Pyatt David, Natelson Ethan, Golden Robert
Summit Toxicology, L.L.P., 509 N Bermont, Lafayette, CO 80026, USA.
Regul Toxicol Pharmacol. 2008 Jun;51(1):119-33. doi: 10.1016/j.yrtph.2008.03.003. Epub 2008 Mar 18.
The United States Environmental Protection Agency (EPA) recently proposed a hypothetical mode of action (MOA) to explain how inhaled formaldehyde (FA) might induce leukemia, lymphoma and a variety of other lymphohematopoietic (LHP) malignancies in occupationally exposed workers. The central hypothesis requires that B lymphocytes or hematopoietic progenitor cells (HPC) present at the "portal of entry (POE)" undergo sustained mutagenic change as a result of direct FA exposure. These modified cells would then migrate back to the bone marrow or primary lymphatic tissue and subsequently develop into specific LHP disease states. Chemical interaction at the POE is an absolute requirement for the hypothesized MOA as there is no convincing evidence that inhaled FA causes distant site (e.g., bone marrow) toxicity. The purpose of this review is to critically evaluate this proposed MOA within the context of the existing data concerning the toxicokinetic and biological properties of FA, the current understanding of the induction of chemically-induced leukemias and lymphomas, as well as within EPA's specific guidelines for evaluating the MOA of chemically-induced cancers. Specifically, we examine the scientific support for the hypothesis that FA exposure may induce carcinogenic transformation of localized lymphocytes or peripheral hematopoietic progenitor cells (HPC) in the absence of discernable systemic hematopoietic toxicity (i.e., peripheral transformation). While little or no empirical evidence exists upon which to fully evaluate the proposed hypothesis, available data does not support the proposed concept of "peripheral transformation" at the chemical entry site. Numerous animal bioassays evaluating chronic inhalation of FA clearly do not support this hypothesis since no properly conducted study as ever shown an increase in any LHP malignancy. Moreover, the notion that FA can cause any LHP malignancy is not supported with either epidemiologic data or current understanding of differing etiologies and risk factors for the various hematopoietic and lymphoproliferative malignancies. It is therefore concluded that existing science does not support the proposed MOA as a logical explanation for proposing that FA is a realistic etiological factor for any LHP malignancy.
美国环境保护局（EPA）最近提出了一种假设的作用模式（MOA），以解释吸入甲醛（FA）如何在职业暴露工人中诱发白血病、淋巴瘤和多种其他淋巴造血（LHP）恶性肿瘤。核心假设要求在“进入门户（POE）”处存在的B淋巴细胞或造血祖细胞（HPC）由于直接接触FA而经历持续的诱变变化。这些修饰后的细胞随后会迁移回骨髓或初级淋巴组织，并随后发展为特定的LHP疾病状态。POE处的化学相互作用是假设的MOA的绝对必要条件，因为没有令人信服的证据表明吸入的FA会导致远处部位（如骨髓）毒性。本综述的目的是在有关FA的毒代动力学和生物学特性的现有数据、对化学诱导的白血病和淋巴瘤诱导的当前理解以及EPA评估化学诱导癌症的MOA的特定指南的背景下，对这一提出的MOA进行批判性评估。具体而言，我们研究了以下假设的科学依据：在没有可察觉的全身性造血毒性（即外周转化）的情况下，FA暴露可能诱导局部淋巴细胞或外周造血祖细胞（HPC）发生致癌转化。虽然几乎没有实证证据可用于全面评估提出的假设，但现有数据不支持在化学进入部位提出的“外周转化”概念。许多评估长期吸入FA的动物生物测定显然不支持这一假设，因为没有任何一项进行得当的研究表明任何LHP恶性肿瘤有所增加。此外，无论是流行病学数据还是对各种造血和淋巴增殖性恶性肿瘤的不同病因和风险因素的当前理解，都不支持FA会导致任何LHP恶性肿瘤的观点。因此得出结论，现有科学不支持将提出的MOA作为认为FA是任何LHP恶性肿瘤的现实病因因素这一观点的合理解释。
