Slikker W, Scallet A C, Gaylor D W
Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR 72079-9502, USA.
Toxicol Lett. 1998 Dec 28;102-103:429-33. doi: 10.1016/s0378-4274(98)00335-x.
Domoic acid is a tricarboxylic amino acid that is structurally-related to kainic acid and glutamic acid. It is produced by phytoplankton that may contaminate seafood. To determine domoate's toxicological effects and their pathogenesis, cynomolgus monkeys were dosed intravenously at one of a range of bolus doses from 0.25 to 4.0 mg/kg. Histochemical staining, using silver methods, revealed degenerating axons and cell bodies. Doses in the range of 0.5-1.0 mg/kg produced a small area of silver grains restricted to axons of the hippocampal CA2 stratum lucidum, the most sensitive brain area identified. Quantitation of the abundance of these silver grains yielded continuous dose-response data. A four step quantitative risk estimation approach was used: (1) determination of a dose-response model; (2) determination of the distribution of measurements (variability) about the model; (3) determination of an adverse or abnormal level with the use of the control data; and (4) estimation of the probability that a measure is beyond the abnormal level as a function of dose. The currently used safety-factor (S-F) approach, the benchmark (BM) approach and this quantitative (Q) approach was used to assess the same data set. Assuming a 5% oral absorption of domoic acid, acceptable doses would be achieved if subjects ate 200 g of seafood containing 12, 6 and 10 ppm domoic acid for the S-F, BM and Q approaches, respectively. This quantitative approach uses all the available data, takes into account the variability of the data and provides an actual risk at a given dose of domoic acid.
软骨藻酸是一种三羧酸氨基酸，其结构与 kainic 酸和谷氨酸相关。它由可能污染海产品的浮游植物产生。为了确定软骨藻酸酯的毒理学效应及其发病机制，对食蟹猴静脉注射 0.25 至 4.0 mg/kg 一系列大剂量中的一种。使用银染法进行组织化学染色，显示出轴突和细胞体退变。0.5 - 1.0 mg/kg 范围内的剂量在海马 CA2 透明层轴突处产生一小片银颗粒区域，这是已确定的最敏感脑区。对这些银颗粒丰度进行定量得出连续的剂量反应数据。采用了四步定量风险评估方法：(1) 确定剂量反应模型；(2) 确定围绕模型的测量分布（变异性）；(3) 使用对照数据确定不良或异常水平；(4) 估计作为剂量函数的测量值超出异常水平的概率。使用当前使用的安全系数 (S - F) 方法、基准 (BM) 方法和这种定量 (Q) 方法对同一数据集进行评估。假设软骨藻酸的口服吸收率为 5%，对于 S - F、BM 和 Q 方法，若受试者分别食用 200 g 含有 12 ppm、6 ppm 和 10 ppm 软骨藻酸的海产品，将达到可接受剂量。这种定量方法使用了所有可用数据，考虑了数据的变异性，并提供了给定剂量软骨藻酸时的实际风险。
