Toxicity assessment of the novel psychoactive substance HU-210 (Hebrew University 210; CAS: 112830-95-2): First insight into toxicophores and critical toxicity parameters (acute toxicity, health effects, genotoxicity, skin and eye irritation, cardiotoxicity and endocrine disruption) using in silico methods for applications in clinical and forensic toxicology.

PURPOSE: For the first time, the toxicity of HU-210, a synthetic cannabinoid, has been assessed using nine different in silico methods, representing a novel approach in substance safety research. Given the scant data on HU-210's human toxicological impact, our research sought to predict toxicophores and key toxicological endpoints for clinical toxicology and forensic purposes.

METHODS

We applied nine different in silico predictive methods, including: StopTox, AdmetSAR 3.0, ACD/Labs Percepta, ProTox 3.0, PreADMET, ADMETlab 2.0, OCHEM, TEST and VEGA QSAR to evaluate key toxicological endpoints: acute toxicity (LD50 for different species and route of exposure), genetic toxicity (Ames test), skin and eye irritation, health effects (gastrointestinal system, kidneys, liver, blood, lungs, and cardiovascular system), cardiotoxicity (hERG blocker/inhibitor and IC50) and endocrine system disruption. These in silico methods utilized computational models and existing databases to assess HU-210's chemical interactions and toxicological profiles across several parameters.

RESULTS

Predictive analyses indicated moderate acute toxicity risks for HU-210, particularly affecting the cardiovascular, renal, and pulmonary systems. While genotoxicity appeared low, substantial concerns were raised regarding its potential to disrupt the endocrine system. Despite variances in individual software predictions, the consensus underscored significant caution regarding HU-210's safety profile.

CONCLUSIONS

Our findings emphasize the need for comprehensive toxicological assessments of new psychoactive substances (NPS) like HU-210 and highlight the critical role of in silico studies as preliminary research tools. Although these predictions provide valuable insights for clinical toxicology (expected health effects, genotoxicity, cardiotoxicity, endocrine system disruption) and forensic toxicology (especially acute toxicity), further experimental research is crucial. Notably, toxicophore analysis identified aromatic and unsaturated moieties within the chromene core of HU-210 as structural alerts potentially associated with toxicity. Regulatory bodies should consider these potential risks, highlighting the importance of ongoing vigilance in monitoring synthetic cannabinoids-an aspect particularly crucial from a forensic toxicology perspective.