Poland Craig A, Lombaert Noömi, Mackie Carol, Renard Alain, Sinha Parikhit, Verougstraete Violaine, Lourens Nicky J J
Regulatory Compliance Limited, 6 Dryden Road, Loanhead, Midlothian, EH20 9TY, UK; Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
International Zinc Association, Reach Cadmium Consortium, Avenue de Tervueren 168/Box 4, B-1150, Brussels, Belgium.
Toxicology. 2021 Nov;463:152969. doi: 10.1016/j.tox.2021.152969. Epub 2021 Oct 1.
Cadmium toxicity occurs where there is absorption and accumulation of cadmium ions (Cd) in tissues beyond tolerable levels. Significant differences in the release of Cd from cadmium compounds in biological fluids, like gastric fluid, may indicate differences in bioavailability and absorption. This means that direct read-across from high solubility cadmium compounds to lower solubility compounds may not accurately reflect potential hazards. Here, the relative bioaccessibility in gastric fluid of cadmium telluride and cadmium chloride was evaluated using in vitro bioelution tests whilst the toxicokinetic behavior of these two compounds were compared after dietary administration for 90 days in male and female Wistar Han rats following OECD TG 408. Cadmium chloride was highly bioaccessible, whilst cadmium telluride showed low solubility in simulated gastric fluid (90 % and 1.5 % bioaccessibility, respectively). This difference in bioaccessibility was also reflected by a difference in bioavailability as shown by the difference in the liver and kidney concentrations of cadmium after repeat oral exposure. Feeding at doses of 750 and 1500 ppm of cadmium telluride did not result in tissue cadmium levels above the lower limit of quantification (LLOQ). In contrast, feeding with a lower test substance concentration yet higher concentration of bioaccessible cadmium (30 ppm cadmium chloride) resulted in tissue accumulation of cadmium. Only slight, non-adverse changes in hematology and clinical chemistry parameters were seen at these doses, indicating an absence of significant cadmium mediated toxicity towards target organs (kidney and liver), reflected in minimal cadmium accumulation in these organs. This study demonstrates that bioelution tests can help determine the bioaccessibility of cadmium, which can be used to estimate the potential for target tissue toxicity based on known toxicokinetic profiles and threshold levels for cadmium toxicity, while reducing and refining animal testing.
当镉离子（Cd）在组织中的吸收和积累超过可耐受水平时，就会发生镉中毒。镉化合物在生物流体（如胃液）中释放镉的显著差异，可能表明生物利用度和吸收存在差异。这意味着从高溶解度镉化合物直接类推到低溶解度化合物可能无法准确反映潜在危害。在此，使用体外生物洗脱试验评估了碲化镉和氯化镉在胃液中的相对生物可及性，同时按照经合组织TG 408，在雄性和雌性Wistar Han大鼠经口给药90天后，比较了这两种化合物的毒代动力学行为。氯化镉具有很高的生物可及性，而碲化镉在模拟胃液中的溶解度较低（生物可及性分别为90%和1.5%）。重复口服暴露后，肝脏和肾脏中镉浓度的差异表明，这种生物可及性的差异也反映在生物利用度的差异上。以750和1500 ppm的剂量投喂碲化镉，并未导致组织镉水平高于定量下限（LLOQ）。相比之下，投喂较低浓度的受试物质但生物可及性镉浓度较高（30 ppm氯化镉）会导致镉在组织中蓄积。在这些剂量下，血液学和临床化学参数仅出现轻微的、非有害的变化，表明不存在镉对靶器官（肾脏和肝脏）的显著毒性作用，这体现在这些器官中镉的蓄积极少。这项研究表明，生物洗脱试验有助于确定镉的生物可及性，基于已知的毒代动力学特征和镉毒性阈值水平，可用于估计靶组织毒性的可能性，同时减少和优化动物试验。
