Teratogenicity studies timing

Segment 11 teratogenicity study. This concentrates on the most sensitive part of gestation, from the time of implantation imtil major organogenesis is complete. This is the period during which a test substance is most likely to cause malformation of the embryo. Exposure of the mother to the test substance is usually confined to this period. Conventionally, the study is conducted in rats and rabbits. Rabbits are intolerant to antibiotics and the mouse is an acceptable alternative in most cases. 

Hexachlorobutadiene did not adversely affect reproduction in animals except at high doses (150 mg/kg/day for 10 weeks). Although there was some evidence of fetotoxicity in animals after inhalation (10 ppm) or oral (15 mg/kg/day) exposure, embryolethality and teratogenicity were not detected. Oral studies in animals indicate that hexachlorobutadiene may increase the risk of renal cancer at dose levels of 20 mg/kg/day. The effects of hexachlorobutadiene are most pronounced after repeated chronic exposure to low doses, suggesting that effects are cumulative. For this reason, there is greater concern for populations living near hazardous waste sites, where exposure to low levels may occur for long periods of time, than for acute exposure scenarios. 

In the 1990s, ECVAM held a forum to vet and evaluate new alternative assays, and developed a list of compounds for testing (24). The key driver for this activity was the fact that DART studies require large numbers of animals. The primary focus of this activity was embryo-fetal toxicity. The list generated from this forum was tested in three assays (later validated by ECVAM) (1) the micromass assay, (2) the rat WEC assay, and (3) the embryonic stem cell test (25). Compounds on the Brown list were classified as either strong, weak, or non-teratogens. The three assays successfully predicted the compound classification about 80% of the time. However, the embryonic stem cell test later performed poorly on a different group of chemicals with known in vivo activities (26). 

There is no evidence of developmental toxicity of CS in the Upshall study, but the exposure conditions were limited. The short (5 min/d) exposures and seemingly low dosages did not fully test the potential teratogenicity of CS. In riot-control situations, humans may oe exposed to CS at 4-10 mg/m3,46 and the absolute concentrations used in this study were 6, 20, and 60 rng/m. Without considering time of exposure, the sixfold difference in concentrations (60 vs. 10 mg/np) between humans and test animals may not constitute a sufficient margin for an adequate assessment of terato-... 

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