Large effects from small exposures. I. Mechanisms for endocrine-disrupting chemicals with estrogenic activity.
Large effects from small exposures. I. Mechanisms for endocrine-disrupting chemicals with estrogenic activity.
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小型暴露产生的很大影响。 I.具有雌激素活性的内分泌干扰化学物质的机制。
DOI：
10.1289/ehp.5494
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发表时间：
2003-06
影响因子：
10.4
通讯作者：
vom Saal, Frederick S
中科院分区：
文献类型：
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作者：
Welshons, Wade V;Thayer, Kristina A;Judy, Barbara M;Taylor, Julia A;Curran, Edward M;vom Saal, Frederick S
有关自然和环境激素的基本作用机制的信息，结合有关内源性激素浓度的信息，揭示了具有雌激素活性的内分泌干扰化学品（EEDC）如何在远低于目前毒理学研究中测试的浓度下发挥活性。因此，在EEDC的毒理学研究中仅使用非常高的剂量可能会大大低估生物活性。具体而言：a）EEDC的激素作用机制和递送生理学准确地预测了生物活性的低剂量范围，这是传统毒理学测试所遗漏的。B）毒理学假设，在非常宽的剂量范围内从高剂量线性外推，以预测EEDC受体占用生理范围内剂量的反应是有效的;但是，由于受体介导的反应饱和，因此该假设无效。c）此外，受体介导的反应可以随着剂量的增加而先增加后减少，这与剂量-反应关系是单调的假设相矛盾。d）外源性雌激素调节具有生理活性的系统，因此已经高于阈值，这与EEDC内分泌反应阈值的传统毒理学假设相矛盾。这四个基本问题对于管理机构所使用的风险评估方法来说是有问题的，因为它们挑战了传统上使用高剂量试验外推法来预测在低得多的环境相关剂量下的反应。这些剂量在野生动物和人类目前接触多种化学品的范围内。这些问题因以下事实而加剧：适合于内分泌反应研究的阳性和阴性对照的类型不是传统毒理学试验的一部分，并且经常被省略，或者当存在时被误解。
Information concerning the fundamental mechanisms of action of both natural and environmental hormones, combined with information concerning endogenous hormone concentrations, reveals how endocrine-disrupting chemicals with estrogenic activity (EEDCs) can be active at concentrations far below those currently being tested in toxicological studies. Using only very high doses in toxicological studies of EEDCs thus can dramatically underestimate bioactivity. Specifically: a) The hormonal action mechanisms and the physiology of delivery of EEDCs predict with accuracy the low-dose ranges of biological activity, which have been missed by traditional toxicological testing. b) Toxicology assumes that it is valid to extrapolate linearly from high doses over a very wide dose range to predict responses at doses within the physiological range of receptor occupancy for an EEDC; however, because receptor-mediated responses saturate, this assumption is invalid. c) Furthermore, receptor-mediated responses can first increase and then decrease as dose increases, contradicting the assumption that dose-response relationships are monotonic. d) Exogenous estrogens modulate a system that is physiologically active and thus is already above threshold, contradicting the traditional toxicological assumption of thresholds for endocrine responses to EEDCs. These four fundamental issues are problematic for risk assessment methods used by regulatory agencies, because they challenge the traditional use of extrapolation from high-dose testing to predict responses at the much lower environmentally relevant doses. These doses are within the range of current exposures to numerous chemicals in wildlife and humans. These problems are exacerbated by the fact that the type of positive and negative controls appropriate to the study of endocrine responses are not part of traditional toxicological testing and are frequently omitted, or when present, have been misinterpreted.