The impact of complex environmental chemical mixtures on chronic kidney disease: A mixture analysis approach in a national population

Chronic kidney disease represents a significant global health burden. Exposure to environmental endocrine-disrupting chemicals, particularly heavy metals and phthalate metabolites, is increasingly associated with renal dysfunction. However, previous research has primarily focused on individual chemicals, leaving a gap in understanding the health effects of real-world co-exposure to complex mixtures of these contaminants. We applied several statistical analysis methods (including multivariable logistic regression, restricted cubic splines regression, quantile g-computation, and Bayesian kernel machine regression) to examine data from 6902 adults participating in the National Health and Nutrition Examination Survey between 2005 and 2018. Lead (Pb) and cadmium were consistently associated with an increased risk of impaired renal function across all models. Pb exhibited a U-shaped exposure-response relationship. Mercury was not significantly associated with renal impairment. Among phthalates metabolites, mono-(2-ethyl-5-oxohexyl) phthalate was associated with an increased risk, whereas mono-(2-ethyl)hexyl phthalate was linked to a reduce risk. In mixture analyses, metals predominated the overall nephrotoxic associations (Bayesian kernel machine regression group PIP = 0.997), with Pb identified as the primary contributor. Significant interactions were observed between Pb and other metals, as well as several phthalate metabolites. Pb and cadmium are associated with nephrotoxicity, and their combined effects may be amplified when present in mixtures. Phthalates exhibit metabolite-specific associations and primarily act as effect modifiers. Regulatory frameworks must transition from single-chemical assessments to cumulative risk assessment paradigms to effectively address real-world co-exposures.