DEVELOPMENTAL TOXICITY OF CARBENDAZIM - COMPARISON OF NO-OBSERVED-ADVERSE-EFFECT LEVEL AND BENCHMARK DOSE APPROACH

The benchmark dose (BD) approach has been applied to foetal data from four gavage segment II studies (rat studies 1 and 2, rabbit study, ham ster study) on the teratogenic benzimidazole carbendazim. Nineteen par ameters were assessed using the log-normal model as a practical tool t o derive BDs; good model fitting was observed for all except two param eters. Data were evaluated on a 'perimplant/foetus' basis; BDs were de rived from response rate increases of 1, 5 and 10%. The values were co mpared to the lowest-observed-adverse-effect levels (LOAELs) and no-ob served-adverse effect levels (NOAELs) obtained by Fisher's exact test on a 'per-implant/foetus' basis. Frank effects observed only at the to p dose and/or small sample size tended to increase the 95% confidence limits and this influenced the determination of BD. Generally, the BD approach provided slightly more conservative estimates than NOAEL; ove rall, BD01 and BD05 were similar to NOAEL, or even lower for several p arameters. The LOAEL in most cases was similar to BD10. Reference dose s obtained by dividing BD01 by a 10 or 100 uncertainty factor, corresp onded to residual risks of 10(-5) or below. For two critical parameter s (hydrocephalus in rat study 1 and resorption rate in the rabbit stud y) a NOAEL could not be found, whereas a BD was always determined. (C) 1998 Elsevier Science Ltd. All rights reserved.