects.