Effects of di-n-butyl phthalate (DBP) on male reproductive development in the rat:: Implications for human risk assessment
Effects of di-n-butyl phthalate (DBP) on male reproductive development in the rat:: Implications for human risk assessment
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DOI：
10.1016/s0278-6915(99)00128-3
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发表时间：
2000-04-01
影响因子：
4.3
通讯作者：
Mylchreest, E
中科院分区：
文献类型：
--
作者：
Foster, PMD;Cattley, RC;Mylchreest, E
国家毒理学计划（NTP）在SD大鼠中进行了一项连续繁殖研究，通过饲料给予邻苯二甲酸二正丁酯（DBP），剂量水平高达650 mg/kg/天。在亲代中，对繁殖的影响是适度的（给药后窝仔数和幼仔体重略有下降）。然而，FI雄性后代的生育力显著降低（650 mg/kg/天），达到成年后精子计数减少和生殖道畸形。本研究未确定无可见不良作用水平（NOAEL）[最低可见不良作用水平（LOAEL）66 mg/kg/天]。在CIIT进行的一项研究中，这些不良变化中的大多数可以在相似的剂量范围内重现，但给药方案要短得多，涵盖了关键的发育窗口期（妊娠第12-20天）。DBP的默认风险评估表明参考剂量（RfD）为66 μ g/kg/天，基于LOAEL为66 mg/kg/天，种间和个体间差异的默认因子为10，且无NOAEL。人类接触数据将表明在参考剂量范围内婴儿（通过配方奶粉）的最坏情况。默认风险评估似乎不合适，因为啮齿类动物与灵长类动物不同，经口给药后，邻苯二甲酸二酯（包括DBP）在肠道中广泛代谢为单酯。认为单酯是诱导特定邻苯二甲酸酯生殖和发育毒性的活性成分。因此，如果人类通过环境暴露于二酯产生极低水平的单酯，则通过口服途径产生任何生殖或发育毒性的可能性似乎极低。(C)2000爱思唯尔科技有限公司版权所有。
The National Toxicology Program (NTP) conducted a continuous breeding study in SD rats with di-n-butyl phthalate (DBP) given via the diet at dose levels of up to 650 mg/kg/day. In the parental generation effects on reproduction were modest (small decreases in litter size and pup weight following treatment). However, the FI male offspring had marked decreases in fertility (at 650 mg/kg/day), with reduced sperm counts and reproductive tract malformations on reaching adulthood. A no-observed-adverse-effect level (NOAEL) was not established for the study [lowest-observed-adverse-effect level (LOAEL) 66mg/kg/day]. In a study conducted at CIIT, the majority of these adverse changes could be reproduced over a similar dose range, but with a much shorter dosing regimen covering a critical window of development (gestation days 12-20). A default risk assessment for DBP indicates a reference dose (RfD) of 66 mu g/kg/day, based on a LOAEL of 66 mg/kg/day and default factors of 10 for inter-species and inter-individual differences and the lack of a NOAEL. Human exposure data would indicate worst-case scenarios to infants (via formula) in the dose range of the RfD. A default risk assessment appears to be inappropriate since rodents, unlike primates, metabolize phthalate diesters (including DBP) to monoesters extensively in the gut following oral administration. It is believed that the monoester is the active principle for induction of reproductive and developmental toxicity of specific phthalate esters. Thus, if humans produce very low levels of the monoester from an environmental exposure to the diester, the likelihood of any reproductive or developmental toxicity via the oral route appears extremely remote. (C) 2000 Elsevier Science Ltd. All rights reserved.