Aquatic Toxicology ( IF 4.5 ) Pub Date : 2020-09-15 , DOI: 10.1016/j.aquatox.2020.105616 Chelsea Grimard , Annika Mangold-Döring , Markus Schmitz , Hattan Alharbi , Paul D. Jones , John P. Giesy , Markus Hecker , Markus Brinkmann
Understanding internal dose metrics is integral to adequately assess effects environmental contaminants might have on aquatic wildlife, including fish. In silico toxicokinetic (TK) models are a leading approach for quantifying internal exposure metrics for fishes; however, they often do not adequately consider chemicals that are actively biotransformed and have not been validated against early-life stages (ELS) that are often considered the most sensitive to the exposure to contaminants. To address these uncertainties, TK models were parameterized for the rapidly biotransformed chemical benzo[a]pyrene (B[a]P) in embryo-larval and adult life stages of fathead minnows. Biotransformation of B[a]P was determined through measurements of in vitro clearance. Using in vitro-in vivo extrapolation, in vitro clearance was integrated into a multi-compartment TK model for adult fish and a one-compartment model for ELS. Model predictions were validated using measurements of B[a]P metabolites from in vivo flow-through exposures to graded concentrations of water-borne B[a]P. Significantly greater amounts of B[a]P metabolites were observed with exposure to greater concentrations of parent compound in both life stages. However, when assessing biotransformation capacity, no differences in phase I or phase II biotransformation were observed with greater exposures to B[a]P. Results of modelling suggested that biotransformation of B[a]P can be successfully implemented into in silico models to accurately predict life stage-specific abundances of B[a]P metabolites in either whole-body larvae or the bile of adult fish. Models developed increase the scope of applications in which TK models can be used to support environmental risk assessments.
中文翻译:
the头min鱼(Pimephales promelas)中苯并[ a ] up的吸收和生物转化的体外-体内和跨生命期外推法
了解内部剂量指标对于充分评估环境污染物可能对包括鱼类在内的水生野生生物的影响至关重要。毒理动力学(TK)模型是量化鱼类内部暴露指标的一种领先方法。但是,他们通常没有充分考虑经过积极生物转化且尚未针对通常被认为对接触污染物最敏感的生命早期阶段(ELS)进行验证的化学物质。为了解决这些不确定性,针对在胖头min鱼的幼虫和成年生命阶段中快速生物转化的化学苯并[ a ] re(B [ a ] P)参数化了TK模型。B [ a ] P的生物转化通过测量体外清除率。使用体外-体内外推法,将体外清除率整合到成年鱼的多室TK模型和ELS的一室模型中。模型预测是通过使用B [ a ] P代谢物的体内流通量暴露于分级的水性B [ a ] P浓度的测量来验证的。在两个生命阶段,暴露于更高浓度的母体化合物时,观察到大量的B [ a ] P代谢产物。但是,在评估生物转化能力时,在B [ a]暴露量更大的情况下,未观察到I期或II期生物转化的差异。] P。建模结果表明,B [ a ] P的生物转化可以成功地应用于计算机模拟模型,以准确预测成年鱼全身或幼体中B [ a ] P代谢产物的生命阶段特异性丰度。开发的模型扩大了可将传统知识模型用于支持环境风险评估的应用范围。