Validation, Optimization, and Application of the Zebrafish Developmental Toxicity Assay for Pharmaceuticals Under the ICH S5(R3) Guideline

Abstract

The zebrafish as an alternative animal model for developmental toxicity testing has been extensively investigated, but its assay protocol was not harmonized yet. This study has validated and optimized the zebrafish developmental toxicity assay previously reported by multiple inter-laboratory studies in the United States and Europe. In this study, using this classical protocol, of 31 ICH-positive compounds, 23 compounds (74.2%) were teratogenic in zebrafish, five had false-negative results, and three were neither teratogenic nor non-teratogenic according to the protocol standard; of 14 ICH-negative compounds, 12 compounds (85.7%) were non-teratogenic in zebrafish and two had false-positive results. After we added an additional TI value in the zebrafish treated with testing compounds at 2 dpf along with the original 5 dpf, proposed a new category as the uncategorized compounds for those TI values smaller than the cutoff both at 2 dpf and 5 dpf but inducing toxic phenotypes, refined the testing concentration ranges, and optimized the TI cut-off value from ≥ 10 to ≥ 3 for compounds with refined testing concentrations, this optimized zebrafish developmental assay reached 90.3% sensitivity (28/31 positive compounds were teratogenic in zebrafish) and 88.9% (40/45) overall predictability. Our results from this study strongly support the use of zebrafish as an alternative in vivo method for screening and assessing the teratogenicity of candidate drugs for regulatory acceptance.

Safety and efficacy evaluation of halicin as an effective drug for inhibiting intestinal infections

“…Zebrafish were an excellent model organism, especially for the study of drug-induced embryonic teratogenesis, as they allowed for more direct and clear observation of embryonic conditions ( Song et al, 2021 ). To investigate the genotoxicity of halicin, we utilized zebrafish for an embryonic teratogenicity experiment.…”

Green Prospective Approach of Chromium Zinc Oxide Nanoparticles for Highly Ultrasensitive Electrochemical Detection of Anti-hypotensive Medication in Various Matrices

“…Numerous greenness assessment tools have recently been reported. The Eco-scale is an evaluation tool that handles the method’s penalty points (PPs). − Several factors are used for calculating PP, including the quantity and quality of the materials, power consumption by the instruments, number of reagents utilized through the procedures, quantity of produced waste, and the safety of the analyst. Furthermore, the eco-scale score is determined as 100-PP after computing the overall PPs from the preceding four processes.…”

O Pentáculo Do Bem Estar Como Instrumento De Avaliação Do Modo De Vida Na Atenção Primária a Saúde

“…Apesar dos esforços, ainda não há um consenso padronizado sobre a definição do termo nutracêutico, porém este termo tem sido utilizado para abranger diversos compostos bioativos, como polifenóis, vitaminas, minerais, pigmentos, ácidos graxos, aminoácidos, probióticos, entre outros (CHANDRA et al, 2022;ALALI et al, 2021). Diante disto, um interesse crescente sobre abordagens alternativas que complementassem a medicina convencional, a partir de produtos naturais, com princípio ativo capaz de atenuar os sinais e sintomas fisiopatológicos foi observado, entretanto, apesar de serem nutracêuticos, estudos de toxicidade são imprescindíveis antes de avaliar as potenciais atividades biológicas, uma vez que, a toxicidade de um composto bioativo, a depender da dose, tempo de exposição e estágio de desenvolvimento, pode ocasionar repercussões nocivas, de gravidade, muitas vezes irreparável, como por exemplo, a teratogenicidade (responsável por cerca de 5 -10% das anomalias congênitas) (SELDERSLAGHS et al, 2012;SONG et al, 2021).…”