Chemically induced supernumerary lumbar ribs in CD‐1 mice: Size distribution and dose response

Abstract

Supernumerary ribs (SNR) of differing sizes are commonly observed in rodent developmental toxicity studies, and the significance of treatment-related increases in SNR in standard studies has been contentious. We induced dose-related increases in SNR in fetal CD-1 mice by treating on gestation days 7-8 with benomyl (BEN; 0, 75, 150 mg/kg/d), dinoseb (DIN; 0, 30, 50 mg/kg/d); 2-methoxyethanol (2-ME; 0, 75, 150 mg/kg/d), or valproic acid (VPA; 0, 125, 250 mg/kg/d). Incidences of SNR were 9.3-27.6% in controls and 19.3-84.4% in the high dosage groups. SNR length showed a bimodal distribution with peaks at 0.3-0.4 mm and 0.9-1.1 mm in both treated and control groups. Based on length distributions, we used an actual length of 0.6 mm to separate short (rudimentary) from long (extra) SNR. DIN, 2-ME, and VPA induced a dose-related increase of extra ribs, while the incidence of rudimentary ribs remained at control levels. There was no apparent correlation of the presence of either type of SNR in a fetus and the occurrence of other anomalies. These data support the idea that extra and rudimentary SNR may reflect separate developmental phenomena, and should be considered and reported separately in developmental toxicity studies for risk assessment.

Developmental Toxicity of Nitrophenolic Herbicide Dinoseb, 2-Sec-Butyl-4,6-Dinitrophenol

“…The authors suggested that supernumerary ribs are indicative of basic alterations in the development of the axial skeleton (Branch et al, 1996). A similar study conducted by Rogers et al (2004) revealed a dose-related increased incidence of mouse fetuses with supernumerary ribs following maternal administration of dinoseb in NaOH at 50 mg/kg bw/day on GDs 7-8 and suggested that increased incidence of supernumerary ribs in fetuses is toxicologically significant. Skeletal anomalies such as sternum or vertebral centrum defects and fused ribs were also detected in fetuses of mice given dinoseb on GDs 7-8 at 50 mg/kg bw/day in NaOH.…”

“…In mice, gavage dosing of dinoseb during organogenesis induced skeletal variations and growth retardation at or above maternally toxic levels (26-50 mg/kg bw/day) (Branch et al, 1996;Kavlock et al, 1985). Teratogenic effects were observed without maternal toxicity at 50 mg/kg bw/day by gavage in CD-1 mice (Rogers et al, 2004). Doses of dinoseb in rats during organogenesis induced skeletal variations and growth retardation at maternally toxic levels (8.0-20 mg/kg bw/day) by gavage and (6.52-15 mg/kg bw/day) by feeding (Giavini et al, 1986;Matsumoto et al, 2010).…”

“…Skeletal anomalies such as sternum or vertebral centrum defects and fused ribs were also detected in fetuses of mice given dinoseb on GDs 7-8 at 50 mg/kg bw/day in NaOH. Although the treatment regimes of Branch et al (1996) and Rogers et al (2004) were essentially the same, they obtained different developmental effects in fetuses of mice given dinoseb at 50 mg/kg bw/day. Rogers et al (2004) used 25 pregnant mice.…”

“…Although the treatment regimes of Branch et al (1996) and Rogers et al (2004) were essentially the same, they obtained different developmental effects in fetuses of mice given dinoseb at 50 mg/kg bw/day. Rogers et al (2004) used 25 pregnant mice. On the other hand, Branch et al (1996) used only two pregnant mice, which is too few to evaluate the developmental toxicity.…”

“…A dose of 32 mg/kg bw/day dinoseb during GDs 13-15 induced absent or not ossified sternebrae. The dose levels that caused these adverse effects in fetuses were also lethal to some dams (Gibson, 1973 CD-1 mouse 26, 33 mg/kg GD 7 Supernumerary ribs (Kavlock et al, 1985) CD-1 mouse 50 mg/kg GDs 7-8 Supernumerary ribs, ↓fetal weight (Branch et al, 1996) CD-1 mouse 50 mg/kg GDs 7-8 Supernumerary ribs, sternum and (Rogers et al, 2004) vertebral …”