ORCID Identifier(s)

0009-0007-0851-7409

Graduation Semester and Year

Fall 2024

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Earth and Environmental Science

Department

Earth and Environmental Sciences

First Advisor

Elsa Pirouz

Second Advisor

Amir Shahmoradi

Abstract

Rheumatoid Arthritis (RA) is a multifactorial autoimmune disease influenced by both genetic and environmental factors. The increasing prevalence of organophosphate esters (OPEs) as chemical additives raises significant concerns regarding their potential impact on RA and other chronic conditions, including Type 2 Diabetes (T2D). This dissertation investigates the associations between OPE exposure, RA risk, and the interplay between RA and T2D, using advanced epidemiological, statistical methods, and machine learning models. Data from the National Health and Nutrition Examination Survey (NHANES) from 2011–2018 were analyzed, focusing on adults aged ≥20 years. Multivariable logistic regression, propensity score matching (PSM), Two-Indices Weighted Quantile Sum (2i-WQS) regression, and Bayesian Kernel Machine Regression (BKMR) were employed to evaluate cumulative OPE exposure and its contributions to RA and T2D. Additionally, nonlinear associations were examined using smooth curve fittings and generalized additive models. The analysis included 5,490 participants (RA: 319, non-RA: 5,171). Higher quartiles of diphenyl phosphate (DPHP) and dibutyl phosphate (DBUP) exposure were significantly associated with increased RA prevalence (e.g., DPHP Q4: OR 1.45, 95% CI: 1.03– ii 2.04; DBUP Q4: OR 4.42, 95% CI: 1.01–2.01), while bis(1,3-dichloro-2-propyl) phosphate (BDCPP) showed a protective effect (Q4: OR 0.60, 95% CI: 0.42–0.85). Subgroup analyses revealed stronger associations among females and individuals aged ≥60 years. Additionally, individuals with RA exhibited a 28% higher risk of developing T2D (OR = 0.72, 95% CI: 0.61–0.84, p < 0.0001) compared to non-RA individuals, even after PSM adjustments. Further analysis using 2i-WQS regression demonstrated that DPHP and DBUP contributed significantly to the positive WQS index, with weights of 0.381 and 0.339, respectively. Conversely, BDCPP and BCPP were linked to the negative WQS index, with weights of 0.619 and 0.288, suggesting potential protective effects. Interaction analyses revealed a strong positive interaction between DPHP and BDCPP, where higher BDCPP levels amplified DPHP’s association with RA. Moderate interaction effects were observed for DBUP, while BCEP and BCPP showed minimal interaction effects with other OPEs. These findings underscore the complex relationships between OPE exposures and RA, highlighting the need for a mixture-based approach in environmental health research. The nuanced interactions identified through advanced modeling techniques provide critical insights into the mechanisms underlying RA pathogenesis and its association with chronic conditions like T2D. This study reinforces the significance of addressing environmental exposures through targeted public health interventions, particularly for vulnerable populations such as older adults and females.

Keywords

Rheumatoid Arthritis, NHANES, Type 2 diabetes, Pathogenesis, Organophosphate Esters, Causal Inferences, Propensity Score Matching, 2 indices-Weighted Quantile Sum, Bayesian Kernel Machine Regression.

Disciplines

Chemical Actions and Uses | Design of Experiments and Sample Surveys | Environmental Health and Protection | Environmental Indicators and Impact Assessment | Environmental Monitoring | Environmental Public Health | Epidemiology | Health Services Research | Multivariate Analysis | Other Statistics and Probability

License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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Available for download on Sunday, December 13, 2026

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