Phthalates and Cumulative Risk Assessment The Tasks Ahead (2008) / Chapter Skim
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Appendix D: Evaluating Multiple End Points Simultaneously in a Mixture of Three Antiandrogens: A Case Study
Appendix D: Evaluating Multiple End Points Simultaneously in a Mixture of Three Antiandrogens: A Case Study
Pages 160-188
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From page 160... ...
. One advantage of pseudolikelihood approaches over conditional models is that estimation of a joint benchmark dose is possible; this lends itself to quantitative risk assessment (Geys et al.
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. Test chemicals and mixtures were administered by gavage to time-mated nulliparous, young adult Wistar rats from gestation day 7 to the day before expected birth and on postnatal days 1-16.
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This flexible approach can handle multiple types of response variables and may include different desirability functions for each variable. Subjectivity in specifying the functions may be minimized by using consensus expert opinion.
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Desirability functions for organ weights (ventral prostate, seminal vesicles, and LABC) in terms of percentage of control were also based on the lower 1-percentile of the unexposed group (di = 0.9)
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] To control for litter effects, the dose-response data were analyzed with a generalized nonlinear mixed-effects model approach with litter as an added random effect.
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Toxicity index 0.98 0.61 0.27 a "Desirability score" can be read from Figure D-1 for observed response values. Observed responses are transformed to %control values for organ weights.
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The disconnected line segments in the plots illustrate that most pups were either evaluated with AGD and NR or had organ weights measured. In general, the control group and lowestmixture dose group (7.87 mg/kg)
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An advantage of using such a score in evaluation of mixtures is that end points may be combined across studies and chemicals by transforming all end points into a common unitless scale of 0-1. The subjectivity of the initial step of specifying the desirability shapes may be minimized by specifying values on the curves from summary statistics in the control group or by using consensus from subject-matter experts (Coffey et al.
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For general use of composite scores, further evaluation, discussion, and acceptance of the shapes of the desirability functions are necessary. The central motivation is to be able to use a composite score to represent the whole set of common adverse outcomes identified to be of interest for a mixture.
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Appendix D 169 A B
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170 Phthalates and Cumulative Risk Assessment: The Tasks Ahead C D
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. Asterisks represent observed data points.
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172 Phthalates and Cumulative Risk Assessment: The Tasks Ahead B Desirability End point C Desirability End point End point
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Appendix D 173 D Desirability End point End point E Desirability End point
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174 Phthalates and Cumulative Risk Assessment: The Tasks Ahead F Desirability End point FIGURE D-2 Profile plots for individual pups (connected line segment) in each dose group of mixture data.
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Appendix D 175 B C
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176 Phthalates and Cumulative Risk Assessment: The Tasks Ahead D FIGURE D-3 Average calculated toxicity index (composite desirability score) per litter vs dose of three single chemicals and mixture.
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Appendix D 177 B Desirability End point C Desirability End point
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178 Phthalates and Cumulative Risk Assessment: The Tasks Ahead D Desirability End point E Desirability End point
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Appendix D 179 F Desirability End point G Desirability End point
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180 Phthalates and Cumulative Risk Assessment: The Tasks Ahead H Desirability End point I Desirability End point
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Appendix D 181 J Desirability End point K Desirability End point
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182 Phthalates and Cumulative Risk Assessment: The Tasks Ahead L Desirability End point M Desirability End point
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Appendix D 183 N Desirability End point O Desirability End point
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184 Phthalates and Cumulative Risk Assessment: The Tasks Ahead P Desirability End point Q Desirability End point
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Appendix D 185 R Desirability End point S Desirability End point
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186 Phthalates and Cumulative Risk Assessment: The Tasks Ahead T Desirability End point U Desirability End point FIGURE D-4 Profile plots from the single chemical dose-response data.
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2001. Two latent variable risk assessment approach for mixed continuous and discrete outcomes from devel opmental toxicity data.
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2005. Optimization of correlated multiple quality characteristics using desir ability function.
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