Os estágios iniciais do desenvolvimento do zebrafish como modelo alternativo para predizer a toxicidade oral aguda in vivo
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2021-02-11
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Universidade Federal de Goiás
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Zebrafish (Danio rerio) early-life stages offer a complex and multicellular system integrating
various tissues and differentiation processes. In addition, the zebrafish embryos are structurally
and functionally similar to vertebrates, including humans. The acute toxicity test with
zebrafish embryos and larvae is already worldwide recognized as an alternative model for ecotoxicological
assessment, but it is not include in normative of the Council fot the Control of
Animal Experimentation (CONCEA), wich recognize the use of alternative methods validated in
research activities in Brazil. This organism model can filling the gap between conventional in
vitro and in vivo tests for extrapolation of data for humans, the present study aimed to assess
the acute toxicity of substances with different Global Harmonization System (GHS) categories
using zebrafish early-life stage to determine LC50 values and compared with in vivo (LD50)
acute oral toxicity data from literature, in order to generate a model to prediction acute oral
toxicity. This prediction model was evaluated by the application of a drug candidate (LQFM
021). Fifteen substances were evaluated by Fish Embryo Acute Toxicity (FET) test (OECD
236). Parameter evaluated was lethal and sublethal effects after 96 h of exposure. A linear regression-
model using the log-transformed of the LC50 values and LD50 was generated for the
estimated of LD50 from LC50 values. This model resulted in the following equation Log LD50
(mg/kg) = 0.5749 x log LC50 (mg/L) + 1.284. The method domain of application was 53.33%
and the R2 was 0,66. Sublethal effects indicate that substances more toxic presented more
abnormalities. The DL50 predicted with FET testing LQFM 021, which classified as category 4
in GHS acute oral systemic toxicity assessment, was of 408.52 mg/kg, which also classified as
Category 4. In this work, Quantitative Activity-Activity Relationship (QAAR) models were also
developed, based on the data obtained in the FET test with zebrafish. This model using seven
toxicological descriptors generated statistically predictive models with R2 values ranging from
0.80 to 0.95 and in combination with the Random Forest method it presented the best performance
in the prediction of acute oral toxicity in vivo. Therefore, our results suggest that
early-life stages of zebrafish could be at least a refinement in the sense of the principles of
the 3R’s to predict acute oral toxicity in vivo, being as an intermediary in the preclinical evaluation
between in vitro and in vitro.
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BRITO, L. B. Os estágios iniciais do desenvolvimento do zebrafish como modelo alternativo para predizer a toxicidade oral aguda in vivo. 2021. 91 f. Tese (Doutorado em Ciências Farmacêuticas) - Universidade Federal de Goiás, Goiânia, 2021.