Abstract

Background:

Established breast cancer risk factors, such as hormone replacement therapy and reproductive history, are thought to act by increasing estrogen and progesterone (P4) activity.

Objective:

We aimed to use in vitro screening data to identify chemicals that increase the synthesis of estradiol (E2) or P4 and evaluate potential risks.

Method:

Using data from a high-throughput (HT) in vitro steroidogenesis assay developed for the U.S. Environmental Protection Agency (EPA) ToxCast program, we identified chemicals that increased estradiol (E2-up) or progesterone (P4-up) in human H295R adrenocortical carcinoma cells. We prioritized chemicals by their activity. We compiled in vivo studies and assessments about carcinogenicity and reproductive/developmental (repro/dev) toxicity. We identified exposure sources and predicted intakes from the U.S. EPA’s ExpoCast.

Results:

We found 296 chemicals increased E2 (182) or P4 (185), with 71 chemicals increasing both. In vivo data often showed effects consistent with this mechanism. Of the E2- and P4-up chemicals, about 30% were likely repro/dev toxicants or carcinogens, whereas only 5–13% were classified as unlikely. However, most of the chemicals had insufficient in vivo data to evaluate their effects. Of 45 chemicals associated with mammary gland effects, and also tested in the H294R assay, 29 increased E2 or P4, including the well-known mammary carcinogen 7,12-dimethylbenz(a)anthracene. E2- and P4-up chemicals include pesticides, consumer product ingredients, food additives, and drinking water contaminants.

Discussion:

The U.S. EPA’s in vitro screening data identified several hundred chemicals that should be considered as potential risk factors for breast cancer because they increased E2 or P4 synthesis. In vitro data is a helpful addition to current toxicity assessments, which are not sensitive to mammary gland effects. Relevant effects on the mammary gland are often not noticed or are dismissed, including for 2,4-dichlorophenol and cyfluthrin. Fifty-three active E2-up and 59 active P4-up chemicals that are in consumer products, food, pesticides, or drugs have not been evaluated for carcinogenic potential and are priorities for study and exposure reduction. https://doi.org/10.1289/EHP8608

中文翻译：

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应用体外测定法来鉴定增加雌二醇和孕酮合成并是潜在乳腺癌风险因素的化学物质

摘要

背景：

已确定的乳腺癌风险因素，例如激素替代疗法和生殖史，被认为是通过增加雌激素和孕激素 (P4) 活性而起作用。

客观的：

我们旨在使用体外筛选数据来识别增加雌二醇 (E2) 或 P4 合成的化学物质并评估潜在风险。

方法：

使用为美国环境保护署 (EPA) ToxCast 计划开发的高通量 (HT)体外类固醇生成测定的数据，我们确定了增加人类 H295R 肾上腺皮质癌中雌二醇 (E2-up) 或黄体酮 (P4-up) 的化学物质细胞。我们根据化学品的活动优先考虑化学品。我们汇编了关于致癌性和生殖/发育 (repro/dev) 毒性的体内研究和评估。我们从美国环保署的 ExpoCast 中确定了暴露源和预测摄入量。

结果：

我们发现 296 种化学物质增加了 E2 (182) 或 P4 (185)，其中 71 种化学物质都增加了。体内数据通常显示出与这种机制一致的效果。在 E2- 和 P4-up 化学品中，大约 30% 可能是生殖/衍生毒物或致癌物，而只有 5-13% 被归类为不太可能。然而，大多数化学物质没有足够的体内数据来评估它们的效果。在与乳腺效应相关的 45 种化学物质中，也在 H294R 测定中进行了测试，其中 29 种增加了 E2 或 P4，包括众所周知的乳腺致癌物 7,12-二甲基苯（a）蒽。E2-和 P4-up 化学品包括杀虫剂、消费品成分、食品添加剂和饮用水污染物。

讨论：

美国 EPA 的体外筛选数据确定了数百种化学物质，它们应被视为乳腺癌的潜在危险因素，因为它们增加了 E2 或 P4 的合成。体外数据是对目前对乳腺影响不敏感的毒性评估的有益补充。对乳腺的相关影响通常不会被注意到或被忽视，包括 2,4-二氯苯酚和氟氯氰菊酯。消费品、食品、杀虫剂或药物中的 53 种活性 E2-up 和 59 种活性 P4-up 化学品尚未评估致癌潜力，是研究和减少接触的重点。https://doi.org/10.1289/EHP8608