Phthalates and Cumulative Risk Assessment The Tasks Ahead (2008) / Chapter Skim
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Appendix C: Analysis of a Mixture of Five Phthalates: A Case Study
Appendix C: Analysis of a Mixture of Five Phthalates: A Case Study
Pages 147-159
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From page 147... ...
The mixture BMD depends on the mixing ratio of the components, and a tiered analysis strategy is described to determine critical doses of the chemicals in the mixture. Howdeshell et al.
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From page 148... ...
The illustration is concluded with a description of a tiered analytic strategy for mixtures. METHODS Data were kindly provided by Earl Gray, Jr., in the Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, Environmental Protection Agency, Research Triangle Park, NC.
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From page 149... ...
. It was assumed that the observed relative testosterone concentration differed from the model mean, µ, by additive independent zero-mean normally distributed random terms representing between-pup (within-litter)
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Therefore, the later analyses were based on percent control values, which were calculated by dividing the average testosterone concentration per pup by the corresponding intrablock average control mean. The nonlinear logistic mixed-effects model was fitted to the dose-response data from each single chemical and to the mixture data in terms of total dose; the model allowed intralitter correlated data.
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From page 151... ...
It is of interest to determine a critical dose for the mixture of five phthalates and compare the adjusted critical doses of the individual components with their unadjusted critical doses. When the mixing ratio of the chemicals is specified, a BMD can be estimated for the mixture by using dose addition.
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From page 152... ...
Table 2-2 presents urinary concentrations of metabolites of the parent compounds, but the fraction of the parent diester that ends up in the urine varies widely among the phthalates. For example, 5-10% of DEHP is excreted as TABLE C-1 Estimated BMDs Associated with 5% BMRa for Single Chemicals and Mixture Data Based on Nonlinear Logistic Model and Estimated with Mixed-Effects Model Accounting for Intralitter Correlated Datab Lower One-Sided 95% Chemical BMD (mg/kg-d)
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From page 153... ...
of a mixture and the adjusted critical values for the components clearly depend on the mixing ratio. How should adjusted critical doses be specified for individual chemicals in a mixture when exposure information is not available (that is, the doses and mix
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From page 154... ...
The point of the analysis illustrated here was to determine a mixture BMD by using dose addition and to show that its value depends on the mixing ratio.
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From page 155... ...
(2008) compare BMDs for experimentally observed mixture data with a fixed mixing ratio and the corresponding BMD under additivity.
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From page 156... ...
156 Phthalates and Cumulative Risk Assessment: The Tasks Ahead B DBP 1.6 1.4 Testosterone (fraction of control)
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From page 157... ...
) vs dose of five single chemicals with maximum likelihood dose-response curves used in additivity model.
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From page 158... ...
) and model-predicted dose-response curves for mixture of five phthalates based on the nonlinear logistic model for the mixture data (solid curve)
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From page 159... ...
2008. A mixture of five phthalate esters inhibits fetal testicular testosterone production in the Sprague-Dawley rat in a cumulative, dose additive manner.
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