Proposed key characteristics of neurotoxic chemicals

A critical component of evaluating whether a chemical can cause human neurotoxicity is hazard identification, which typically involves a comprehensive literature search to identify and synthesize epidemiological, animal, and mechanistic data for the chemical of interest. The key characteristics (KCs) concept has proven to be a useful tool for searching, organizing, and evaluating mechanistic data for hazard identification. KCs are the established chemical and biological properties of known human neurotoxic agents based on understanding of their mechanisms of neurotoxicity. KCs were originally developed for carcinogens but have now also been published for endocrine- and metabolism-disruptors and various organ-selective toxic chemicals. To identify KCs associated with neurotoxic chemicals, an expert committee was convened to consider current mechanistic understanding of chemicals known to be neurotoxic in humans with the goal of identifying established molecular and cellular actions of neurotoxic chemicals. After extensive discussion, the committee reached consensus on 10 KCs. Here, we describe the 10 proposed KCs and provide chemical-related examples to support their inclusion. Several important considerations emerged from the committee's deliberations including: (1) a mechanistic action need not be unique to neurotoxicity to be considered a KC of neurotoxic chemicals; (2) many, if not most, neurotoxic chemicals exhibit multiple KCs, and the relative importance of any specific KC and/or its causal relationship to other KCs may vary depending on life stage at the time of exposure and/or the exposure paradigm; and (3) data indicating a chemical exhibits one or more KCs of neurotoxic chemicals suggests that the chemical poses a neurotoxic hazard but does not necessarily identify the risk that the chemical presents to humans. These considerations, as well as potential applications of KCs in neurotoxicology, are discussed. The committee also strongly recommended that the list of proposed KCs of neurotoxic chemicals be viewed as a "living document" that is reviewed and revised in response to emerging insights on mechanisms of neurotoxicity, as well as lessons learned from the application of these proposed KCs, including but not limited to their use as a tool for the systemic identification and review of mechanistic data for assessment of neurotoxic hazards.