Caldwell Jane C, Jinot Jennifer, DeVoney Danielle, Gift Jeff S
National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC, USA.
Environ Mol Mutagen. 2008 Mar;49(2):155-64. doi: 10.1002/em.20356.
The European Food Safety Authority (EFSA) released a 2006 report questioning the relationship of aspartame exposure with increased incidence of lymphomas/leukemias in a European Ramazzini Foundation (ERF) rat study. The EFSA report suggested that the lymphoma/leukemia findings were most likely explained by infection in the rat colony. The ERF has also conducted the only available long-term oral study of methyl tertiary-butyl ether (MTBE). Thus, using the EFSA report as support, some have now raised questions about the human relevance of MTBE-associated hemolymphoreticular tumors reported by the ERF in female rats as well as whether their incidence was elevated above background levels. In this report, we discuss the hypothesized mode of action (MOA) of infection-induced lymphoma and its relevance to MTBE-associated lymphomas. We address the relationship of rat strain and study duration to lymphoma susceptibility and review evidence of low background rates of this tumor in control animals at the ERF, similar survival rates for female rats at the ERF and National Toxicology Program (NTP), and chemical- and gender-specificity of tumor induction for this type of tumor in studies at the ERF. We find that the background incidence of hemolymphoreticular tumors in female rats in the MTBE study is consistent with contemporaneous studies at the ERF and that there is an exposure-related effect, which is unlikely to be due to infections. We examine more recent tumor classification schemes for lymphomas, which support the combination of lymphoblastic leukemias and lymphomas reported by Belpoggi et al. ([1995] Toxicol Ind Health 11:119-149; [1998] Eur J Oncol 3:201-206).
欧洲食品安全局（EFSA）发布了一份2006年的报告，对欧洲拉马齐尼基金会（ERF）大鼠研究中阿斯巴甜暴露与淋巴瘤/白血病发病率增加之间的关系提出质疑。EFSA的报告表明，淋巴瘤/白血病的研究结果很可能是由大鼠群体中的感染所解释的。ERF还开展了唯一一项关于甲基叔丁基醚（MTBE）的长期口服研究。因此，一些人以EFSA的报告为依据，现在对ERF报告的雌性大鼠中与MTBE相关的血淋巴网状肿瘤与人类的相关性以及其发病率是否高于背景水平提出了疑问。在本报告中，我们讨论了感染诱导淋巴瘤的假设作用模式（MOA）及其与MTBE相关淋巴瘤的相关性。我们阐述了大鼠品系和研究持续时间与淋巴瘤易感性的关系，并回顾了ERF对照动物中该肿瘤低背景发生率的证据、ERF和国家毒理学计划（NTP）中雌性大鼠相似的存活率，以及ERF研究中该类型肿瘤诱导的化学和性别特异性。我们发现，MTBE研究中雌性大鼠血淋巴网状肿瘤的背景发生率与ERF同期研究一致，并且存在与暴露相关的效应，这不太可能是由感染导致的。我们研究了淋巴瘤的最新肿瘤分类方案，该方案支持贝尔波吉等人（[1995]《毒理学与工业卫生》11:119 - 149；[1998]《欧洲肿瘤学杂志》3:201 - 206）报告的淋巴细胞白血病和淋巴瘤的合并情况。
