title: Benchmark dose approaches in chemical health risk assessment in relation to number and distress of laboratory animals.
abstract: Use of benchmark dose (BMD) approaches is expected to increase substantially, with growing awareness among researchers and inclusion in regulatory testing guidance documents such as REACH. The BMD approach has clear advantages over the No-Observed-Adverse-Effect-Level (NOAEL) approach in defining toxicological thresholds, risk levels, and points of departure as the basis for setting guidance and limit values. Several aspects of the BMD may increase the use of laboratory animals; the optimal number of dose groups for BMD calculation is between five and ten, rather than the current standard of four; also, experiments with more animals will result in narrow confidence intervals. However, this paper presents several counterarguments suggesting that design of experiments suited for BMD analyses might be used to decrease the distress and use of laboratory animals. If experiments are performed with unequal group size, with fewer animals in the high response dose groups and more animals close to toxicological threshold, the aggregated distress might be reduced. In addition, there is a need to evaluate how the total number of animals affects the quality of BMD (e.g. in terms of confidence intervals). Development of strategies for optimal design of experiments requires tools which evaluate experimental designs from an ethical perspective; a concept of distress-adjusted number of animals is suggested.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, P.O. Box 210, SE-171 77 Stockholm, Sweden. mattias.oberg@ki.se
authors.forename: Mattias
authors.initials: M
authors.lastname: Oberg
mesh_terms: D000818:Animals; D000830:Animals, Laboratory; D019985:Benchmarking; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D015233:Models, Statistical; D019055:No-Observed-Adverse-Effect Level; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D012107:Research Design; D018570:Risk Assessment; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D004364:Pharmaceutical Preparations