Scholarlink

<p>Copper is an essential trace element, yet concerns regarding its toxic potential have gained increasing attention, particularly with regard to nanoparticulate forms of copper oxides. Both CuO and Cu<sub>2</sub>O are currently authorised in the EU for use in agriculture, biocides, and animal nutrition, but regulatory clarity regarding their nanoforms remains limited. This comprehensive review—combining narrative, bibliometric, and systematic approaches—addressed three key questions: (i) whether CuO and Cu<sub>2</sub>O nanoparticles are sufficiently considered within EU regulations to prevent unintentional oral exposure via the food and feed chain, (ii) whether these nanoparticles can cross the intestinal barrier as intact particles and accumulate in tissues, and (iii) whether they elicit distinct biological responses, including regulated cell death pathways such as cuproptosis. With respect to question (i), a detailed analysis of EU legal frameworks revealed a heterogeneous regulatory landscape and a lack of binding provisions that would preclude unintended presence of copper oxide nanoforms in regulated materials. Although some nano-specific data requirements exist, empirical information on nanoparticulate fractions in commercial products is still lacking. With respect to questions (ii) and (iii), our systematic literature analysis supports consistent intracellular uptake of CuO and Cu<sub>2</sub>O nanoparticles, yet direct evidence for transport of intact particles across the intestinal barrier is scarce. Mechanistic evidence supports cuproptosis as a key pathway for CuO nanoparticle toxicity, while the extent to which these effects differ quantitatively from ionic copper remains unclear due to insufficient data using appropriate experimental controls. Notably, a pronounced data gap was identified for Cu<sub>2</sub>O nanoparticles across all evaluated domains. Finally, to organise and integrate the mechanistic evidence presented, we developed an adverse outcome pathway (AOP), registered as AOP 590 in the AOP Wiki, describing how increased intracellular copper can induce cuproptosis via disruption of energy metabolism. Collectively, these findings highlight the need for coordinated analytical, mechanistic, and regulatory research to support evidence-based risk assessment of CuO and Cu<sub>2</sub>O nanoparticles in the food and feed context.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Copper oxide nanoparticles: from EU-regulatory landscape and mechanistic toxicity towards a cuproptosis-linked adverse outcome pathway

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月27日

查看全文
  • Sophie Scholz,
  • Julia Prinz,
  • Linde Sevenants,
  • Andrea Holzwarth,
  • Birgit Mertens,
  • Robert Pieper,
  • Vera Ritz,
  • Kirsten Schulz,
  • Holger Sieg,
  • Aswin Mangerich,
  • Linda Böhmert

摘要

Copper is an essential trace element, yet concerns regarding its toxic potential have gained increasing attention, particularly with regard to nanoparticulate forms of copper oxides. Both CuO and Cu2O are currently authorised in the EU for use in agriculture, biocides, and animal nutrition, but regulatory clarity regarding their nanoforms remains limited. This comprehensive review—combining narrative, bibliometric, and systematic approaches—addressed three key questions: (i) whether CuO and Cu2O nanoparticles are sufficiently considered within EU regulations to prevent unintentional oral exposure via the food and feed chain, (ii) whether these nanoparticles can cross the intestinal barrier as intact particles and accumulate in tissues, and (iii) whether they elicit distinct biological responses, including regulated cell death pathways such as cuproptosis. With respect to question (i), a detailed analysis of EU legal frameworks revealed a heterogeneous regulatory landscape and a lack of binding provisions that would preclude unintended presence of copper oxide nanoforms in regulated materials. Although some nano-specific data requirements exist, empirical information on nanoparticulate fractions in commercial products is still lacking. With respect to questions (ii) and (iii), our systematic literature analysis supports consistent intracellular uptake of CuO and Cu2O nanoparticles, yet direct evidence for transport of intact particles across the intestinal barrier is scarce. Mechanistic evidence supports cuproptosis as a key pathway for CuO nanoparticle toxicity, while the extent to which these effects differ quantitatively from ionic copper remains unclear due to insufficient data using appropriate experimental controls. Notably, a pronounced data gap was identified for Cu2O nanoparticles across all evaluated domains. Finally, to organise and integrate the mechanistic evidence presented, we developed an adverse outcome pathway (AOP), registered as AOP 590 in the AOP Wiki, describing how increased intracellular copper can induce cuproptosis via disruption of energy metabolism. Collectively, these findings highlight the need for coordinated analytical, mechanistic, and regulatory research to support evidence-based risk assessment of CuO and Cu2O nanoparticles in the food and feed context.