Convergent endocrine disruption by emerging food-borne contaminants: towards a Pathway Disruption Load (PDL)

Abstract

A variety of endocrine-relevant contaminant categories are now chronically co-exposed to the human population through the food chain, including direct dietary intake, packaging migration, and drinking-water pathway, such as per- and polyfluoroalkyl substances (PFAS), bisphenol analogues/phthalates, and micro- and nanoplastics (MNPs). There exists a fundamental incongruity between the current regulation of chemicals and our exposures to them. Regulatory agencies currently tend to test substances individually, but rising evidence on population-based studies shows that combined exposures are leading to thyroid ailments, metabolic issues, and negative reproductive outcomes. This review brings together mechanistic, toxicological, and human evidence that these structurally diverse contaminants functionally intersect three endocrine- and barrier-relevant signaling pathways: (i) the thyroid axis, (ii) nuclear receptor and steroidogenic signaling, (iii) gut barrier-inflammation circuits. Since the mixtures encountered in the real world cause cumulative stress on these common pathways, it is suggested that a pathway-based measurement be developed: the Pathway Disruption Load (PDL). PDL is operationalized: Tier 1 comprises pathway-specific biomarkers (TSH, free T4, sex-steroid panels, zonulin, LBP). Tier 2 is performed by applying receptor/enzyme assays (ER/AR/TR, TPO inhibition) of pertinent matrices (food extracts, water, serum) to measure the total endocrine activity, including unknown co-migrants. A combination of Tier 1 biological response and Tier 2 functional burden gives a realistic and chemical-agnostic foundation for cumulative risk evaluation, and provides a foodomics-relevant bridge between food-matrix signals (e.g., packaging/food extracts) and human biomonitoring/omics-derived biomarkers, and it also agrees with the current EFSA mixture guidance and key-characteristics frameworks. Operational priorities are re-analysis of biomarker-rich cohorts, pathway-level panels, and mixture toxicology at human-relevant doses.

Keywords

endocrine disruptors / per- and polyfluoroalkyl substances / phthalates / microplastics / foodomics / exposome / food safety / cumulative risk assessment

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