目前的出版物描述了迄今为止尚未发表的(关键)指南和GLP兼容的碳酸锂在大鼠中的生殖和发育毒性研究,包括与现有文献相比,他们在人类危害评估方面的解释和结论。特别注意锂离子相关作用的靶器官和剂量反应,以区分主要(药代动力学/药效学)作用和全身性和靶器官毒性的次要作用。在大鼠的关键两代生殖毒性(OECDTG416)研究中,通过口服灌胃给予5、15和45mg/kgbw/d(0.95、2.9和8.6mgLi+/kgbw/d)的剂量,导致全身亲代毒性为15mg/kgbw/d(2.9mgLi/kgbw/d),生殖毒性和胎儿毒性为45mg/kgbw/d(8.6mgLi/kgbw/d)。在肝脏(细胞质稀疏)和肾脏(扩张的肾小管)中始终观察到靶器官的变化。在大鼠的关键发育毒性(OECDTG414)研究中,通过口服灌胃给予的剂量为10、30和90mg/kgbw/d(1.9、5.7和17.1mgLi/kgbw/d),导致NO(A)ELs为30mg/kgbw/d(5.7mgLi/kgbw/d)(母体毒性)和90mg/kgbw/d(17mgLi/kgbw/d)(胎儿毒性和致畸胎性)。最高剂量90mg/kgbw/天导致明显的毒性迹象和在毒性范围内的峰值血浆浓度(>1.0mEq锂/L)。在生殖和发育器官中未发现碳酸锂的毒性作用。对精子没有不良影响(总运动性,在两代大鼠生殖毒性研究中观察到睾丸和附睾尾精子的进行性运动和形态)。在这项研究中,对生育率指数或产仔数也没有影响,在两代生殖毒性和发育毒性研究中,也没有任何胎儿效应,在剂量下已经导致了大坝的全身毒性。在发育毒性研究中报告了次要作用,例如体重(增加)和食物消耗减少。在这些关键的哺乳动物研究中,在剂量水平上没有任何生殖/发育发现,导致试验动物明显的全身毒性,并不表示在药物使用过程中接触锂可能对人类生殖或发育毒性产生直接关注。
The current publication describes most recent so far unpublished (key)
guideline and GLP compliant reproductive and developmental toxicity studies of lithium carbonate in rats, including their interpretation and conclusions in terms of human hazard assessment when compared to existing literature. Particular attention was paid to the target organs and dose response of lithium ion related effects to differentiate between a primary (pharmacokinetic/pharmacodynamic) action and secondary effects as a result of systemic and target organ toxicity. In the key two-generation reproduction toxicity (OECD TG 416) study in rats, doses of 5, 15 and 45 mg/kg bw/d (0.95, 2.9 and 8.6 mg Li+/kg bw/d) were given by oral gavage, resulting in clear NOAELs of 15 mg/kg bw/d (2.9 mg Li+/kg bw/d) for systemic parental toxicity and 45 mg/kg bw/d (8.6 mg Li+/kg bw/d) for reproductive toxicity and fetal toxicity. Target organ changes were consistently observed in liver (cytoplasmic rarefaction) and kidney (dilated tubuli). In the key developmental toxicity (OECD TG 414) study in rats, doses given by oral gavage were 10, 30 and 90 mg/kg bw/d (1.9, 5.7 and 17.1 mg Li+/kg bw/d) was investigated resulting in NO(A)ELs of 30 mg/kg bw/d (5.7 mg Li+/kg bw/d) (maternal toxicity) and 90 mg/kg bw/d (17 mg Li+/kg bw/d) (fetal toxicity and teratogenicity). The highest dose of 90 mg/kg bw/day resulted in clear signs of toxicity and peak plasma concentrations at the toxic range (>1.0 mEq lithium/L). Toxic effects of lithium carbonate were not seen in the reproductive and developmental organs. No adverse effects on sperm (total motility, progressive motility and morphology of testicular and cauda epididymal sperm) were observed in the two-generation rat reproduction toxicity study. There was also no impact on fertility indices or on litter sizes in this study, nor were there any fetal effects in the two-generation reproduction toxicity and developmental toxicity study at doses causing already systemic toxicity in the dams. Secondary effects such as decreased weight (gain) and food consumption were reported in the developmental toxicity study. The absence of any reproductive/developmental findings at dose levels causing clear systemic toxicity in the test animals in these key mammalian studies, does not suggest an immediate concern for possible human reproductive or developmental toxicity effects from exposure to lithium during drug use.