饵料中地西泮在鲤鱼体内残留分布代谢、烹饪消减及膳食摄入风险评估
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1.中国水产科学研究院;2.上海海洋大学水产与生命学院;3.北京市农产品质量安全中心

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S91

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Residue Distribution, Cooking Reduction, and Dietary Risk Assessment of Diazepam in Cyprinus carpio from Bait
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1.Chinese Academy of Fishery Sciences;2.Shanghai Ocean University;3.Beijing Municipal Quality Safety Center for Agricultural Products

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    摘要:

    地西泮(diazepam, DZP)是一种长效苯二氮类镇静剂,临床上主要用于治疗焦虑、失眠、癫痫等疾病。长期或不当使用安定可引起嗜睡、头痛、幻听等不良反应,并对肝脏造成负担。在新生儿中,由于其穿过胎盘和血脑屏障的能力,它甚至可能导致长期认知障碍。DZP在中国被列为第二类精神药物,尚未被批准作为水产养殖兽药,在水产养殖中使用DZP属于违规行为。GB 31650-2019《食品安全国家标准食品中兽药最大残留限量》明确规定,动物源性食品中不得检出DZP。然而,在草鱼(Ctenopharyngodon idellus)、鲫(Carassius auratus)和鲤(Cyprinus carpio)等淡水产品中DZP却偶有检出。水产品中DZP残留可能来自水污染或投入品,前期有较多关于药浴暴露途径的研究,而关于通过饵料引入残留风险的研究相对有限。本研究选择鲤作为研究对象,使用含DZP的饵料进行灌胃给药,并在给药后1 h至288 h内,定时对皮肌、血浆、鳃、肝、肾等组织进行取样,采用高效液相色谱-串联高分辨质谱技术,检测各组织中DZP及其代谢物去甲西泮(nordazepam, NZP)、替马西泮(temazepam, TMZ)和奥沙西泮(oxazepam, OZP)的残留量,旨在明确鲤鱼摄食含DZP的饵料后,DZP及其代谢物残留在鲤鱼体内的分布代谢规律。结果表明,18℃下,鲤鱼经含3 mg/kg和30 mg/kg DZP饵料单次灌胃后,DZP在鲤鱼鱼体内迅速达到较高的残留量,48 h后肝和鳃中迅速降低,其余组织还维持较高水平,DZP在鲤鱼中的主要代谢产物为OZP和NZP,可食用皮肌组织中DZP含量降至检出限(0.5 μg/kg)以下时间较长。为进一步明确评价常见不同烹饪方式对DZP残留的消减效果,开展了常见水煮和油炸烹饪方式在不同时间对鲤鱼可食用皮肌组织中DZP残留的消除效果。结果表明,油炸处理相较清蒸处理方式能有效降低残留,且代谢物分析显示油炸前期DZP消减以转移为主,后期以降解为奥沙西泮为主,这与DZP及其代谢物的溶解性与热敏性密切相关。基于DZP实验暴露浓度下鲤鱼食用皮肌组织中DZP的残留水平,结合每日允许摄入量值(ADI)开展膳食摄入风险评估,分析发现在实验浓度条件下鲤鱼可食用皮肌组织的膳食暴露风险均处于可接受水平。本研究为科学评估由饵料引入的DZP风险提供了数据支撑,为制定相关监管策略、保障水产品质量安全和消费者健康奠定了科学基础。

    Abstract:

    Diazepam is a long-acting benzodiazepine sedative primarily used clinically for treating anxiety, insomnia, epilepsy, and other conditions. It works mainly by enhancing the effect of the γ-aminobutyric acid (GABA) neurotransmitter to inhibit central nervous system activity, thereby producing various pharmacological effects such as sedation, hypnosis, anticonvulsant action, and central muscle relaxation. Prolonged or improper use of diazepam may cause adverse reactions including drowsiness, headaches, auditory hallucinations, and impose a burden on the liver. In newborns, it may even lead to long-term cognitive impairment due to its ability to cross the placental and blood-brain barriers. Diazepam is classified as a Schedule II psychotropic substance in China and has not been approved as a veterinary drug for aquaculture. GB 31650—2019 "National Food Safety Standard - Maximum Residue Limits for Veterinary Drugs in Foods" explicitly stipulates that diazepam shall not be detected in animal-derived food products, reflecting strict regulatory control over its presence in the food chain. However, diazepam has been occasionally detected in freshwater aquatic products such as grass carp, crucian carp, and common carp, raising concerns about food safety and public health. The contamination sources of DZP residues in aquatic products may originate from water pollution or input materials, with the issue of DZP residues caused by fishing baits being particularly prominent. Some scholars have found through simulated aquaculture environment medicated bath exposure that DZP has a relatively long metabolic cycle in aquatic products, requiring an extended withdrawal period to ensure the quality and safety of aquatic products. Accumulation is particularly evident in metabolically active tissues such as the liver and kidneys, where biotransformation occurs. However, research on residual metabolic risks introduced through bait remains relatively limited. To address this gap, Cyprinus carpio were selected as the research subjects and were orally administered bait containing diazepam (DZP). Tissue samples, including skin muscle, plasma, gills, liver, and kidneys, were collected at scheduled intervals from 1 hour to 288 hours post administration. High-performance liquid chromatography-tandem high-resolution mass spectrometry was employed to detect the residues of DZP and its metabolites—nordazepam (NZP), temazepam (TZP), and oxazepam (OZP) in various tissues. This study investigated the distribution and metabolic patterns of DZP and its metabolite residues in Cyprinus carpio following the ingestion of DZP-containing bait to assess the absorption, distribution, metabolism, and elimination dynamics of DZP. The results indicated that at 18°C, after a single oral administration of feed containing 3 mg/kg and 30 mg/kg DZP to Cyprinus carpio, DZP rapidly accumulated in their bodies and reached high residual levels. The residue distribution exhibited distinct tissue specificity: within 48 hours, DZP concentrations in the liver and gills decreased significantly, suggesting these metabolic and respiratory organs possess strong clearance capabilities. In contrast, residual concentrations remained high in edible tissues such as skin muscle, reflecting strong accumulation tendency of DZP in lipid-rich tissues. The primary metabolites of DZP were OZP and NZP. It is noteworthy that the time required for DZP in edible tissues to decrease to the detection limit (0.5 μg/kg) was relatively long, indicating its prolonged elimination half-life. In order to evaluate the effect of different cooking methods on the reduction of DZP residues, the effects of steaming and frying cooking methods on the elimination of DZP residues in edible skin and muscle tissue of carp were carried out at different times. The results demonstrated that during the initial frying stage, the dominant mechanism was the transfer of DZP to the cooking medium, while in later stages, thermal-induced conversion to OZP became the primary pathway, a process closely related to its solubility and thermal sensitivity. Based on the residual levels of DZP in the edible skin and muscle tissues of Cyprinus carpio under experimental exposure concentrations, a dietary intake risk assessment was conducted in conjunction with the Acceptable Daily Intake (ADI) value. The results indicated that the dietary exposure risk of DZP in the edible skin muscle tissues of Cyprinus carpio under experimental conditions was at an acceptable level. The residual dietary intake risk introduced by the extremely high-concentration DZP bait still requires attention to avoid potential harm to human health. This study systematically reveals the residual dynamics and transformation mechanisms of DZP in Cyprinus carpio, providing data support for the scientific evaluation of DZP risks introduced through feed and establishes a scientific foundation for formulating relevant regulatory strategies to ensure aquatic product quality and consumer health.

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  • 收稿日期:2025-12-04
  • 最后修改日期:2025-12-29
  • 录用日期:2025-12-29
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