Silent Spring Institute, Newton, Massachusetts, USA.
School of Public Health, University of California, Berkeley, Berkeley, California, USA.
Environ Health Perspect. 2024 Jan;132(1):17002. doi: 10.1289/EHP13233. Epub 2024 Jan 10.
Chemicals that induce mammary tumors in rodents or activate estrogen or progesterone signaling are likely to increase breast cancer (BC) risk. Identifying chemicals with these activities can prompt steps to protect human health.
We compiled data on rodent tumors, endocrine activity, and genotoxicity to assess the key characteristics (KCs) of rodent mammary carcinogens (MCs), and to identify other chemicals that exhibit these effects and may therefore increase BC risk.
Using authoritative databases, including International Agency for Research on Cancer (IARC) Monographs and the US Environmental Protection's (EPA) ToxCast, we selected chemicals that induce mammary tumors in rodents, stimulate estradiol or progesterone synthesis, or activate the estrogen receptor (ER) . We classified these chemicals by their genotoxicity and strength of endocrine activity and calculated the overrepresentation (enrichment) of these KCs among MCs. Finally, we evaluated whether these KCs predict whether a chemical is likely to induce mammary tumors.
We identified 279 MCs and an additional 642 chemicals that stimulate estrogen or progesterone signaling. MCs were significantly enriched for steroidogenicity, ER agonism, and genotoxicity, supporting the use of these KCs to predict whether a chemical is likely to induce rodent mammary tumors and, by inference, increase BC risk. More MCs were steroidogens than ER agonists, and many increased both estradiol and progesterone. Enrichment among MCs was greater for strong endocrine activity vs. weak or inactive, with a significant trend.
We identified hundreds of compounds that have biological activities that could increase BC risk and demonstrated that these activities are enriched among MCs. We argue that many of these should not be considered low hazard without investigating their ability to affect the breast, and chemicals with the strongest evidence can be targeted for exposure reduction. We describe ways to strengthen hazard identification, including improved assessments for mammary effects, developing assays for more KCs, and more comprehensive chemical testing. https://doi.org/10.1289/EHP13233.
能够在啮齿动物中诱导乳腺肿瘤或激活雌激素或孕激素信号的化学物质可能会增加乳腺癌（BC）的风险。识别具有这些活性的化学物质可以促使采取措施保护人类健康。
我们编译了关于啮齿动物肿瘤、内分泌活性和遗传毒性的数据，以评估啮齿动物乳腺致癌剂（MCs）的关键特征（KC），并确定其他具有这些作用且可能因此增加 BC 风险的化学物质。
我们使用了包括国际癌症研究机构（IARC）专论和美国环境保护署（EPA）ToxCast 在内的权威数据库，选择了能够在啮齿动物中诱导乳腺肿瘤、刺激雌二醇或孕酮合成或激活雌激素受体（ER）的化学物质。我们根据遗传毒性和内分泌活性的强度对这些化学物质进行分类，并计算了 MCs 中这些 KC 的过度表达（富集）。最后，我们评估了这些 KC 是否可以预测一种化学物质是否有可能诱导乳腺肿瘤。
我们确定了 279 种 MCs 和另外 642 种刺激雌激素或孕激素信号的化学物质。MCs 在类固醇生成、ER 激动剂和遗传毒性方面明显富集，支持使用这些 KC 来预测一种化学物质是否有可能诱导啮齿动物乳腺肿瘤，并由此推断增加 BC 风险。作为 ER 激动剂，MCs 中的类固醇生成剂更多，许多化学物质既能增加雌二醇又能增加孕酮。在 MCs 中，内分泌活性强的化学物质比弱或无活性的化学物质的富集程度更高，且具有显著的趋势。
我们确定了数百种具有可能增加 BC 风险的生物学活性的化合物，并证明这些活性在 MCs 中富集。我们认为，在没有调查其对乳房影响的能力的情况下，许多此类化合物不应被视为低危害，并且具有最强证据的化学物质应作为减少暴露的目标。我们描述了加强危害识别的方法，包括改进对乳腺影响的评估、开发更多 KC 的测定方法以及更全面的化学测试。https://doi.org/10.1289/EHP13233.
