Altered Operant Responding for Motor Reinforcement and the Determination of Benchmark Doses Following Perinatal Exposure to Low-Level 2,3,7,8-Tetrachlorodibenzo-p-Dioxin

• Published in: Environmental health perspectives 2001-06, Vol.109 (6), p.621-627
• Main Authors: Markowski, Vincent P., Zareba, Grazyna, Stern, Sander, Cox, Christopher, Weiss, Bernard
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Benchmarking; Chemical hazards; Conditioning, Operant; Dosage; Dose response relationship; Dose-Response Relationship, Drug; Environmental health; Environmental Pollutants - administration & dosage; Environmental Pollutants - adverse effects; Estrus; Estrus cycle; Female; Mating behavior; Motor Activity - drug effects; Physical Conditioning, Animal; Polychlorinated Dibenzodioxins - administration & dosage; Polychlorinated Dibenzodioxins - adverse effects; Pregnancy; Pregnancy, Animal; Proestrus; Rats; Rats, Sprague-Dawley; Reinforcement Schedule; Wheels
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/ehp.01109621

Pregnant Holtzman rats were exposed to a single oral dose of 0, 20, 60, or 180 ng/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the 18th day of gestation. Their adult female offspring were trained to respond on a lever for brief opportunities to run in specially designed running wheels. Once they had begun responding on a fixed-ratio 1 (FR1) schedule of reinforcement, the fixed-ratio requirement for lever pressing was increased at five-session intervals to values of FR2, FR5, FR10, FR20, and FR30. We examined vaginal cytology after each behavior session to track estrous cyclicity. Under each of the FR values, perinatal TCDD exposure produced a significant dose-related reduction in the number of earned opportunities to run, the lever response rate, and the total number of revolutions in the wheel. Estrous cyclicity was not affected. Because of the consistent dose-response relationship at all FR values, we used the behavioral data to calculate benchmark doses based on displacements from modeled zero-dose performance of 1% ( ED01) and 10% ( ED10), as determined by a quadratic fit to the dose-response function. The mean ED10 benchmark dose for earned run opportunities was 10.13 ng/kg with a 95% lower bound of 5.77 ng/kg. The corresponding ED01 was 0.98 ng/kg with a 95% lower bound of 0.83 ng/kg. The mean ED10 for total wheel revolutions was calculated as 7.32 ng/kg with a 95% lower bound of 5.41 ng/kg. The corresponding ED01 was 0.71 ng/kg with a 95% lower bound of 0.60. These values should be viewed from the perspective of current human body burdens, whose average value, based on TCDD toxic equivalents, has been calculated as 13 ng/kg.