Moser V C, Phillips P M, Levine A B, McDaniel K L, Sills R C, Jortner B S, Butt M T
Neurotoxicology Division, NHEERL/ORD, US Environmental Protection Agency, Research Triangle Park, North Carolina, 27711, USA.
Toxicol Sci. 2004 May;79(1):112-22. doi: 10.1093/toxsci/kfh081. Epub 2004 Feb 19.
An evaluation of potential adverse human health effects of disinfection byproducts requires study of both cancer and noncancer endpoints; however, no studies have evaluated the neurotoxic potential of a common haloacetic acid, dibromoacetic acid (DBA). This study characterized the neurotoxicity of DBA during 6-month exposure in the drinking water of rats. Adolescent male and female Fischer 344 rats were administered DBA at 0, 0.2, 0.6, and 1.5 g/l. On a mg/kg/day basis, the consumed dosages decreased greatly over the exposure period, with average intakes of 0, 20, 72, and 161 mg/kg/day. Weight gain was depressed in the high-concentration group, and concentration-related diarrhea and hair loss were observed early in exposure. Testing with a functional observational battery and motor activity took place before dosing and at 1, 2, 4, and 6 months. DBA produced concentration-related neuromuscular toxicity (mid and high concentrations) characterized by limb weakness, mild gait abnormalities, and hypotonia, as well as sensorimotor depression (all concentrations), with decreased responses to a tail-pinch and click. Other signs of toxicity at the highest concentration included decreased activity and chest clasping. Neurotoxicity was evident as early as one month, but did not progress with continued exposure. The major neuropathological finding was degeneration of spinal cord nerve fibers (mid and high concentrations). Cellular vacuolization in spinal cord gray matter (mostly) and in white matter (occasionally) tracts was also observed. No treatment-related changes were seen in brain, eyes, peripheral nerves, or peripheral ganglia. The lowest-observable effect level for neurobehavioral changes was 20 mg/kg/day (produced by 0.2 g/l, lowest concentration tested), whereas this dosage was a no-effect level for neuropathological changes. These studies suggest that neurotoxicity should be considered in the overall hazard evaluation of haloacetic acids.
对消毒副产物潜在的人类健康不良影响进行评估需要同时研究癌症和非癌症终点；然而，尚无研究评估常见卤乙酸二溴乙酸（DBA）的神经毒性潜力。本研究对大鼠饮用水中6个月暴露期内DBA的神经毒性进行了表征。给青春期雄性和雌性Fischer 344大鼠分别给予浓度为0、0.2、0.6和1.5 g/l的DBA。以mg/kg/天为基础，在暴露期间摄入剂量大幅下降，平均摄入量分别为0、20、72和161 mg/kg/天。高浓度组体重增加受到抑制，且在暴露早期观察到与浓度相关的腹泻和脱发。在给药前以及给药后1、2、4和6个月进行了功能性观察组合测试和运动活动测试。DBA产生了与浓度相关的神经肌肉毒性（中浓度和高浓度），其特征为肢体无力、轻度步态异常和肌张力减退，以及感觉运动抑制（所有浓度），对夹尾和点击的反应减弱。最高浓度下的其他毒性迹象包括活动减少和抱胸。神经毒性早在1个月时就很明显，但并未随着持续暴露而进展。主要的神经病理学发现是脊髓神经纤维变性（中浓度和高浓度）。还观察到脊髓灰质（主要）和白质（偶尔）束中的细胞空泡化。在脑、眼、外周神经或外周神经节中未观察到与治疗相关的变化。神经行为变化的最低可观察效应水平为20 mg/kg/天（由0.2 g/l产生，为测试的最低浓度），而该剂量对神经病理学变化为无效应水平。这些研究表明，在对卤乙酸进行总体危害评估时应考虑神经毒性。
