Alignment of convergent mechanisms with pathway-driven and mixture-risk frameworks.
| Mechanistic node (from Table 1) | Representative contaminants | Recognized/policy-relevant endpoint | Applicable framework/hook | How it supports PDL | Key sources |
|---|---|---|---|---|---|
| Thyroid-axis disruption via TTR competition and enhanced clearance | PFAS in the food chain | Altered circulating thyroid hormone; developmental thyroid concerns | EFSA Scientific Committee 2019 guidance on combined exposure; KC “alters hormone transport” | Group all TTR-active PFAS and other TTR-active food contaminants for thyroid risk | [25, 77] |
| PPAR-centered metabolic signaling activation | PFAS, some plasticizers | Dyslipidemia, insulin resistance, metabolic-syndrome-like outcomes | Consensus on key characteristics of metabolism-disrupting agents; EFSA combined-exposure workflow | Clusters PFAS with other MDAs that hit the PPAR/metabolic node | [18, 72] |
| ER/AR perturbation by bisphenol analogues | BPS, BPF, BPAF | Reproductive, obesogenic, and anti-androgenic signals are already recognized for BPA | KC EDC paper; EFSA grouping logic | Prevents regrettable substitution by keeping BPA replacements in the same cumulative group | [37, 39, 77] |
| Steroidogenesis interference by phthalate monoesters | DEHP, DBP, DnBP metabolites | Reduced sex-steroid output, male reproductive endpoints | EFSA 2019 combined-exposure guidance; KC “alters hormone synthesis” [77] | Maps any co-migrant or phthalate that suppresses StAR/CYP11A1 into a single reproductive-risk lane | [35, 46] |
| Gut-barrier injury and dysbiosis from MNPs | PS, PE, PP microplastics in food/water | Increased intestinal permeability and low-grade inflammation | 2024–2025 MNP gut-toxicity reviews | Defines barrier-inflammatory as a horizontal pathway for particles and co-ingested EDCs | [50, 59, 72] |
| Co-exposure amplification by particle-bound chemicals | Food-borne MNPs carrying BPA, phthalates, PCBs | Effective EDC-mixture exposure (higher internal dose than chemical alone) | EFSA 2019 and 2021 grouping documents | Places “MNP + adsorbed EDC” in the same cumulative group as free EDCs | [52, 53, 77] |
This table shows that the mechanistic nodes in Table 1 can be plugged directly into existing European and international tools for combined exposure and endocrine-disruptor evaluation. It links thyroid, metabolic, reproductive, and barrier endpoints to EFSA’s 2019 guidance on combined exposure. BPA: bisphenol A; BPAF: bisphenol AF; BPF: bisphenol F; BPS: bisphenol S; DBP: dibutyl phthalate; DEHP: di(2-ethylhexyl) phthalate; DnBP: di-n-butyl phthalate; EDC: endocrine-disrupting chemicals; EFSA: European Food Safety Authority; ER/AR: estrogen receptor/androgen receptor; KC: key characteristics; MDAs: metabolism-disrupting agents; MNPs: micro- and nanoplastics; PCBs: polychlorinated biphenyls; PDL: Pathway Disruption Load; PE: polyethylene; PFAS: per- and polyfluoroalkyl substances; PP: polypropylene; PPAR: peroxisome proliferator-activated receptor; PS: polystyrene; TTR: transthyretin.