2025 Theses Doctoral

Cadmium exposure in the United States: Environmental sources and its effect on chronic lower respiratory disease

Sobel, Marisa H.

The story of cadmium (Cd) is a story of public health. From its discovery by government mandated pharmaceutical protection, to its implications on occupational safety and the health of the worker, to its long-lasting impact as an industrial pollutant affecting both nature and general population human health. As long as we have known about cadmium, we have been learning about its toxicity. 208 years later, we are experiencing political turmoil, scientific skepticism of the masses, and a changing climate. Yet we continue to take on the charge of public health. This dissertation builds on the years of dedication of scientists, physicians, public health practitioners, and policy makers to not only understand the world we live in, but to play a part in the effort to make health viable and possible for all. One aspect of continued burden of disease is chronic lower respiratory disease (CLRD). It consistently ranks as a leading cause of death globally, continues to be included in the ten leading causes of disability-adjusted life years (DALYs) globally for adults older than 50, and is experienced disproportionately among historically marginalized communities. CLRD is a complex disease comprised of different lung conditions, including chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, asthma, without a cure. Identifying CLRD in early stages could improve long-term CLRD prognosis. As such, there is a great need to identify modifiable components of complex risk factors of CLRD.

Metals such as Cd are components of well-established CLRD risk factors (i.e., tobacco, occupational exposures, and air pollution). There is a growing body of evidence supporting the role of chronic metal exposure on CLRD development but is it unclear how metals interact and the extent to which low-level metal exposure leads to CLRD-related mortality. Additionally, the scope of Cd exposure for the general population needs continued evaluation. Tobacco smoke is a major source of Cd exposure in the general population, however, sources of Cd exposure among nonsmokers is less clear, yet increasingly relevant to the US population. Currently there are unexplained differences in urinary Cd levels that persist by sociodemographic characteristics.

The goal of this dissertation is to evaluate the Cd exposure profile and Cd-related CLRD risk in a multi-ethnic cohort of US adults. Data is leveraged from the Multi-Ethnic Study of Atherosclerosis (MESA), a multicenter, longitudinal cohort study.

Chapter 1 provides the foundation for this dissertation by giving a brief history of Cd, including describing major sources of exposure and relevant toxicological information, providing adequate background on CLRD, and lastly a description of potential mechanisms tying the two together.

In Chapter 2, we characterized urinary Cd (uCd) levels across geographic regions and sociodemographic categories to better identify sources and contributors of elevated exposure. uCd levels differed significantly by age, sex, cigarette use, and race/ethnicity, but did not differ by study site or dietary factors. Chinese participants had higher uCd levels compared to other self-reported race/ethnicities, particularly among younger participants, females, never smoking or other tobacco product use, and those born outside of the United States. Smoking continues to have important implications for Cd burden among the general population. However, our results also highlight non-smoking Chinese women and Chinese participants born outside the US are a particularly vulnerable subgroup affected by higher long-term Cd exposure and body burden.

In Chapter 3 we characterize the longitudinal relationship between uCd and both subclinical markers of CLRD (lung function and quantitative emphysema) and clinical CLRD events. In adjusted models, comparing the highest to lowest uCd quartiles, FEV1 was- 467 mL (95%CI: -629, -305 mL) lower at baseline, increased by 5.81 mL (95%CI 3.37, 8.24 mL) annually, and was -409 mL (95%CI: -569, -249 mL) lower at 10 years after baseline; quantitative emphysema, was -0.003% (95%: -0.22, 0.21) lower at baseline, increased by 0.13% (95%CI: 0.11%, 0.15%) annually, and was 0.50% (95%CI: 0.18, 0.82) higher at 10 years after baseline for a 10-year change. The HR (95%CI) comparing participants in the highest vs lowest quartile of uCd for a primary CLRD-related event was 2.88 (95%CI: 1.52, 5.43) and for CLRD-related mortality was 4.97 (95%CI: 1.32, 18.77). Associations were stronger among older adults, men, and smokers. Evidence from this chapter concludes that exposure to Cd may increase CLRD risk.

Chapter 4 evaluates the relationship between urinary metals beyond Cd, and clinical CLRD events. In single metal analyses, the adjusted hazard ratio (HR 95% CI) for any CLRD-related event per interquartile range (IQR) increase in urinary metal was 1.52 (1.33, 1.73) for Cd, 1.16 (1.06, 1.27) for Co, 1.12 (1.05, 1.20) for Cu, and 1.18 (1.08, 1.30) for Zn. Associations persisted among never-smokers for Cu (1.18 [95%CI 1.07, 1.30]) and Zn (1.20 [95%CI 1.02, 1.43]). Results remained statistically significant when limiting analyses to primary CLRD events. The adjusted joint HR per IQR increase in a 15-metal mixture for any CLRD event was positive and statistically significant (1.54 [1.20, 1.97]) with the largest beta estimates for Cd, Co, Cu, and Zn. Though we caution the interpretation of the mixture analysis, we provide evidence that urinary excretion of multiple metals may increase clinical CLRD risk.

And finally, Chapter 5 summarizes the overall findings and puts them into context of the greater public health domain. Key findings will be discussed alongside overall limitations, together with the questions generated from results and their implication for public health at large.