Todd D Blessinger1, Susan Y Euling2, Lily Wang3, Karen A Hogan4, Christine Cai4, Gary Klinefelter5, Anne-Marie Saillenfait6. 1. Center for Public Health and Environmental Assessment (CPHEA), Mail code 8623R, USA; United States (US) Environmental Protection Agency, Washington, DC 20460, USA. Electronic address: blessinger.todd@epa.gov. 2. Office of Children's Health Protection (OCHP), Mail code 1107T, USA; United States (US) Environmental Protection Agency, Washington, DC 20460, USA. 3. CPHEA, US Environmental Protection Agency, Mail code B243-01, Research Triangle Park, NC 27711, USA. 4. Center for Public Health and Environmental Assessment (CPHEA), Mail code 8623R, USA; United States (US) Environmental Protection Agency, Washington, DC 20460, USA. 5. National Health and Environmental Effects Research Lab (NHEERL), USA; United States (US) Environmental Protection Agency, Washington, DC 20460, USA. 6. Institut National de Recherche et de Sécurité, Vandoeuvre, France.
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. Published by Elsevier Ltd.
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. Published by Elsevier Ltd.
Entities:
Keywords:
Diisobutyl phthalate; Dose-response modeling; Male reproductive development; Nested model; Ordinal data analysis; Phthalate syndrome
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