Silva Elisabete, Scholze Martin, Kortenkamp Andreas
The School of Pharmacy, University of London, London, United Kingdom.
Environ Health Perspect. 2007 Dec;115 Suppl 1(Suppl 1):91-7. doi: 10.1289/ehp.9363.
Certain effects induced by endocrine-disrupting chemicals (EDCs) may occur at dose levels lower than those normally tested in toxicology, but few systematic dose-response studies have been carried out in the low-dose range.
The high statistical power afforded by a high-throughput in vitro assay such as the E-Screen assay was exploited with the aim of producing low-dose estimates for 24 estrogenic chemicals, including endogenous hormones and xenoestrogens.
Unusual dose-response curves with inverted U-shapes were not observed in the low-dose range. Instead, many chemicals exhibited curves with very small gradients at low doses, and this complicated the reliable estimation of low effects. Systematic comparisons between the outcomes of hypothesis-testing procedures (lowest observed effect concentrations--LOECs, no observed effect concentrations--NOECs) and regression modeling approaches (EC(01)--effective concentration causing a 1% effect, EC(05)--effective concentration causing a 5% effect) produced estimates that agreed reasonably well. In many cases, NOECs were shown to be associated with proliferative responses of 1-2%. This is in contrast with the widespread perception of NOECs as values that signal complete absence of effects. For many of the tested xenoestrogens, the NOECs, EC(01), and EC(05) were in the nanomolar range, and comparisons with measured serum and adipose tissue levels in Europe revealed considerable overlaps in some cases.
Our studies illustrate the difficulties that may be encountered during the estimation of low doses in vivo. High statistical power is required when the underlying dose-response curves are shallow. Through the use of large sample sizes and numerous repeats, the experimental power of the E-Screen assay was sufficiently high to measure effect magnitudes of around 1-2% with reliability. However, such resources are usually not available for in vivo testing, with the consequence that the statistical detection limits are considerably higher. If this coincides with shallow dose-response curves in the low-effect range (which is normally not measurable in vivo), the limited resolving power of in vivo assays may seriously constrain low-dose testing.
内分泌干扰化学物（EDC）诱导的某些效应可能在低于毒理学常规测试剂量的水平下出现，但在低剂量范围内进行的系统性剂量反应研究较少。
利用诸如E-Screen检测等高通量体外检测所具有的高统计效能，旨在对包括内源性激素和外源性雌激素在内的24种雌激素化学物进行低剂量估计。
在低剂量范围内未观察到异常的倒U形剂量反应曲线。相反，许多化学物在低剂量时呈现出梯度非常小的曲线，这使得低效应的可靠估计变得复杂。假设检验程序（最低观察到效应浓度——LOECs，未观察到效应浓度——NOECs）和回归建模方法（EC(01)——引起1%效应的有效浓度，EC(05)——引起5%效应的有效浓度）结果之间的系统比较产生了相当吻合的估计值。在许多情况下，NOECs与1%-2%的增殖反应相关。这与普遍认为NOECs表示完全无效应的观点形成对比。对于许多测试的外源性雌激素，NOECs、EC(01)和EC(05)处于纳摩尔范围，与欧洲测量的血清和脂肪组织水平进行比较发现，在某些情况下有相当大的重叠。
我们的研究说明了在体内低剂量估计过程中可能遇到的困难。当潜在的剂量反应曲线较浅时，需要高统计效能。通过使用大样本量和大量重复实验，E-Screen检测的实验效能足够高，能够可靠地测量约1%-2%的效应幅度。然而，体内测试通常无法获得这些资源，结果是统计检测限要高得多。如果这与低效应范围内较浅的剂量反应曲线（通常在体内无法测量）同时出现，体内检测有限的分辨能力可能会严重限制低剂量测试。
