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Threshold analysis of selected dose-response data for endocrine active chemicals

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Abstract:

Using a biologically relevant mathematical model, the Michaelis-Menten equation, we examined published data from endocrine active chemicals for evidence of no-threshold dose-response curves. Data were fit to a modified Michaelis-Menten equation which accounted for total background response. Subsequently, the data sets were analyzed using non-linear regression in order to estimate the four parameters of interest (non-hormone controlled background (Bnh), maximum response (Rmax), endogenous hormone level (D0), and the dose at which a half-maximal response was observed (ED50)) and to determine the fit to the fully modified Michaelis-Menten equation. Subsequently, response data were adjusted to account for Bnh and then normalized to Rmax, while dose data were adjusted to account for D0 and then normalized to the ED50. This data set was combined into a single, composite data set and fit to the fully modified Michaelis-Menten equation. We examined 31 data sets (24 endpoints) from studies on 9 different chemical/hormone treatments. Twenty-six of the data sets fit the modified Michaelis-Menten equation with high multiple correlation coefficients (r>0.90). The normalized data demonstrated a good fit to the modified Michaelis-Menten equation. These results indicate that a variety of biological responses fit the modified Michaelis-Menten equation, which does not have a threshold dose term.

Keywords: Dose-response; Michaelis-Menten; endocrine disruptor; endogenous dose; non-hormone controlled background; risk assessment; threshold

Document Type: Original Article

Affiliations: 1: Division of Genetic and Reproductive Toxicology, and 2: Office of the Director, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, HFT-130, Jefferson, AR, USA 72079

Publication date: March 1, 2001

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