Dose-Response Modeling and Benchmark Calculations from Spontaneous Behavior Data on Mice Neonatally Exposed to 2,2′,4,4′,5-Pentabromodiphenyl Ether

• Published in: Toxicological sciences 2004-10, Vol.81 (2), p.491-501
• Main Authors: Sand, Salomon, von Rosen, Dietrich, Eriksson, Per, Fredriksson, Anders, Viberg, Henrik, Victorin, Katarina, Filipsson, Agneta Falk
• Format: Article
• Language: English
• Subjects: Algorithms; Animals; Animals, Newborn - physiology; Behavior, Animal - drug effects; benchmark dose; Data Interpretation, Statistical; dose-response; Dose-Response Relationship, Drug; Female; Halogenated Diphenyl Ethers; health risk assessment; Hydrocarbons, Brominated - toxicity; Kinetics; Likelihood Functions; Male; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Models, Statistical; Motor Activity - drug effects; Phenyl Ethers - toxicity; Polybrominated Biphenyls; spontaneous behavior; Toxicity Tests - standards; Toxicity Tests - statistics & numerical data; Toxicity Tests/standards/statistics & numerical data
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/kfh222

In this paper the benchmark dose (BMD) method was introduced for spontaneous behavior data observed in 2-, 5-, and 8-month-old male and female C57Bl mice exposed orally on postnatal day 10 to different doses of 2,2′,4,4′,5-pentabromodiphenyl ether (PBDE 99). Spontaneous behavior (locomotion, rearing, and total activity) was in the present work quantified in terms of a fractional response defined as the cumulative response after 20 min divided by the cumulative response produced over the whole 1-h test period. The fractional response contains information about the time-response profile (which differs between the treatment groups) and has appropriate statistical characteristics. In the analysis, male and female mice could be characterized by a common dose-response model (i.e., they responded equally to the exposure to PBDE 99). As a primary approach, the BMD was defined as the dose producing a 5 or 10% change in the mean fractional response. According to the Hill model, considering a 10% change the lower bound of the BMD for rearing, locomotion, and total activity was 1.2, 0.85, and 0.31 mg PBDE 99/kg body weight, respectively. A probability-based procedure for BMD modeling was also considered. Using this methodology, the BMD was defined as corresponding to an excess risk of 5 or 10% of falling below cutoff points representing adverse levels of fractional response.