RESUMEN
In order to examine the mechanistic basis between combined effects and mechanisms of action, two osteolathyrogens, beta-aminopropionitrile (betaAPN) and diethyldithiocarbamate (DTC), were tested together on Xenopus embryos. In a separate test, DTC was also tested with copper sulfate to determine the importance of copper in DTC-induced osteolathyrism. Frog embryos (Xenopus laevis) were exposed for 96 h, with daily solution removal and replacement. Preserved tadpoles were evaluated for osteolathyritic lesions. For the betaAPN:DTC test, a 1.2-factor matrix design was used, producing two single chemical and seven mixture-response curves. The chi(2) goodness-of-fit test was used to compare the experimental mixture-response curves with theoretical effects for two combined effects models, dose-addition and independence. All seven mixture curves were consistent with expected results for dose-addition, but the correlations were generally not high. For the DTC:copper test, the three mixture-response curves generated showed that added copper increased the DTC-alone EC(50), but there was no corresponding right shift at the top of the response curves, as observed previously with betaAPN and copper. In the betaAPN:DTC and DTC:copper tests, DTC alone showed a biphasic concentration-osteolathyrism curve, and the slope of the response curve for DTC alone in each test was statistically different than the slope for the betaAPN alone response curve. Taken together, the results suggest the potential for a second osteolathyritic effect of DTC that affected the combined toxicity enough to produce a dose-addition correlation without the chemicals necessarily having the same mechanism.
Asunto(s)
Aminopropionitrilo/toxicidad , Quelantes/toxicidad , Ditiocarba/toxicidad , Latirismo/inducido químicamente , Xenopus laevis/embriología , Animales , Sulfato de Cobre/toxicidad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Embrión no Mamífero/efectos de los fármacos , Pruebas de ToxicidadRESUMEN
Two nitrile combinations, beta-aminopropionitrile (beta APN) with aminoacetonitrile (AAN) and betaAPN with beta APN (as a sham combination), were evaluated using the frog embryo mixture toxicity assay to determine their combined osteolathyritic effects and to compare the results with theoretical effects for two combined effects models. In separate tests each nitrile was tested with copper sulfate to determine the importance of copper in osteolathyrogen-induced disruption of connective tissue cross-linking. Frog embryos (Xenopus laevis) were exposed for 96 h, with daily solution removal and replacement. Preserved tadpoles were evaluated for osteolathyritic lesions. For the nitrile:nitrile combinations, the chi(2) goodness-of-fit test was used to compare the resulting mixture-response curves to theoretical curves for dose-addition and independence. For beta APN with AAN, the combined osteolathyritic effect for five of the seven mixture curves generated was greater than expected for each of the combined effects models. For beta APN with beta APN, the combined effect for all seven mixture curves was consistent with dose-addition, the combined effect expected for chemicals inducing toxicity by the same mechanism. For the nitrile:copper combinations, the EC(50) for beta APN-induced osteolathyrism was increased two- to threefold (i.e. made less toxic) by co-administration with copper sulfate, while the EC(50) for AAN-induced osteolathyrism was unchanged. The results are consistent with the idea that beta APN and AAN induce osteolathyrism, at least in part, by different mechanisms.