Supernumerary ribs in developmental toxicity bioassays and in human populations: Incidence and biological significance

Supernumerary or accessory ribs (SNR), either lumbar (LR) or cervical (CR), are a common finding in standard developmental toxicology bioassays. The biological significance of these anomalies within the regulatory arena has been problematic and the subject of some debate. In rodents, the spontaneous incidence of SNR is species and strain related and ranges from <1% to >30%. Compound-induced LR are induced by a wide variety of chemical and physical agents when pregnant animals are exposed during specific gestational periods. A significant portion of the agent-induced LR may be due to maternal factors, as it has been shown that stress alone will induce LR in rodents. SNR are not isolated phenomena and signify basic alterations in the architecture of the axial skeleton. LR are associated with longer ribs, increased numbers of vertebrosternal ribs, and the presence of extra presacral vertebrae ("anteriorization"). CR are associated with reduced numbers of vertebrosternal ribs ("posteriorization"). It is evident that SNR are not a single anomaly, but consist of two unrelated structures: an extra rib that has a cartilaginous segment at the distal end, and an ossification site that lacks cartilage. These have a bimodal size distribution, with the population of extra ribs being significantly longer than the ossification sites, and 0.6 mm can be used as an approximate length for distinguishing the two populations in mice. Extra ribs are permanent structures in contrast to ossification sites that disappear postnatally, probably becoming part of the lateral transverse vertebral processes. SNR are also found in humans although, in contrast to laboratory species, CR are more commonly noted. SNR are associated with adverse heath effects, and CR with inducing thoracic outlet disease characterized by diminished blood flow and altered position of the ganglia and nerve roots in the area of the C7-T1 vertebrae. LR are associated with lower back pain and L4-5 degeneration. The incidence of CR is greatly reduced in adult humans as compared to fetuses, and it has been hypothesized that fetal "SNR" may be largely composed of ossification sites that disappear postnatally. The mechanisms involved in the formation of extra ribs are not understood at this time, although the fact that the early sensitive periods for their initiation during embryogenesis is coupled with the associated changes in the axial skeleton argues for their induction being due to fundamental changes in gene expression. The sum of the experimental evidence supports the idea of SNR being composed of two different structures: extra ribs that are permanent dysmorphological structures that may be induced by xenobiotics and/or maternal stress, and ossification sites that may be transient variations in the formation of the lateral processes of the vertebrae.