Toxic effects of cyclophosphamide in differentiating chicken limb bud cell culture using rat liver 9,000 g supernatant or rat liver cells as an activation system: An in vitro short-term test for proteratogens

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Abstract
Cells from 4‐day chicken embryo limb buds plated as micromass cultures differntiate and form cartilage nodules after a 5‐ to 6‐day growth period. The innate ability of these cells to biotransform compounds, such as cyclophosphamide (CP), into reactive metabolites is apparently inadequate. Protocols used rat liver S9 from Aroclor 1254 pretreated (PCB) rats or hepatocytes from control rats or polychlorinated biphenyls (PCB)‐pretreated rats and were added to micromass cultures with CP causing concentration‐related toxicity in the cell cultures. Coculturing chicken limb bud cells with PCB‐hepatocytes was the most efficient method, yielding an IC50 of 2 μg CP per ml. Toxic CP metabolites accumulated in the medium of PCB‐hepatocyte cultures and were quite stable. The toxicity of bioactivated CP was nearly identical for both proliferation and cartilage proteoglycan accumulation.