Ordinal Dose-Response Modeling Approach for the Phthalate Syndrome
Background: The phthalate syndrome (PS) is a collection of related male reproductive developmental effects, ranging in severity, that have been observed in rats after gestational exposure to one or more developmentally-toxic phthalates. For the purposes of statistical analysis, the PS is defined as a single endpoint upon which one dose-response analysis is conducted, rather than conducting multiple analyses on all the individual endpoints which comprise it.
Objective: To improve dose-response modeling approaches for the PS by accounting for differing severity levels among the PS endpoints.
Methods: Ordinal dose-response modeling was performed on the PS using data from a published study of diisobutyl phthalate (DIBP) gestational exposure to male Sprague-Dawley rats. To incorporate PS endpoint severity, the endpoints were categorized into ordinal levels based on male developmental effects and the endpoint’s impact on fertility. Then, a benchmark dose was estimated for each ordinal level. A bootstrap procedure was used to account for the nested nature of the data. A comparison of the estimates between the ordinal and the dichotomous model was also performed.
Results: The ordinal version of the log-logistic model applied to the data categorized by severity level of PS endpoints provided results that were less variable than the traditional dichotomous application.
Conclusion: The ordinal dose-response modeling method accounts for severity differences among dichotomous PS endpoints and can be used in both single phthalate and cumulative phthalate risk assessments.