DeSesso J M, Jacobson C F, Scialli A R, Farr C H, Holson J F
Mitretek Systems, Inc., McLean, Virginia 22102, USA.
Reprod Toxicol. 1998 Jul-Aug;12(4):385-433. doi: 10.1016/s0890-6238(98)00021-5.
A critical analysis of the literature base regarding the reproductive and developmental toxicity of arsenic compounds, with emphasis on inorganic arsenicals, was conducted. The analysis was stimulated by the great number of papers that have purported to have shown an association between exposure of pregnant laboratory animals to arsenic compounds and the occurrence of offspring with cranial neural tube defects, particularly exencephaly. For the most part, the literature reports of arsenic developmental toxicity in experimental animals are inadequate for human risk assessment purposes. Despite the shortcomings of the experimental database, several conclusions are readily apparent when the animal studies are viewed collectively. First, cranial neural tube defects are induced in rodents only when arsenic exposure has occurred early in gestation (on Days 7 [hamster, mouse], 8 [mouse], or 9 [rat]). Second, arsenic exposures that cause cranial neural tube defects are single doses that are so high as to be lethal (or nearly so) to the pregnant animal. Third, the effective routes of exposure are by injection directly into the venous system or the peritoneal cavity; even massive oral exposures do not cause increases in the incidence of total gross malformations. Fourth, repetition of similar study designs employing exaggerated parenteral doses is the source of the large number of papers reporting neural tube defects associated with prenatal arsenic exposure. Fifth, in five repeated dose studies carried out following EPA Guidelines for assessing developmental toxicity, arsenic was not teratogenic in rats (AsIII, 101 micromol/kg/d, oral gavage; 101 micromol/m3, inhalation), mice (AsV, 338 micromol/kg/d, oral gavage; est. 402 micromol/kg/d, diet), or rabbits (AsV, 21 micromol/kg/d, oral gavage). Data regarding arsenic exposure and adverse outcomes of pregnancy in humans are limited to several ecologic epidemiology studies of drinking water, airborne dusts, and smelter environs. These studies failed to (1) obtain accurate measurements of maternal exposure during the critical period of organogenesis and (2) control for recognized confounders. The lone study that examined maternal arsenic exposure during pregnancy and the presence of neural tube defects in progeny failed to confirm a relationship between the two. It is concluded that under environmentally relevant exposure scenarios (e.g., 100 ppm in soil), inorganic arsenic is unlikely to pose a risk to pregnant women and their offspring.
对有关砷化合物生殖和发育毒性的文献库进行了批判性分析，重点关注无机砷。大量声称已表明怀孕实验动物接触砷化合物与出现患有颅神经管缺陷（尤其是无脑儿）的后代之间存在关联的论文激发了此次分析。在很大程度上，关于实验动物中砷发育毒性的文献报告对于人类风险评估而言并不充分。尽管实验数据库存在缺陷，但当对动物研究进行综合审视时，一些结论显而易见。首先，仅在妊娠早期（仓鼠、小鼠为第7天，小鼠为第8天，大鼠为第9天）接触砷时，啮齿动物才会诱发颅神经管缺陷。其次，导致颅神经管缺陷的砷暴露是单剂量且剂量高到足以对怀孕动物致死（或几乎致死）。第三，有效的暴露途径是直接静脉注射或腹腔注射；即使大量口服暴露也不会导致总体严重畸形发生率增加。第四，采用夸张的肠胃外剂量重复类似研究设计是大量报告与产前砷暴露相关的神经管缺陷的论文的来源。第五，在按照美国环境保护局评估发育毒性的指南进行的五项重复剂量研究中，砷对大鼠（三价砷，101微摩尔/千克/天，经口灌胃；101微摩尔/立方米，吸入）、小鼠（五价砷，338微摩尔/千克/天，经口灌胃；估计402微摩尔/千克/天，饮食）或兔子（五价砷，21微摩尔/千克/天，经口灌胃）均无致畸性。关于人类砷暴露与妊娠不良结局的数据仅限于几项关于饮用水、空气中灰尘和冶炼厂周边环境的生态流行病学研究。这些研究未能（1）在器官发生关键期准确测量母体暴露量，以及（2）控制公认的混杂因素。唯一一项研究孕妇孕期砷暴露与后代神经管缺陷情况的研究未能证实两者之间存在关联。结论是，在与环境相关的暴露情景下（例如土壤中100 ppm），无机砷不太可能对孕妇及其后代构成风险。
