Hideshi Tsusaki | PubMed Health

PubMedDate not supplied

In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects tooth development in rhesus monkeys.

We thought to validate the current tolerable daily intake (TDI) value for dioxin (4 pg/kg) in Japan. Pregnant rhesus monkeys received an initial dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 0, 30, or 300 ng/kg subcutaneously) on day 20 of gestation; the dams received additional injection of 5% of the initial dose every 30 days until day 90 after delivery. The teeth of stillborn, postnatally dead, and surviving offspring (now approximately 4 years old) were evaluated. None of the offspring in the 0 and 30 ng/kg groups (n=17 and 15, respectively) had tooth abnormalities, whereas 10 of 17 in the 300 ng/kg had them. These findings suggest the lowest-observed adverse-effect level (LOAEL) for TCDD in the rhesus monkey is between 30 and 300 ng/kg, and probably is close to that for rodents (86 ng/kg) on which the current TDI was based. It is reasonable to conclude that the current TDI needs no immediate modification.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Evaluation of cardiac function in primates using real-time three-dimensional echocardiography as applications to safety assessment.

INTRODUCTION: A timed non-invasive determination of cardiac function is potentially important for safety pharmacology and toxicity studies. The objectives of this study were to evaluate the accuracy of real-time three-dimensional (RT3D) echocardiography measurements of the left ventricular (LV) volume and LV function and to investigate the effects of some drugs on LV function in cynomolgus monkeys. METHODS: RT3D echocardiography was performed (SONOS 7500, Philips Med Sys) under isoflurane inhalation. RT3D echocardiography measurements and reconstructions were obtained using Tom-Tec (4DLV analysis). We determined end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF), stroke volume (SV), cardiac output (CO) and heart rate as assessments of LV function. EDV, calculated from two-dimensional (2D) echocardiography and RT3D echocardiography, and the actual LV volume were evaluated and compared. Furthermore, each parameter was determined before and after intravenous infusion (5 or 10 min) of propranolol, verapamil and dobutamine. RESULTS: A strong correlation was found between the actual LV volume and that calculated from RT3D echocardiography (r=0.96, p<0.001). Propranolol (0.1 mg/kg/10 min, n=5) caused an increase in ESV, but not EDV, resulting in a decrease in EF and SV, while verapamil produced increases in both EDV and ESV. Dobutamine (0.01 mg/kg/5 min, n=5) produced decreases in both EDV and ESV and thereby the increased CO resulted from the increased SV. DISCUSSION: These results demonstrate that RT3D echocardiography provides a feasible and accurate estimation of LV volume and EF for safety pharmacology and toxicity studies.

Animals↗