Threshold analysis of selected dose‐response data for endocrine active chemicalsNote
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.
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ABSTRACT: This paper will review briefly the use of wildlife as models in the study of how mix- tures, low doses, and the embryonic environment modulate the action of endocrine active substances (EASs). In so doing, it will show how the issue of low dosages must be consid- ered within the context of mixtures present in the environment and the endocrine background of the exposed individual.That is, in nature, EASs usually are found in mixtures in which the constituent parts are in concentrations well below their NOAEL (no observed adverse effect level) as determined in single compound studies in the laboratory.In addition, exposure al- ways occurs on organisms in various endocrine states. Thus, the issue of mixtures and dosages must always be considered within the context of the endocrine background. Finally, the effects of exposure are passed down through the generations. The question of exposure then at the level of the individual becomes very complicated, as it must take into account that at every life stage, the naturally occurring endocrine milieu of the organism (or tissue), any EAS burden inherited from the mother or built up over the individual's life, and the social en- vironment in which the individual develops and interacts as an adult, will influence the re- sponse to acute exposure.Pure and Applied Chemistry 11/2003; 75:2305-2320. DOI:10.1351/pac200375112305 · 3.11 Impact Factor
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ABSTRACT: Dose-response characteristics for endocrine disruption have been major focuses in efforts to understand potential impacts on human and ecological health. Issues include as- sumptions of thresholds for developmental effects, effects at low doses with nonmonotonic (e.g., "U-shaped") behaviors, population vs. individual responses, and background exposures (e.g., dietary phytoestrogens). Dose-response analysis presents a challenge because it is multidisciplinary, involving biologists and mathematicians. Statistical analyses can be valu- able for evaluating issues such as the reproducibility of data as illustrated for contradictory findings on low-dose effects. Mechanistically based modeling provides insights into how per- turbations of biological systems by endocrine active substances can create different dose-re- sponse behaviors. These analyses have demonstrated that higher order behaviors resulting from the interaction of component parts may appear highly nonlinear, thresholded, low-dose linear, or nonmonotonic, or exhibit hysteresis. Some effects need to be evaluated as popula- tion impacts. For example, alterations in male:female ratio may be important at the popula- tion level even though not adverse for the individual. Descriptions of the contributions of background exposures to dose-response behaviors are essential. The challenge for improv- ing dose-response analyses is to better understand how system characteristics create differ- ent dose-response behaviors. Such generalizations could then provide useful guidance for developing risk assessment approaches.Pure and Applied Chemistry 11/2003; 75:2159-2166. DOI:10.1351/pac200375112159 · 3.11 Impact Factor
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ABSTRACT: Endocrine disruption (ED) as a named field of research has been very active for over 10 years, but effects in wildlife that would now be labeled as ED have been studied since the 1940s. This paper briefly surveys the progress in wildlife studies that has been made to date and draws out the major themes and issues that have been identified. In particular, it dis- cusses information concerning causative substances, modes of action, ubiquity of effects across taxa, individual- and population-level impacts, and the importance of low-dose and mixture effects. The main conclusion is that while most wildlife taxa are showing some ED effects at some locations, good evidence for population-level impacts is still limited to a few groups. In order to improve both the interpretation of field observations and the way in which environmental risk assessments are conducted, we need to develop an enhanced ability to predict effects on populations and communities from a knowledge of effects on individuals.Pure and Applied Chemistry 11/2003; 75:2197-2206. DOI:10.1351/pac200375112197 · 3.11 Impact Factor