Reiss Richard, Gaylor David
Sciences International, Inc., Alexandria, VA 22304, USA.
Regul Toxicol Pharmacol. 2005 Oct;43(1):55-65. doi: 10.1016/j.yrtph.2005.06.012.
A meta-analysis of several rat toxicity studies for dimethoate was conducted to determine the most sensitive endpoint for use in risk assessment. The analysis was motivated by a recent developmental neurotoxicity (DNT) study, which identified the same no observed adverse effect level (NOAEL) for pup mortality and cholinesterase inhibition. The pup mortality NOAEL was lower than that determined in a range-finding study for the DNT and other reproduction studies, and was highly influenced by a single total litter loss in the middle dose group, which made interpretation difficult. First, a meta-analysis was conducted of four recent studies by gavage dosing with very similar designs, including the DNT. Benchmark dose (BMD) modeling was used to determine the appropriate point of departure for regulatory purposes, the lower limit of the BMD for a 5% incidence for pup mortality (BMDL(5)) and the lower limit of a 10% inhibition of brain cholinesterase (BMDL(10)), the asterisk denotes that the BMD is based on continuous response variable as opposed to an incidence level. For pup mortality, the BMDL(5) for post-natal days (PND) 1-4 was 0.64 mg/kg/day. For cholinesterase inhibition, the lowest BMDL(10) was 0.19 mg/kg/day for the dams at gestation day 20. These results show that the regulatory point-of-departure for cholinesterase inhibition is more than threefold lower than pup mortality. Thus, risk assessments protecting against cholinesterase inhibition are likely to also be protective of pup mortality. In addition, cholinesterase inhibition and pup mortality were evaluated in two 2-generation reproduction studies by dietary exposure. Also, cholinesterase inhibition was evaluated in a 28-day dietary study. Dietary exposure is more relevant than gavage exposures for many human risk assessment scenarios. There was no consistent pup mortality at the highest doses of the two 2-generation dietary studies (6.0 and 6.5mg/kg/day). The average BMD(10)s for brain cholinesterase inhibition for the 2-generation studies was 0.65 mg/kg/day, with a range of 0.49--0.96 mg/kg/day. This suggests that cholinesterase inhibition is at least a 10-fold more sensitive endpoint than pup mortality for dietary exposures. For the 28-day dietary study, the BMD(10) for brain cholinesterase inhibition was 1.1mg/kg/day for males and 0.70 mg/kg/day for females. The exposure duration in the 28-day dietary study is closest to the durations in the gavage studies. Compared to the dams in the gavage studies, which had a BMDL(10) of 0.19 mg/kg/day, the animals were more than threefold more sensitive to cholinesterase inhibition by gavage compared to dietary exposure.
对几种乐果大鼠毒性研究进行了荟萃分析，以确定用于风险评估的最敏感终点。该分析是受最近一项发育神经毒性（DNT）研究的推动，该研究确定了幼崽死亡率和胆碱酯酶抑制的相同未观察到有害作用水平（NOAEL）。幼崽死亡率的NOAEL低于DNT和其他生殖研究的剂量探索研究中确定的水平，并且受到中剂量组一次总窝仔丢失的高度影响，这使得解释变得困难。首先，对包括DNT在内的四项设计非常相似的近期灌胃给药研究进行了荟萃分析。采用基准剂量（BMD）建模来确定监管目的的适当起始点，即幼崽死亡率5%发生率的BMD下限（BMDL(5)）和脑胆碱酯酶10%抑制的下限（BMDL(10)*），星号表示该BMD基于连续反应变量而非发生率水平。对于幼崽死亡率，出生后第1 - 4天的BMDL(5)为0.64 mg/kg/天。对于胆碱酯酶抑制，妊娠第20天母鼠的最低BMDL(10)*为0.19 mg/kg/天。这些结果表明，胆碱酯酶抑制的监管起始点比幼崽死亡率低三倍多。因此，预防胆碱酯酶抑制的风险评估可能也能保护幼崽死亡率。此外，在两项两代生殖研究中通过饮食暴露评估了胆碱酯酶抑制和幼崽死亡率。并且，在一项28天的饮食研究中评估了胆碱酯酶抑制。对于许多人类风险评估情况，饮食暴露比灌胃暴露更相关。在两项两代饮食研究的最高剂量（6.0和6.5mg/kg/天）下没有一致的幼崽死亡率。两代研究中脑胆碱酯酶抑制的平均BMD(10)为0.65 mg/kg/天，范围为0.49 - 0.9
