Environmental chemicals are part of our daily lives and can contribute to diseases of the nervous system, respiratory tract, and heart. The lecture showed why traditional epidemiological and biomonitoring studies by themselves are not enough and how the Adverse Outcome Pathways (AOP) framework can help them. An integrated AOP-based approach delivers mechanistic evidence, early biomarkers, and better public health protection.
Chemicals around us and the limits of human studies
In everyday life we are exposed to air polluted with fine particles, heavy metals, pesticides, and components of consumer products, such as bisphenols. Substances enter the body through inhalation, food and water, or through the skin. Exposure is associated with neurological and respiratory diseases, including asthma and lung cancer, as well as cardiovascular and liver diseases. The spectrum of effects is broad and often develops slowly.
Epidemiological studies seek the link between exposure and health outcomes through effect biomarkers, that is, measurable biological, physiological, or behavioral changes. Their weakness is that they usually provide only weak evidence of causality because the mechanism remains unclear. Human biomonitoring, in turn, provides data on internal dose and on biomarkers of exposure as well as effect, but these are often nonspecific indicators tied to late stages of disease. These limitations complicate effective public health protection.
AOP as a bridge between exposure and outcome
An Adverse Outcome Pathway is a conceptual framework that organizes existing knowledge into a sequence of steps from the initial molecular event to an adverse outcome at the population level. It starts with a molecular initiating event, followed by measurable key events at the cellular or tissue level, and ends with a clinically relevant outcome. Such a “map” connects individual lines of evidence and makes the mechanism understandable. It also enables a clearer definition of what needs to be measured.
When epidemiological data are linked with AOPs, mechanistic understanding improves and biomarkers that are predictive and translatable to the adverse outcome can be identified. Subsequent implementation of these biomarkers into biomonitoring makes it possible to detect early changes at the molecular or cellular level. At the same time, threshold concentrations important for risk assessment and management can be determined. The result is more targeted regulation and better disease prevention.
Case studies: bisphenol A and the heart under pressure
An international team assembled an AOP network for the developmental neurotoxicity of bisphenol A, which converges on a shared key event: reduced release of BDNF, an important factor in brain development. They chose BDNF DNA methylation and BDNF levels in serum and urine as candidate biomarkers. In a child cohort, they measured urinary BPA concentrations at ages 9–11 and assessed BDNF as well as thought problems in adolescence. They found that childhood BPA exposure is longitudinally associated with BDNF DNA methylation and with later thought problems, supporting the utility of the biomarker.
A second line of work focused on cardiotoxicity: systematic reviews showed that exposure to PM2,5/PM10, arsenic, or lead is associated with cardiac remodeling that leads to left ventricular dysfunction. In parallel, an AOP framework supported by in vitro and in vivo evidence was developed, and a physiological model with cardiomyocytes and multi-omic measurements is being developed to search for biomarkers for future biomonitoring. AOPs are already helping to refine safe exposure limits, but challenges remain: limited coverage of mechanisms, the effects of mixtures, and low-dose, long-term exposures. We also need quantitative AOPs, which are crucial for the next generation of risk assessment.
