Clegg D J, van Gemert M
van Gemert & Hauswirth, L.L.C., Charlotte Hall, Maryland, USA.
J Toxicol Environ Health B Crit Rev. 1999 Jul-Sep;2(3):211-55. doi: 10.1080/109374099281179.
Chlorpyrifos is an extensively used organophosphate insecticide with numerous agricultural crop and urban pest control uses. Dow AgroSciences, one of the manufacturers of chlorpyrifos, convened a panel of toxicology and medical experts to consider the available scientific literature (both published papers and unpublished reports from Dow AgroSciences) on chlorpyrifos with respect to determining the acute and chronic toxicological reference doses (RfD) for chlorpyrifos. The most sensitive effect observed in the body of animal and human studies on chlorpyrifos is the inhibition of the various cholinesterases. In animal studies chlorpyrifos is not carcinogenic, teratogenic, or mutagenic. Reproductive toxicity studies indicate some effects on postnatal survival, but these effects were seen at doses higher than maternal toxic dose levels. There are no clinical signs of cholinergic toxicity below 70% inhibition of brain cholinesterase. Cognitive or behavioral defects are not observed until substantial brain cholinesterase inhibition occurs. There are no indications that chlorpyrifos caused delayed neurotoxicity at dose levels below twice the oral LD50. The panel members stated that plasma cholinesterase was an inappropriate endpoint for the RfD. They recommended that brain, erythrocyte cholinesterase depression and clinical signs were appropriate as endpoints for the RfD. Plasma cholinesterase should be used only as an indicator of exposure. After a thorough review of the experimental animal literature, it was determined that the chlorpyrifos repeated-exposure RfD based on application of a 100-fold uncertainty factor on the no observed adverse effects level (NOAEL) for brain cholinesterase inhibition or on a 10-fold uncertainty factor on the NOAEL for erythrocyte cholinesterase inhibition is 0.01 mg/kg/d. Based on the human volunteer studies, which indicate a repeated-dose NOAEL of 0.1 mg/kg/d for erythrocyte cholinesterase inhibition, and then using a 10-fold uncertainty factor, the RfD is again 0.01 mg/kg/d. In this human volunteer study on d 9 (last day) of administration, 1 individual in the 0.1 mg/kg/day dose group was removed from the study due to a "cold" (runny nose, blurred vision, and a feeling of faintness). He was asymptomatic 12 h later. To some degree this diagnosis is supported by the hematology, since lymphocyte counts were reduced and neutrophil counts were increased markedly, indicating a possible inflammatory reaction on d 8 of dosing, clearing by posttreatment d 5. In the absence of any indication of erythrocyte cholinesterase inhibition and with plasma cholinesterase inhibition being greater in two of the four other individuals treated at the same dose level, these signs and symptoms are unlikely to have been induced by cholinesterase inhibition. The panel concluded that the symptoms this individual displayed were not an appropriate endpoint for the RfD. The single-exposure reference dose can be based on the human data. No erythrocyte cholinesterase inhibition or clinical signs of toxicity were observed after a single oral dose of 0.5 mg/kg. Utilizing a 10-fold uncertainty factor, the single-dose RfD is 0.05 mg/kg.
毒死蜱是一种广泛使用的有机磷杀虫剂，在众多农作物和城市害虫防治中都有应用。毒死蜱的制造商之一陶氏益农公司召集了一个毒理学和医学专家小组，审议关于毒死蜱的现有科学文献（已发表论文和陶氏益农公司未发表的报告），以确定毒死蜱的急性和慢性毒理学参考剂量（RfD）。在关于毒死蜱的动物和人体研究中观察到的最敏感效应是对各种胆碱酯酶的抑制。在动物研究中，毒死蜱没有致癌性、致畸性或致突变性。生殖毒性研究表明对出生后存活有一些影响，但这些影响出现在高于母体毒性剂量水平的剂量下。在脑胆碱酯酶抑制低于70%时，没有胆碱能毒性的临床体征。直到脑胆碱酯酶受到大量抑制时才观察到认知或行为缺陷。没有迹象表明在低于口服半数致死剂量（LD50）两倍的剂量水平下毒死蜱会导致迟发性神经毒性。专家小组成员指出，血浆胆碱酯酶不适宜作为RfD的一个终点指标。他们建议脑、红细胞胆碱酯酶抑制和临床体征适宜作为RfD的终点指标。血浆胆碱酯酶仅应用作暴露指标。在对实验动物文献进行全面审查后，确定基于对脑胆碱酯酶抑制的未观察到有害作用水平（NOAEL）应用100倍不确定性系数或对红细胞胆碱酯酶抑制的NOAEL应用10倍不确定性系数，毒死蜱重复暴露的RfD为0.01毫克/千克/天。基于人体志愿者研究，该研究表明红细胞胆碱酯酶抑制的重复剂量NOAEL为0.1毫克/千克/天，然后使用10倍不确定性系数，RfD同样为0.01毫克/千克/天。在这项人体志愿者研究中，在给药第9天（最后一天），0.1毫克/千克/天剂量组中有1名个体因“感冒”（流鼻涕、视力模糊和头晕感）退出研究。12小时后他无症状了。从某种程度上讲，血液学检查支持这一诊断，因为淋巴细胞计数减少而中性粒细胞计数显著增加，表明在给药第8天可能有炎症反应，在治疗后第5天消退。在没有任何红细胞胆碱酯酶抑制迹象且在相同剂量水平接受治疗的其他四名个体中有两名的血浆胆碱酯酶抑制更严重的情况下，这些体征和症状不太可能是由胆碱酯酶抑制引起的。专家小组得出结论，该个体表现出的症状不适宜作为RfD的一个终点指标。单次暴露参考剂量可基于人体数据。单次口服0.5毫克/千克后未观察到红细胞胆碱酯酶抑制或毒性临床体征。利用10倍不确定性系数，单次剂量RfD为0.05毫克/千克。
