Moving Beyond Single-Pollutant Approaches: Advancing Mixture Toxicity and Cumulative Risk Assessment in Environmental Toxicology
DOI:
https://doi.org/10.66021/zenodo.18975974Keywords:
mixture toxicity, cumulative risk assessment, concentration addition, Bayesian kernel machine regression, adverse outcome pathways, New Approach Methodologies, probabilistic risk characterizationAbstract
Background: Regulatory risk assessment predominantly evaluates chemicals in isolation, ignoring ubiquitous human exposure to complex mixtures. This disconnect undermines public health protection, particularly for contaminants sharing modes of action (MoAs).
Methodology: We implemented an integrated cumulative risk assessment framework combining New Approach Methodologies (NAMs), Adverse Outcome Pathways (AOPs), and advanced mixture statistics (BKMR, WQS). Thirty-seven prioritized chemicals were evaluated using in vitro screening, in vivo verification, and transcriptomics. PBPK modeling aligned in vitro concentrations with human biomonitoring equivalents.
Results: Environmentally relevant mixtures elicited significant synergistic effects (Combination Index = 0.72 [95% CI: 0.61–0.84]). Probabilistic Hazard Index distributions indicated 18–34% of the simulated population exceeded risk thresholds, substantially higher than single-chemical assessments (3–7%). Inter-individual toxicokinetic variability was the primary driver of uncertainty.
Conclusions: Single-pollutant paradigms systematically underestimate cumulative risk. The Researcher recommends regulatory agencies adopt MoA-based grouping and probabilistic risk characterization. Transitioning beyond single-chemical evaluation is essential for protecting public health in a multi-pollutant reality.
