Exposure–Adaptive Capacity Framework for Environmental Chemical Mixtures and Metabolic Resilience: A Critical Review and Operational Proposal

Abstract

Environmental chemical exposures are increasingly recognized as contributors to metabolic dysfunction, particularly when they occur as chronic, low-dose mixtures rather than as isolated high-dose toxicants. However, current approaches often focus on exposure intensity, single-compound hazard or isolated biomarker associations, and provide limited explanation for why individuals with comparable exposure profiles may develop markedly different metabolic outcomes. This semi-systematic review proposes an Exposure–Adaptive Capacity (EAC) framework to interpret the metabolic consequences of environmental chemical mixtures through the interaction between exposure burden and host adaptive capacity. A structured literature search covered PubMed/MEDLINE, Scopus and Web of Science records published through 30 June 2026; a reviewer-triggered PubMed/MEDLINE update was executed on 30 July 2026 using harmonized British and American dyslipidaemia/dyslipidemia terms, explicit eligibility domains and evidence-mapping procedures. The review integrates epidemiological, mechanistic, toxicological and translational evidence related to environmental chemicals, metabolic dysfunction, mitochondrial impairment, oxidative stress, inflammation, endocrine disruption, metabolic resilience and biomarkers. The evidence indicates that several chemical classes, including per- and polyfluoroalkyl substances, bisphenols, phthalates, pesticides, persistent organic pollutants and selected metals, converge on mitochondrial bioenergetics, redox regulation, inflammatory signalling, endocrine and nuclear receptor activity, nutrient-sensing networks and adipose tissue function. The EAC framework defines exposure burden as the cumulative biological pressure imposed by chemical mixtures and adaptive capacity as the organism’s functional ability to buffer, compensate for or recover from exposure-induced metabolic stress. To make the framework empirically testable, we specify measurable domains for exposure burden, adaptive capacity and EAC mismatch, and distinguish biomarkers of exposure, early biological effect, adaptive capacity, metabolic dysfunction and vulnerability. A quotient-based expression is retained only as a heuristic representation, while empirical testing is proposed through exposure-by-adaptive-capacity interaction models and complementary multidimensional approaches. The framework provides a structured basis for future exposomic, epidemiological and translational studies by shifting attention from exposure alone to the balance between environmental pressure and biological resilience.