title: Statistical methodology to determine kinetically derived maximum tolerated dose in repeat dose toxicity studies.
abstract: Several statistical approaches were evaluated to identify an optimum method for determining a point of nonlinearity (PONL) in toxicokinetic data. (1) A second-order least squares regression model was fit iteratively starting with data from all doses. If the second order term was significant (α<0.05), the dataset was reevaluated with successive removal of the highest dose until the second-order term became non-significant. This dose, whose removal made the second order term non-significant, is an estimate of the PONL. (2) A least squares linear model was fit iteratively starting with data from all doses except the highest. The mean response for the omitted dose was compared to the 95% prediction interval. If the omitted dose falls outside the confidence interval it is an estimate of the PONL. (3) Slopes of least squares linear regression lines for sections of contiguous doses were compared. Nonlinearity was suggested when slopes of compared sections differed. A total of 33 dose-response datasets were evaluated. For these toxicokinetic data, the best statistical approach was the least squares regression analysis with a second-order term. Changing the α level for the second-order term and weighting the second-order analysis by the inverse of feed consumption were also considered. This technique has been shown to give reproducible identification of nonlinearities in TK datasets.
authors.affiliation: Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI 48674, USA.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: McFadden
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bartels
authors.forename: David L
authors.initials: DL
authors.lastname: Rick
authors.forename: Paul S
authors.initials: PS
authors.lastname: Price
authors.forename: Donald D
authors.initials: DD
authors.lastname: Fontaine
authors.forename: Shakil A
authors.initials: SA
authors.lastname: Saghir
mesh_terms: D000818:Animals; D003627:Data Interpretation, Statistical; D004334:Drug Administration Schedule; D016018:Least-Squares Analysis; D020714:Maximum Tolerated Dose; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D010575:Pesticides / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D011237:Predictive Value of Tests; D051381:Rats; D059551:Toxicity Tests, Subacute / Q000706:statistics & numerical data*
chemical_list: D010575:Pesticides