A comparative 90-day toxicity study of allyl acetate, allyl alcohol and acrolein.
A comparative 90-day toxicity study of allyl acetate, allyl alcohol and acrolein.
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DOI：
10.1016/j.tox.2008.08.014
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发表时间：
2008-11-20
期刊：
影响因子：
4.5
通讯作者：
Irwin, Richard D.
中科院分区：
文献类型：
--
作者：
Auerbach, Scott S.;Mahler, Joel;Travlos, Gregory S.;Irwin, Richard D.
乙酸烯丙酯（AAC）、烯丙醇（AAL）和丙烯醛（ACR）用于制造洗涤剂、塑料、药品和化学品，并用作农业试剂。这些化学物质之间存在代谢关系，其中乙酸烯丙酯代谢为烯丙醇，随后代谢为高活性α，β-不饱和醛丙烯醛。由于相对于丙烯醛，原氧化剂乙酸烯丙酯和烯丙醇的反应性较弱，我们假设原氧化剂将获得更大的全身暴露，因此向内脏提供更高剂量的丙烯醛。推而广之，我们假设丙烯醛的全身暴露量较高应导致乙酸烯丙酯和烯丙醇处理动物的内脏毒性高于丙烯醛处理动物。为了解决我们的假设，我们比较了所有三种化学品在雄性和雌性Fischer 344/N大鼠和B6 C3 F1小鼠中产生的毒性范围，这些大鼠和小鼠通过灌胃法在0.5%甲基纤维素中每周暴露5天，持续3个月。对大鼠（10只/组）给予0至100 mg/kg乙酸烯丙酯、0至25 mg/kg烯丙醇或0至10 mg/kg丙烯醛。对小鼠（10只/组）给予0至125 mg/kg乙酸烯丙酯、0至50 mg/kg烯丙醇或0至20 mg/kg丙烯醛。最高剂量的乙酸烯丙酯和丙烯醛降低了小鼠和大鼠的存活率。所有三种化学品在两种物种和两种性别中毒性的主要靶器官是前胃;在接触每种化学品后观察到鳞状上皮增生。在这两个种属中，最高乙酸烯丙酯剂量组表现出前胃上皮坏死和出血，最高剂量的丙烯醛导致腺胃出血。乙酸烯丙酯组的肝组织病理学最明显，烯丙醇组也观察到，但丙烯醛组未观察到。所有化学物质对造血系统都有影响，其中乙酸烯丙酯的影响最明显。当剂量受到毒性限制时，乙酸烯丙酯和烯丙醇产生的尿巯基尿酸水平高于最低毒性剂量的丙烯醛。这一观察结果可能是由于吸收后乙酸烯丙酯和烯丙醇生物转化为丙烯醛，表明这些化学物质是增加丙烯醛全身暴露的原氧化剂。丙烯醛全身暴露量增加可能是这些化学品观察到的肝脏毒理学特征差异的原因。
Allyl acetate (AAC), allyl alcohol (AAL), and acrolein (ACR) are used in the manufacture of detergents, plastics, pharmaceuticals, and chemicals and as agricultural agents. A metabolic relationship exists between these chemicals in which allyl acetate is metabolized to allyl alcohol and subsequently to the highly reactive,α,β-unsaturated aldehyde, acrolein. Due to the weaker reactivity of the protoxicants, allyl acetate and allyl alcohol, relative to acrolien we hypothesized the protoxicants would attain greater systemic exposure and therefore deliver higher doses of acrolein to the internal organs. By extension, the higher systemic exposure to acrolein we hypothesized should lead to more internal organ toxicity in the allyl acetate and allyl alcohol treated animals relative to those treated with acrolein. To address our hypothesis we compared the range of toxicities produced by all three chemicals in male and female Fischer 344/N rats and B6C3F1 mice exposed 5 days a week for 3 months by gavage in 0.5% methylcellulose. Rats (10/group) were dosed with 0 to 100 mg/kg allyl acetate, 0 to 25 mg/kg allyl alcohol, or 0 to 10 mg/kg acrolein. Mice (10/group) were dosed with 0 to 125 mg/kg allyl acetate, 0 to 50 mg/kg allyl alcohol, or 0 to 20 mg/kg acrolein. The highest dose of allyl acetate and acrolein decreased survival in both mice and rats. The primary target organ for the toxicity of all three chemicals in both species and sexes was the forestomach; squamous epithelial hyperplasia was observed following exposure to each chemical. In both species the highest allyl acetate dose group exhibited forestomach epithelium necrosis and hemorrhage and the highest dose of acrolein led to glandular stomach hemorrhage. Liver histopathology was the most apparent with allyl acetate, was also observed with allyl alcohol, but was not observed with acrolein. All chemicals had effects on the hematopoietic system with allyl acetate having the most pronounced effect. When dosed at quantities limited by toxicity, allyl acetate and allyl alcohol produce higher levels of urinary mercapturic acids than the minimally toxic dose of acrolein. This observation is likely due to biotransformation of allyl acetate and ally alcohol to acrolein that occurs after absorption and suggests that these chemicals are protoxicants that increase systemic exposure of acrolein. Increased systemic exposure to acrolein is likely responsible for the differences in hepatic toxicological profile observed with these chemicals.
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