Plantade Julie, Baudrot Virgile, Charles Sandrine
CNRS, UMR 5558, Université de Lyon; Université Lyon 1, Cedex, Villeurbanne 69622, France.
CNRS, UMR 5308, Université de Lyon; Université Lyon 1, Cedex 07, Lyon 69364, France.
MethodsX. 2023 Mar 7;10:102114. doi: 10.1016/j.mex.2023.102114. eCollection 2023.
Decisions in Environmental Risk Assessment (ERA) about impacts of chemical compounds on different species are based on critical effect indicators such as the 50% lethal concentration (LC). Regulatory documents recommend concentration-response (or concentration-effect) model fitting on standard toxicity test data to get LC values. However, toxicokinetic-toxicodynamic (TKTD) models proved their efficiency to better exploit toxicity test data, at Tier-2 but also at Tier-1, delivering time-independent indicators. In particular, LC values can be obtained from the reduced General Unified Threshold model of Survival (GUTS-RED) with both variants, Stochastic Death and Individual Tolerance, that include parameter h, the background mortality. Estimating h during the fitting process or not depends on studies and fitting habits, while it may strongly influence the other GUTS-RED parameters, and consequently the LC estimate. We hypothesized that estimating h from all data in all replicates over time should provide more precise LC estimates. We then explored how estimating h impacted: (i) GUTS-RED model parameters; (ii) goodness-of-fit criteria (fitting plot, posterior predictive check, parameter correlations); (iii) LC accuracy and precision. We finally show that estimating h does not impact the LC precision while providing more accurate and precise GUTS parameter estimates. Hence, estimating h would lead to a more protective ERA.
环境风险评估（ERA）中关于化合物对不同物种影响的决策基于诸如50%致死浓度（LC）等关键效应指标。监管文件建议对标准毒性测试数据进行浓度-响应（或浓度-效应）模型拟合以获得LC值。然而，毒代动力学-毒效动力学（TKTD）模型已证明其在二级甚至一级水平上能够更有效地利用毒性测试数据，提供与时间无关的指标。特别是，LC值可以从简化的通用生存阈值模型（GUTS-RED）的两种变体中获得，即随机死亡和个体耐受性，这两种变体都包含参数h，即背景死亡率。在拟合过程中是否估计h取决于研究和拟合习惯，而它可能会强烈影响其他GUTS-RED参数，进而影响LC估计值。我们假设随时间从所有重复实验的所有数据中估计h应该能提供更精确的LC估计值。然后我们探讨了估计h如何影响：（i）GUTS-RED模型参数；（ii）拟合优度标准（拟合图、后验预测检验、参数相关性）；（iii）LC的准确性和精确性。我们最终表明，估计h不会影响LC的精确性，同时能提供更准确和精确的GUTS参数估计值。因此，估计h将导致更具保护性的ERA。
