Ordinal dose-response modeling approach for the phthalate syndrome. (January 2020)

• Record Type: Journal Article
• Authors: Blessinger, Todd D.; Euling, Susan Y.; Wang, Lily; Hogan, Karen A.; Cai, Christine; Klinefelter, Gary; Saillenfait, Anne-Marie
• Is Part Of: Environment international. Volume 134(2020)
• Publication Date: 2020-01
• Subjects: Phthalate syndrome -- Ordinal data analysis -- Dose-response modeling -- Male reproductive development -- Nested model -- Diisobutyl phthalate; Environmental protection -- Periodicals; Environmental health -- Periodicals; Environmental monitoring -- Periodicals; Environmental Monitoring -- Periodicals; Environnement -- Protection -- Périodiques; Hygiène du milieu -- Périodiques; Environnement -- Surveillance -- Périodiques; Environmental health; Environmental monitoring; Environmental protection; Periodicals; 333.705
• DOI: 10.1016/j.envint.2019.105287
• Languages: English
• ISSNs: 0160-4120

Abstract

Highlights: A new method dose-response modeling approach for syndromes of effects was developed. The method accounts for differing endpoint severity such as impact on fertility. The ordinal model results compared favorably to the traditional model. The ordinal modeling method can be expanded to include more severity levels. Abstract: 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 developmentally-toxic phthalates. For statistical purposes, the PS is defined as a single endpoint and one dose-response analysis is conducted, rather than conducting multiple analyses on each individual endpoint. Objective: To improve dose-response modeling approaches for the PS and other syndromes of effects by accounting for differing severity levels among the endpoints. Methods: Ordinal dose-response modeling was performed on PS 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 the expected impact of male developmental endpoint's 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, and a sensitivity analysis was performed to assess the bootstrap results. A comparison of the estimates between the ordinal and the dichotomous model was performed. Results: The ordinal version of the log-logistic model applied to the data categorized by PS endpoint severity level provided benchmark dose estimates that were closer to each other in value and had lower variability than the traditional dichotomous application. The sensitivity analysis confirmed the validity of the bootstrap results. Conclusion: The ordinal dose-response modeling method accounts for severity differences among dichotomous PS endpoints, can be expanded in the future to include more severity levels, and can be used in both single and cumulative phthalate risk assessments.