The influence of dosing volume on the toxicity of p,p'-DDT

In the IPCS Collaborative Study on Neurobehavioral Screening Methods, the "Top Dose" (TD) of p,p'-DDT (oral gavage, in corn oil) was determined to be different depending on the volume of administration: TD = 87 mg/kg when delivered in 1 ml/kg (i.e., 87 mg/ml) vs. TD = 130.5 mg/kg when given at 5 ml/kg (26.1 mg/ml). Two acute dose-response studies were conducted, the only difference being the doses used (pre-established percentages of the TD) and dosing volume (1 and 5 ml/kg); a third study was conducted using a single dose and varying the dosing volume (1 and 5 ml/kg). In the higher-volume study, dose-response curves for almost all the affected endpoints were shifted to the right, and the effects of the highest dose were less severe compared to the lower-volume study. For example, tremors were observed in all rats dosed with 43.5 mg/kg at 1 ml/kg, but only in 40% of the dose group given 65.3 mg/kg at 5 ml/kg. The highest dose groups (100% TD) showed myoclonus in both studies, but the incidence was 100% at 87 mg/kg (1 ml/kg) compared to 60% at 130.5 mg/kg (5 ml/kg). The dose-response curves indicated that the effective doses were generally 2-5 times higher, i.e., less potent, using a volume of 5 ml/kg. In general, the profiles of effect were similar in that the Sensorimotor and Convulsive domains were significantly altered in both studies, but again the dose-response curves were shifted; these domains were affected by both 43.5 and 87 mg/kg at 1 ml/kg, but only by 130.5 mg/kg at 5 ml/kg. The Neuromuscular domain, however, was only affected in the 1 ml/kg study (at 87 mg/kg). These differences in outcome could be due to higher partitioning of DDT into the oil, or increased gut motility, both of which could be due to the larger volume of oil delivered. The findings illustrate the importance of knowing the pharmacokinetic properties of the compound in question, as well as standardization of such variables whenever direct comparisons of dose levels are conducted.