a Exponent Health Sciences , Oakland , CA , USA.
b Exponent Health Sciences , Washington , DC , USA.
Crit Rev Toxicol. 2015;45 Suppl 1:1-56. doi: 10.3109/10408444.2015.1052367.
A 1999 California state agency cancer potency (CP) evaluation of methyl tert-butyl ether (MTBE) assumed linear risk extrapolations from tumor data were plausible because of limited evidence that MTBE or its metabolites could damage DNA, and based such extrapolations on data from rat gavage and rat and mouse inhalation studies indicating elevated tumor rates in male rat kidney, male rat Leydig interstitial cells, and female rat leukemia/lymphomas. More recent data bearing on MTBE cancer potency include a rodent cancer bioassay of MTBE in drinking water; several new studies of MTBE genotoxicity; several similar evaluations of MTBE metabolites, formaldehyde, and tert-butyl alcohol or TBA; and updated evaluations of carcinogenic mode(s) of action (MOAs) of MTBE and MTBE metabolite's. The lymphoma/leukemia data used in the California assessment were recently declared unreliable by the U.S. Environmental Protection Agency (EPA). Updated characterizations of MTBE CP, and its uncertainty, are currently needed to address a variety of decision goals concerning historical and current MTBE contamination. To this end, an extensive review of data sets bearing on MTBE and metabolite genotoxicity, cytotoxicity, and tumorigenicity was applied to reassess MTBE CP and related uncertainty in view of MOA considerations. Adopting the traditional approach that cytotoxicity-driven cancer MOAs are inoperative at very low, non-cytotoxic dose levels, it was determined that MTBE most likely does not increase cancer risk unless chronic exposures induce target-tissue toxicity, including in sensitive individuals. However, the corresponding expected (or plausible upper bound) CP for MTBE conditional on a hypothetical linear (e.g., genotoxic) MOA was estimated to be ∼2 × 10(-5) (or 0.003) per mg MTBE per kg body weight per day for adults exposed chronically over a lifetime. Based on this conservative estimate of CP, if MTBE is carcinogenic to humans, it is among the weakest 10% of chemical carcinogens evaluated by EPA.
1999 年，加利福尼亚州的一个机构对甲基叔丁基醚（MTBE）的致癌潜能（CP）进行了评估，认为从肿瘤数据推断出线性风险外推是合理的，因为有限的证据表明 MTBE 或其代谢物可能会损害 DNA，并且基于来自大鼠灌胃和大鼠及小鼠吸入研究的数据进行了这种外推，这些研究表明雄性大鼠肾脏、雄性大鼠莱迪希氏细胞和雌性大鼠白血病/淋巴瘤的肿瘤发生率升高。最近与 MTBE 致癌潜能相关的数据包括 MTBE 在饮用水中的啮齿动物致癌生物测定；几项新的 MTBE 遗传毒性研究；对 MTBE 代谢物、甲醛和叔丁醇或 TBA 的几项类似评估；以及对 MTBE 和 MTBE 代谢物致癌作用模式（MOA）的最新评估。加利福尼亚州评估中使用的淋巴瘤/白血病数据最近被美国环境保护署（EPA）宣布不可靠。目前需要更新 MTBE CP 的特征及其不确定性，以解决与历史和当前 MTBE 污染有关的各种决策目标。为此，对与 MTBE 和代谢物遗传毒性、细胞毒性和肿瘤形成有关的数据进行了广泛的回顾，以根据 MOA 考虑重新评估 MTBE CP 及其相关不确定性。采用传统方法，即细胞毒性驱动的癌症 MOA 在非常低的非细胞毒性剂量水平下不起作用，结果表明，除非慢性暴露引起靶组织毒性，包括敏感个体，否则 MTBE 不太可能增加癌症风险。然而，基于假设的线性（例如遗传毒性）MOA，对 MTBE 条件下的预期（或合理的上限）CP 进行了估计，对于终生慢性暴露的成年人，每天每千克体重每毫克 MTBE 约为 2×10(-5)（或 0.003）。基于这种 CP 的保守估计，如果 MTBE 对人类具有致癌性，那么它将属于 EPA 评估的最弱的 10%化学致癌物之一。
