Skeletal anomalies

A significant increase in the incidence of fetal soft-tissue and skeletal anomalies was seen following treatment of pregnant rats with HCDD at the 100 jug/kg/day dose level. The incidence of cleft palate, subcutaneous edema, vertebrae with split or unfused centra, and split sternebrae was significantly greater than among control litters or the control fetal popu-... 

Developmental Rat Gd7-17 (Wistar) (GO) 167 500 (20-25% decrease in fetal body weights increase in skeletal anomalies) Shimizu et al. 1992... 

Carbon tetrachloride was fetotoxic to rats when administered on days 6-15 of gestation at 300 or 1000 ppm, 7 hours/day an increase in skeletal anomalies due to delayed development was observed in the offspring. Signs of maternal toxicity included weight loss and hepatic damage. ... 

Intraperitoneal injection of lOmg/1 for 5 days to male rats caused a decrease in average litter size in females mated 3 weeks after exposure and no litters after 4 weeks. Continuous exposure to 32 ppm during gestation caused minor skeletal anomalies in rats and mice."... 

Even if there is little evidence that maternal toxicity (defined as reductions in maternal body weight) is consistently associated with major malformations, there is clear evidence that substantial reduction in maternal weight is linked with other manifestations of developmental toxicity. These manifestations include decreased fetal weights, and skeletal anomalies (e.g., wavy ribs) in rats and decreased fetal weights, post implantation loss, abortions, and skeletal defects in rabbits (e.g., unossified sternebrae, metatarsals, metacarpals, or caudal vertebrae). 

Viable fetuses should be labelled for identification, examined for visible malformations, visceral and skeletal anomalies and variations, sexed and weighed. Since there is an inverse correlation between number of fetuses per litter and individual fetal weight, total litter weight is also a useful measurement. 

TCDD during gestation caused an increased incidence of cleft palate and skeletal anomalies in offspring of rats (Giaviani et al. 1983 Huuskonen et al. 1994), mice (Abbott and Bimbaum 1989a Courtney 1976 Dasenbrock et al. 1992 Neubert and Dillman 1972 Smith et al. 1976 Weber et al. 

In this example, D is some observed end point in the mammal—specific-locus mutation rate, skeletal anomalies, cataracts, or heritable chromosomal damage. The values for D and E are assumed to be the same, although our confidence in the extrapolation would be increased if the observations in D involved several strains of several mammals. There is some possibility of direct dosimetry in man. With molecular dosimetry, the ENA damage in A and B can be measured in the same way. This corrects for differences in mutagen metabolism and mutation processes in the two organisms. B is measured directly in the spermatogonia or oocytes. The mutational end point, C, is whatever is most appropriate for the particular test organism. 

The only estimate of dominant effects in humans comes from mouse data. BEIR III and UNSCEAR both used skeletal anomalies and cataracts as a basis for human radiation-risk estimates. With chemicals, there are greater uncertainties in extrapolating from mouse to man. The skeletal and cataract systems have not been used widely enough for their validity to be assessed, but at present there is little choice but to use these if an estimate must be made. We suggest that the human impact in the first 5-10 generations be estimated as 4 times the first-generation estimate, as explained in Chapter 7. As is also discussed in Chapter 7, there is no feasible way to estimate the total genetic impact. 

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