Historical control data on developmental toxicity studies in rats

Abstract

Historical control data from prenatal developmental toxicity studies in rats have been used to evaluate whether toxicology outcomes were induced by exposure to a chemical or were within the range of spontaneous variation. These data are also important for monitoring animal characteristics. As a follow-up to historical control data from 1998 to 2010, this study analyzed control data from prenatal developmental studies performed in rats from 2011 to 2015. Data were collected from studies performed by 24 Japanese laboratories, including 15 pharmaceutical and chemical companies and nine contract research organizations, in Sprague-Dawley and two-sub-strains of Wistar Hannover rats. The data included maternal reproductive findings at terminal cesarean section and fetal findings, including incidences of spontaneous external, visceral, and skeletal anomalies. No noticeable differences in maternal reproductive data were observed among laboratories. The inter-laboratory variations in the incidences of fetal anomalies seemed to be due to differences in the selection of observation parameters, observation criteria, and classification of the findings, as well as to differences in terminology of fetal alterations. These historical control data may be helpful for adequate interpretation of experimental results and for evaluating the reproductive and developmental toxicities of various chemicals.

5-Fluorocytosine induces fetal skeletal malformations in rats by altering expression of Homeobox genes

“…Their incidence in humans is 3-7% (Nakajima et al, 2014), whereas their incidence among animals differs according to species and strains. For example, the rates of full and short TSR were 1.10% and 8.45%, respectively, in Sprague Dawley (SD) rats, but 2.97% and 49.93%, respectively, in Wistar Hannover (Wistar Han) rats (Kuwagata et al, 2018b), similar to previous findings (Aoyama et al, 2002;Noritake et al, 2013;Ema et al, 2014).…”

Absence of developmental and reproductive toxicity in animals exposed to dolutegravir

“…Considered unrelated to DTG, 1 of 285 pups at 1,000 mg/kg/day (Table ) was noted as having meningocele and an absent eye bulge at birth. These findings were not considered DTG‐related as this was the only newborn with any type of malformation and because similar observations did not occur among offspring gestationally exposed to 1,000 mg/kg/day DTG during the major period of organogenesis in the rat dose range (0 of 95 fetuses) or EFD studies (0 of 285 fetuses), resulting in an overall incidence of 1 of 665 fetal exposures (Table ), and it is well within the historical control background of this strain of rat (Kuwagata et al, ).…”

“…At 1,000 mg/kg/day, one multiply malformed fetus had anasarca, and other malformations involving the heart and great vessels including persistent atrioventricular canal, ventricular septal defect (VSD), and overriding aorta, as well as a malpositioned testis. Observation of anasarca was not considered DTG‐related due to lack of dose–response and because the pattern of malformations was different at both 300 and 1,000 mg/kg/day, and similar background incidences (0–0.4%) have been observed in this strain of rat (Kuwagata et al, ). Another fetus at 1,000 mg/kg/day had an isolated VSD without any effects on great vessels and one fetus from a different litter had an interrupted aortic arch.…”

Induction of a thoracolumbar supernumerary rib in rat developmental toxicity studies: A short discussion on the critical window

“…Understanding the toxicological characteristics of these anomalies is important to determine whether these anomalies indicate a chemical‐induced developmental toxicity or a spontaneous finding. Thoracolumbar supernumerary ribs (TSRs) have been classified as less severe skeletal anomalies, with a relatively high spontaneous incidence in rat fetuses . Current historical control data in Japan have shown that the spontaneous incidence of TSR is 0.09% to 15.1% in Sprague‐Dawley (SD) rats, and 17.8% to 58.1% in Wistar Hannover rats .…”

“…Thoracolumbar supernumerary ribs (TSRs) have been classified as less severe skeletal anomalies, with a relatively high spontaneous incidence in rat fetuses . Current historical control data in Japan have shown that the spontaneous incidence of TSR is 0.09% to 15.1% in Sprague‐Dawley (SD) rats, and 17.8% to 58.1% in Wistar Hannover rats . TSR can also be induced in rodent fetuses by maternal stress, maternal hypoglycemia, and exposure to chemicals and herbs during pregnancy .…”