Chahoud Ibrahim, Paumgartten Francisco J R
Institute of Clinical Pharmacology and Toxicology, Charité University Medical School Berlin, Campus Benjamin Franklin, Garystrabetae 5, 14195 Berlin, Germany.
Environ Res. 2009 Nov;109(8):1021-7. doi: 10.1016/j.envres.2009.07.015. Epub 2009 Sep 16.
The standardization of rodent litter sizes (or culling) in reproductive toxicity studies has become a common practice because it is believed that litter size affects pup postnatal growth and development. A claim has also been made that culling on postnatal day 4 or earlier reduces litter-size-induced variability in the pup growth thereby making statistical detection of toxic effects more sensitive. Although these statements remain controversial, culling has been either recommended or considered optional in current proposals for new OECD guidelines for reproductive/developmental toxicity testing. This study was undertaken to provide data useful for a discussion on the need for culling in reproductive toxicity testing. Along this line, we investigated the effects of rat litter size on maternal body weight gain during pregnancy and lactation as well as on pup growth, somatic maturation and survival to weaning (PND 21). Two-hundred-forty-one untreated pregnant rats (Wistar, Bor:spf, TOR) delivered litters with 1-13 pups, being 10 the most frequent (24%) litter size. Pup mortality was 5.4%, 3.0% and 0.4% in the first, second and third postnatal weeks, respectively. Maternal and pup body weight gains, and the day of appearance of milestones of somatic maturation (fur development, incisor eruption and eye opening) were examined in a subset of litters/mothers (N=180) in which all pups survived to PND 21. An inverse relationship between litter size and pup body weight was found on day of birth (PND 1) and thereafter until PND 21. Delays in the attainment of maturational milestones as litter size increases were also found. These observations indicated that the rate of growth and development of rat pups during suckling period is dependent on the litter size. The consequences of litter-size standardization in toxicity studies are discussed in the light of these findings. Alternative procedures to attenuating litter-size-induced variability in pup growth or its impact on toxicity data evaluation are presented as well.
在生殖毒性研究中对啮齿动物窝仔数进行标准化（或剔除）已成为一种常见做法，因为人们认为窝仔数会影响幼崽出生后的生长和发育。还有人声称，在出生后第4天或更早进行剔除可减少窝仔数引起的幼崽生长变异性，从而使对毒性作用的统计检测更加灵敏。尽管这些说法仍存在争议，但在经合组织新的生殖/发育毒性测试指南的当前提案中，剔除已被推荐或视为可选项。本研究旨在提供数据，以有助于讨论生殖毒性测试中进行剔除的必要性。为此，我们研究了大鼠窝仔数对孕期和哺乳期母鼠体重增加以及对幼崽生长、身体成熟和断奶存活（出生后第21天）的影响。241只未经处理的怀孕大鼠（Wistar，Bor:spf，TOR）产下的窝仔数为1 - 13只，其中10只为最常见的窝仔数（24%）。幼崽死亡率在出生后的第一、第二和第三周分别为 5.4%、3.0%和0.4%。在一部分所有幼崽均存活至出生后第21天的窝仔/母鼠（N = 180）中，检查了母鼠和幼崽的体重增加情况，以及身体成熟里程碑（毛发生长、门齿萌出和睁眼）出现的天数。在出生当天（出生后第1天）及之后直至出生后第21天，发现窝仔数与幼崽体重呈负相关。还发现随着窝仔数增加，达到成熟里程碑的时间会延迟。这些观察结果表明，哺乳期大鼠幼崽的生长和发育速度取决于窝仔数。根据这些发现，讨论了毒性研究中窝仔数标准化的后果。还提出了减少窝仔数引起的幼崽生长变异性或其对毒性数据评估影响的替代方法。
