<p>The intensive use of plant protection products (PPPs) is essential in modern agriculture to ensure food security. PPPs are complex formulations of active substances (ASs) and co-formulants, yet regulatory risk assessment primarily focuses on AS toxicity, often overlooking combined effects. This study assessed the toxicity of three commercial PPPs, their AS-mixtures, and a co-formulant using the in vitro HepaRG liver cell assay and the in vivo zebrafish embryo toxicity test (ZFET). Product 1 contained the AS Benzovindiflupyr (Benzo), and Product 2 contained Benzo and Prothioconazole (Pro). Product 3 contained Pro and Tebuconazole (Teb) and the co-formulant N,N-Dimethyldecanamide&#xa0;(DDA), which was singled out for further investigation. AS were tested in different concentration ranges from 0.03 to 105&#xa0;µmol/L in the ZFET and from 12.8 to 454.8&#xa0;µmol/L in HepaRG cells. AS-mixtures were tested from 0.06 to 50&#xa0;µmol AS/L (ZFET) and from&#xa0;7.7&#xa0;to 312.0&#xa0;µmol AS/L (HepaRG). PPPs were tested from 0.02 to 29.8&#xa0;µmol AS/L (ZFET) and from&#xa0;2.9&#xa0;to&#xa0;312.0&#xa0;µmol AS/L (HepaRG). PPPs were either more or as toxic as their respective AS-mixtures. In the ZFET, Products 1 and 2 showed similar toxicity to their AS-mixtures, while Product 3 showed a fourfold increase. In HepaRG cells, Product 1 was four times and Product 3 three times more toxic than their mixtures. Concentration addition models underestimated observed effects, particularly for Product 3, where co-formulants increased internal AS concentrations in zebrafish embryos. These findings underscore the need for whole mixture-based risk assessment for selected PPPs and support using integrated in vitro/in vivo approaches. Our study highlights the need for holistic PPP evaluation to improve safety assessments and regulatory strategies.</p>

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Comparative toxicity of plant protection products, their active substances and mixtures in zebrafish embryos and HepaRG cells

  • Bente Nissen,
  • Alkiviadis Stagkos-Georgiadis,
  • Martin Krauss,
  • Denise Bloch,
  • Wibke Busch

摘要

The intensive use of plant protection products (PPPs) is essential in modern agriculture to ensure food security. PPPs are complex formulations of active substances (ASs) and co-formulants, yet regulatory risk assessment primarily focuses on AS toxicity, often overlooking combined effects. This study assessed the toxicity of three commercial PPPs, their AS-mixtures, and a co-formulant using the in vitro HepaRG liver cell assay and the in vivo zebrafish embryo toxicity test (ZFET). Product 1 contained the AS Benzovindiflupyr (Benzo), and Product 2 contained Benzo and Prothioconazole (Pro). Product 3 contained Pro and Tebuconazole (Teb) and the co-formulant N,N-Dimethyldecanamide (DDA), which was singled out for further investigation. AS were tested in different concentration ranges from 0.03 to 105 µmol/L in the ZFET and from 12.8 to 454.8 µmol/L in HepaRG cells. AS-mixtures were tested from 0.06 to 50 µmol AS/L (ZFET) and from 7.7 to 312.0 µmol AS/L (HepaRG). PPPs were tested from 0.02 to 29.8 µmol AS/L (ZFET) and from 2.9 to 312.0 µmol AS/L (HepaRG). PPPs were either more or as toxic as their respective AS-mixtures. In the ZFET, Products 1 and 2 showed similar toxicity to their AS-mixtures, while Product 3 showed a fourfold increase. In HepaRG cells, Product 1 was four times and Product 3 three times more toxic than their mixtures. Concentration addition models underestimated observed effects, particularly for Product 3, where co-formulants increased internal AS concentrations in zebrafish embryos. These findings underscore the need for whole mixture-based risk assessment for selected PPPs and support using integrated in vitro/in vivo approaches. Our study highlights the need for holistic PPP evaluation to improve safety assessments and regulatory strategies.