Integrated multi-endpoint hazard prioritization of unregulated industrial contaminants: A safety-first screening framework for emerging environmental threats

The rapid expansion of the industrial chemical space has outpaced regulatory oversight, creating a critical regulatory and environmental blind spot regarding unregulated high-consequence chemicals with limited hazard characterization. While conventional QSAR models focus on predictive accuracy for known chemicals, they often lack the decision-oriented screening required for environmental risk management. Here, we present a “proactive discovery” framework designed to unveil hidden high-consequence threats among 16,000+ structural analogs of toxic industrial chemicals (TICs). The central contribution of this work is the integration of multiple hazard endpoints, including acute, dermal, ocular, respiratory, flammability, reactivity, and aquatic toxicity, onto a single regulatory-aligned 0–4 scale, rather than the prediction of any individual endpoint. By integrating National Fire Protection Association (NFPA) and Globally Harmonized System (GHS) standards into a unified hazard scale, we enable consistent risk prioritization across multiple endpoints. Strictly validated against an independent external set of 112 compounds, the framework demonstrated a “safety-first” predictive capability. To address environmental safety blind spots, the model was optimized to prioritize sensitivity for the highest-hazard category (Class 4). This strategy minimizes false negatives, ensuring that potential ecotoxicological hazards and high-consequence threats are not overlooked in environmental risk assessments. Crucially, this study moves beyond method development to actionable discovery. Applied to more than 16,000 structural analogs of toxic industrial chemicals, this multi-endpoint prioritization identifies a small, actionable subset of unregulated compounds that are classified at the maximum hazard level in two or more endpoints simultaneously, and are therefore strong candidates for immediate regulatory attention. We identified 20 high-priority unregulated candidates, including novel isocyanates and organolead analogs, that exhibit “Dual-Threats” of extreme acute toxicity to mammals and severe risks to aquatic ecosystems. These candidates display hazard profiles that warrant comparison to highly regulated toxic agents (including chemical warfare agents) for precautionary prioritization. Furthermore, our feature importance analysis reveals key molecular determinants driving toxicity, providing mechanistic support for these high-hazard predictions. By openly providing a prioritized list of 20 unregulated high-consequence agents, this study offers an actionable roadmap for policymakers and experimentalists to preemptively secure the chemical safety landscape against emerging high-consequence chemicals.