Analysis of Historical Control Litter Parameters of Reproduction Toxicity Studies in Sprague-Dawley Derived Rats

Nishimura, Michiyo; Kast, A

doi:10.1538/expanim1978.38.2_127

Cited by 4 publications

(3 citation statements)

References 5 publications

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“…1987.Usually, females of about 12 weeks old at mating are used in reproduction studies. These young dams have a fertility rate well above 90% and a pregnancy rate of nearly 100% (Nishimura & Kast 1989) and approximately correspond with women in their teenage. However, results in young dams may not reflect the situation in women above 35 years old, when the risks of adverse pregnancy outcome are increased (Hook 1985).…”

Section: Accepted 25 February 1993mentioning

confidence: 99%

Maternal age, reproduction and chromosomal aberrations in Wistar derived rats

Niggeschulze

Kast

1994

Lab Anim

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SummaryThe fertility of rats ranges from one to 18 months. In standard teratogenicity testing young, mature females are used which may not reflect the situation in women above 35 years old. Reproduction among different age groups of Wistar ats (strain Chbb : THOM) was compared at 3, 6, 9, 12, 15 and 18 months. At least 20 virgin females were inseminated per age group. The copulation rate did not differ between the groups. From the maternal age of 12 months, the pregnancy rate was significantly decreased, from the age of 9 months, the litter values were significantly lowered and the resorption rates were increased. Maternal age did not influence the incidence of fetal variations and malformations. Additionally, the chromosomal aberration rate in the bone marrow was evaluated in male and female rats. Twelve animals of each sex were scheduled per group, and studied at the age of I, 3, 6, 12, 15, 18, 21 or 24 months. In males, the aberration rate increased continuously from 0.18 through 3%, while in females the increase continued from 0.33 to 2.29% at 15 months old when a plateau was reached. When testing new compounds for embryotoxicity or genotoxicity in female rats, the animals should be of comparable age to man in order to avoid a misinterpretation of spontaneous abnormalities. From these studies, however, it was concluded that the use of higher age groups of female rats in teratogenicity studies would not improve the risk assessment.

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Section: Accepted 25 February 1993mentioning

confidence: 99%

Maternal age, reproduction and chromosomal aberrations in Wistar derived rats

Niggeschulze

Kast

1994

Lab Anim

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“…The incidence or means and standard deviations of maternal and fetal observations were calculated and analyzed (Dunnett, 1955;Gad and Weil, 1988). Calculations and statistical analyses of caesarean-section and fetal parameters were performed using the litter as the unit of analysis (Haseman and Hogan, 1975;Nishimura and Kast, 1989). Maternal body weights and maternal body weight gains, uterine weights, calculated daily maternal food consumption (rats only), and fetal body weights were analyzed by one-way analysis of variance.…”

Section: Discussionmentioning

confidence: 99%

Developmental toxicity studies of 2-(difluoromethyl)-dl-ornithine (DFMO) in rats and rabbits

Kirchner

Mercieca²,

Crowell³

et al. 1999

Toxicological Sciences

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DFMO, an irreversible inhibitor of ornithine decarboxylase (ODC), is under development as a chemopreventive drug against cancers with pronounced proliferative phases. In support of human clinical trials, preclinical developmental toxicity studies were conducted in pregnant rats and rabbits. Rats were treated during GD 6-17, and fetuses were obtained by C-section on GD 20. Rabbits were treated during GD 7-20, and fetuses were obtained by C-section on GD 29. The dose range-finding study in rats (5/group at 0, 50, 125, 300, 800, or 1000 mg/kg/day) revealed maternal toxicity at doses > or = 800 mg/kg/day (decreased body weights and food consumption) and developmental toxicity at doses > or = 300 mg/kg/day (increased early resorptions and reduced fetal body weights). In the main study, rats (25/group) received 0, 30, 80, or 200 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 200 mg/kg/day as significantly decreased fetal weights and increased incidence of litters with skeletal variations of 14th rudimentary rib, 14th full rib, and/or 27th presacral vertebrae. There were no treatment-related fetal skeletal malformations or external or visceral anomalies at any dose level. The dose range-finding study in rabbits (5/group at 0, 30, 60, 120, 240, or 500 mg/kg/day) revealed developmental toxicity at doses > or = 60 mg/kg/day (increased resorptions and reduced fetal body weights) in the absence of maternal toxicity. In the main study, rabbits (20/group) received 0, 15, 45, or 135 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 135 mg/kg/day as nonsignificantly increased early resorptions, decreased implantation sites, decreased viable fetuses, and reduced fetal weights. There were no external, visceral, or skeletal anomalies at any dose level. Thus, in the main developmental toxicity studies, DFMO produced developmental but not maternal toxicity at 200 and 135 mg/kg/day in rats and rabbits, respectively. Accordingly, in rats, the maternal no-observable-effect level (NOEL) was 200 mg/kg/day and the fetal NOEL was 80 mg/kg/day; while in rabbits the maternal NOEL was 135 mg/kg/day and the fetal NOEL was 45 mg/kg/day. These fetal NOELs are several-fold higher than the dose level currently used in Phase II and III clinical trials (approximately 13 mg/kg).

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“…In der mittleren Dosis gab es drei Weibchen mit toten Würfen und in der höchsten Dosisgruppe elf, so dass dosisabhängig der Anteil an toten Feten zunahm. Die Inzidenzen für die fetale Mortalität in der Kontrolle fehlen im Registrierungsdossier, aber Analysen historischer Kontrollen zeigen, dass fetale Mortalität im Gegensatz zu Resorptionen zu den seltenen Effekten zählen [28,29] Während der Laktation traten bei den Nachkommen ab der mittleren Dosis vermehrt adverse klinische Befunde auf, die einem Mangel an mütterlicher Fürsorge zugeschrieben wurden: unterkühlte Jungtiere, Dehydrierung, Hypoaktivität und dünnes Erscheinungsbild.…”

Section: Reproduktions-und Entwicklungstoxizitätunclassified

Richtwerte für Acetophenon in der Innenraumluft

2022

Bundesgesundheitsbl

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Analysis of Historical Control Litter Parameters of Reproduction Toxicity Studies in Sprague-Dawley Derived Rats

Cited by 4 publications

References 5 publications

Maternal age, reproduction and chromosomal aberrations in Wistar derived rats

Maternal age, reproduction and chromosomal aberrations in Wistar derived rats

Developmental toxicity studies of 2-(difluoromethyl)-dl-ornithine (DFMO) in rats and rabbits

Richtwerte für Acetophenon in der Innenraumluft

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