A paradigm shift in toxicology from external exposure to internal accumulation
Imagine two people drinking from the same glass of water. One suffers no ill effects, while the other develops a mysterious illness years later. Why the difference? The answer may lie not in the water itself, but in the silent, cumulative record of chemicals already stored in their bodies—their personal "body burden."
For decades, we've measured toxicity by looking at what's in our environment—the amount of a chemical in water, air, or soil. But a scientific paradigm shift is underway, moving the focus from the outside to the inside. This approach, known as the Tissue Residue Approach (TRA), argues that the true key to understanding poisoning lies in measuring the concentration of chemicals that have actually accumulated in an organism's tissues 4 . This revolutionary perspective is forcing us to rethink everything we know about the silent, slow effects of the modern chemical world.
of people have detectable levels of PFAS "forever chemicals" in their blood
industrial chemicals detected in the average human body
The core principle of the TRA is elegantly simple: the toxic effect a chemical has on an organism is more accurately related to its concentration in the target tissue than to the amount it was exposed to in the environment 4 . Think of it like alcohol; its effect isn't determined by how many drinks are on the bar, but by the concentration of alcohol in your bloodstream.
This concept, which has evolved from the "critical body residue" model, uses the internal tissue concentration as the universal yardstick for defining dose-response relationships, evaluating the danger of chemical mixtures, and setting protective environmental guidelines 4 .
Traditionally, toxicity has been assessed using the external dose—parts per million in water or milligrams per kilogram of food. This method has significant blind spots:
Many industrial chemicals, like PFAS "forever chemicals," build up in the body over time, meaning long-term, low-level exposure can create a dangerously high internal dose from a seemingly safe external one 1 .
| Feature | Traditional External Dose Approach | Tissue Residue Approach (TRA) |
|---|---|---|
| Dose Metric | Concentration in water, soil, or air | Concentration in an organism's tissue or blood |
| Handling Mixtures | Difficult, often underestimates risk | Naturally accounts for combined effects of all chemicals present |
| Individual Differences | Ignores variations in metabolism & absorption | Captures unique bioaccumulation for different species/individuals |
| Key Advantage | Simple to measure | More accurately predicts biological effects |
A groundbreaking 2024 study on "forever chemicals" provides a powerful, real-world example of the TRA in action 2 .
Are PFAS chemicals more toxic when mixed together, as they are found in the environment and our bodies?
To answer this, the University at Buffalo-led team took a novel approach designed to reflect actual internal conditions 2 :
Based on CDC data to mimic the average concentration ratios of PFAS found in American blood.
Based on US Geological Survey data to mimic PFAS profiles in U.S. surface water.
The results were striking. While most of the individual PFAS chemicals showed relatively low toxicity on their own, the combined mixtures became decidedly toxic 2 . This "cocktail effect" demonstrated that the chemicals acted in a concentration-additive manner.
A deeper dive into the data revealed another layer. In the water mixture, made up of 12 different PFAS, a chemical called PFOA (common in non-stick pans) was the biggest contributor to overall toxicity, responsible for up to 42% of the cell death, despite being only one component among many 2 .
| PFAS Chemical | Common Historical Use | Contribution to Cytotoxicity | Notes |
|---|---|---|---|
| PFOA | Non-stick cookware, firefighting foam | Up to 42% | Major driver of toxicity despite its concentration in the mixture. |
| PFOS | Stain-resistant fabrics, firefighting foam | ~25% (in neurotoxicity assay) | Significant contributor to nerve cell damage. |
To conduct cutting-edge research like the PFAS mixture study, scientists rely on a sophisticated toolkit.
| Tool/Reagent | Function in Research | Application in the Featured Experiment |
|---|---|---|
| Cell Lines | Living cells grown in culture used as a model to test for toxic effects. | Two specific cell lines were used to test for general cell death and nerve cell damage 2 . |
| Defined Chemical Mixtures | Custom-blended solutions of chemicals prepared at specific, real-world ratios. | Researchers created "blood serum" and "surface water" mixtures based on CDC and USGS data 2 . |
| In Vitro Toxicity Assays | High-throughput laboratory tests that quickly measure specific toxic responses (e.g., cytotoxicity). | Used to efficiently screen the PFAS mixtures for their ability to kill cells or disrupt cell function 2 . |
| Organoid Models | 3D, miniaturized, and simplified versions of an organ grown in a lab. | Not used in this study, but a cutting-edge tool that recapitulates human organ complexity for better safety testing 6 . |
Focus on environmental concentrations with limited consideration of biological uptake and accumulation.
Early recognition that internal concentrations better predict toxicity than external exposure.
Systematic framework using tissue concentrations as the primary metric for risk assessment.
Integration of TRA with advanced analytics to assess combined effects of chemical mixtures.
The Tissue Residue Approach represents a fundamental step toward a more honest and effective science of toxicology.
By focusing on the internal chemical body burden, it provides a clearer, more unified picture of how chemicals truly impact our health and the environment. This shift is crucial in a world saturated with industrial compounds, where understanding the combined effect of multiple chemicals is no longer an academic exercise but a public health imperative 1 2 4 .
TRA enables more accurate assessment of real-world chemical mixtures.
Provides scientific basis for more protective environmental guidelines.
Accounts for individual differences in chemical accumulation.
As the TRA continues to be integrated with other technological breakthroughs—like organoids, 3D bioprinting, and AI-based analysis—our ability to predict and prevent chemical toxicity will only grow more sophisticated 6 . This paradigm empowers us to look beyond what we are exposed to and finally understand what we have become, guiding us toward a future where we can not only clean up our environment but also safeguard the biological integrity of our own bodies.
References will be added here manually.