Pregnant Sprague-Dawley rats received a single oral dose of 0, 20, 60, or 180 ng/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin on day 8 of gestation. Each litter contributed a single male-female pair trained to press a lever to obtain food pellets under two operant behavior procedures. Initially, each lever press was reinforced. The fixed-ratio (FR) requirement was then increased every four sessions from the initial setting of 1 to values between 6 and 71. We then studied responses for 30 days under a multiple schedule combining FR 11 and another schedule requiring a pause of at least 10 sec between responses (DRL 10-sec). TCDD evoked a sexually dimorphic response pattern. Generally, TCDD-exposed males responded at lower rates than control males. In contrast, exposed females responded at higher rates than controls. Each response measure from the mult-FR DRL schedule yielded a male-female difference score. We used the differences in response rate to calculate benchmark doses based on the relative displacement from modeled zero-dose performance of the effective dose at 1% (ED01) and 10% (ED10), as determined by a second-order polynomial fit to the dose-effect function. For the male-female difference in FR rate of responding, the mean ED10 was 2.77 ng/kg with a 95% lower bound of 1.81 ng/kg. The corresponding ED01 was 0.27 ng/kg with a 95% lower bound of 0.18 ng/kg. For the male-female difference in DRL rate, the mean ED10 was 2.97 ng/kg with a 95% lower bound of 2.02 ng/kg. The corresponding ED10 was 0.30 ng/kg with a 95% lower bound of 0.20 ng/kg. These values fall close to, but below, current estimates of human body burdens of 13 ng/kg, based on TCDD toxic equivalents.
Hojo R., Stern S., Zareba G., Markowski V.P., Cox C., Kost J.T., Weiss B. (2002). Environmental Health Perspectives, 110, 247-254 doi: 10.1289/ehp.02110247