Threshold-Dependent Biphasic Association of Blood Cadmium with Testosterone in Men: Implications for Environmental Exposure Risk Assessment

Cadmium (Cd) is a widespread reproductive toxicant conventionally known to suppress testosterone synthesis, but this study first identifies a threshold-dependent biphasic association between blood cadmium (BCd) and serum testosterone in a general male population. Using data from 4,458 US adult males in NHANES (2011-2016), we analyzed nonlinear relationships via restricted cubic splines (RCS) and segmented regression, with subgroup analyses to explore susceptibility. Results revealed a significant biphasic association (Pnonlinear=0.03;Ptrend<0.01), with an inflection point at 0.7 μg/L. Below this threshold, each 1 μg/L increase in BCd was associated with a 93.54 ng/dL rise in testosterone (95% CI:54.21–132.88; P<0.001), while above it, the effect attenuated to 18.67 ng/dL (95% CI:2.94–34.39; P=0.020). Subgroup analyses showed stronger effects in non-smokers (β=67.8 vs. smokers’ β=17.7; Pinteraction=0.029), middle-aged men (40–60 years; β=44.0), and low-BMI individuals (<25 kg/m²; β=36.0). This is the first population-level evidence of Cd-induced testosterone hormesis (low-dose stimulation, high-dose suppression), challenging the linear no-threshold model in Cd risk assessment. The identified 0.7 μg/L threshold informs revisions to environmental standards (e.g., China’s GB 2762-2022) and targeted health monitoring for high-risk subgroups.