Calculation of benchmark doses from teratology data.
The benchmark dose approach has several potential advantages over the no observed adverse effect level (NOAEL) as a basis for risk assessment of toxic chemicals, based upon animal toxicity data. The practical use of the benchmark dose has been evaluated by applying dose-response models to an extensive historical database of teratology bioassays. Doses corresponding to 1 and 5% increases in incidence of lesions are calculated and compared to NOAELs. The statistical accuracy of these estimates was determined by calculating confidence intervals. The lower confidence limit on the 5% benchmark dose (LED05) is found to be comparable to the NOAEL for most datasets, and slightly higher on average. Benchmark doses at the 1% level could not be estimated accurately (i.e., they had wide confidence intervals) for a significant fraction of the datasets. LED01 values were lower on average than the NOAEL. Based on these results, it is concluded that benchmark doses for a 5% increases in incidence can be calculated for most datasets, and could be used as a satisfactory basis for risk assessment, e.g., to set reference doses or acceptable daily intakes. An exception occurs when the benchmark dose exceeds the highest dose of the study. This is only likely to occur when the chemical causes a small, but significant, increase in a finding that is uncommon in untreated animals.
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ZENECA Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom.
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D005069:Evaluation Studies as Topic; D008432:Mathematical Computing; D008954:Models, Biological; D013723:Teratogens / Q000633:toxicity*
D013723:Teratogens