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Heavy metal mixtures exposure and breast cancer risk: synergistic effects with SHBG identified by mediation and moderation models

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Overview

Analysis of 2,939 female NHANES participants from 2013 to 2020 examining associations between blood concentrations of five metals (lead, cadmium, mercury, selenium, manganese) and self-reported breast cancer. Used multivariable logistic regression, WQS, quantile g-computation, BKMR, restricted cubic splines, mediation analysis (via sex hormone-binding globulin), and moderation analysis.

Key numbers

n=2,939 women, NHANES 2013-2020. Median blood metal concentrations: lead 0.59 ug/L, cadmium 0.30 ug/L, mercury 0.34 ug/dL, selenium 185.82 ug/L, manganese 10.36 ug/L.

Single-metal associations (fully adjusted logistic regression):

  • Lead: OR=2.71 (95% CI: 2.22-3.30) for breast cancer; linear dose-response (P nonlinear above 0.05).
  • Mercury: OR=1.34 (95% CI: 1.12-1.61) for breast cancer; linear dose-response.
  • Manganese: OR=0.83 (95% CI: 0.70-0.99); inverse association with breast cancer.
  • Cadmium: OR=1.17 (95% CI: 0.98-1.39); not statistically significant.
  • Selenium: OR=1.07 (95% CI: 0.90-1.27); not statistically significant.

Nonlinear dose-response: significant for cadmium and manganese by restricted cubic splines.

Mixture analysis:

  • WQS: OR=1.43 (p below 0.001); lead as primary contributor.
  • Quantile g-computation: OR=1.28 (p below 0.001); lead as primary contributor.
  • BKMR: consistent associations confirmed.

SHBG pathway: both single and mixture metal exposures showed significant positive associations with sex hormone-binding globulin; each unit increase in SHBG elevated breast cancer risk by 1.65-fold (p below 0.001), linear dose-response. Mediation analysis identified significant masking effects for SHBG in the metal-breast cancer pathway; moderation analysis revealed synergistic interaction between metal exposure and SHBG on breast cancer risk.

Evidence Fitness

Context only. Cross-sectional design; self-reported breast cancer outcome. Lead’s OR of 2.71 for breast cancer is a large effect estimate from a cross-sectional design that cannot establish temporality. The SHBG mediation finding suggests a hormonal pathway but requires prospective confirmation. No food concentration data.

Methods (brief)

NHANES 2013-2020. Blood metals by ICP-MS. Self-reported breast cancer (yes/no). WQS, Qgcomp, BKMR, RCS. Mediation analysis for SHBG. Moderation analysis (metal-by-SHBG interaction). BMI categorized as below 18.5, 18.5-30, and above 30 (not standard WHO classification; noted as a limitation).

Implications

Certification: Lead’s dominant role in a breast cancer mixture analysis reinforces its Tier-1 priority status. The endocrine-disrupting mechanism via SHBG connects to the broader argument that toxic metal exposure affects hormone-dependent diseases through pathways that single-metal thresholds do not capture.

Courses: Useful for demonstrating how mixture methods combined with mediation analysis can identify biological pathways through which mixtures operate.

App: No food concentration data.

Microbiome: Potential gut-estrogen axis crosswalk; not primary focus.

Update history

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