Assessing health risks from multiple environmental stressors: Moving from G×E to I×E

Abstract

Research on disease causation often attempts to isolate the effects of individual factors, including individual genes or environmental factors. This reductionist approach has generated many discoveries, but misses important interactive and cumulative effects that may help explain the broad range of variability in disease occurrence observed across studies and individuals. A disease rarely results from a single factor, and instead results from a broader combination of factors, characterized here as intrinsic (I) and extrinsic (E) factors. Intrinsic vulnerability or resilience emanates from a variety of both fixed and shifting biological factors including genetic traits, while extrinsic factors comprise all biologically-relevant external stressors encountered across the lifespan. The I×E concept incorporates the multi-factorial and dynamic nature of health and disease and provides a unified, conceptual basis for integrating results from multiple areas of research, including genomics, G×E, developmental origins of health and disease, and the exposome. We describe the utility of the I×E concept to better understand and characterize the cumulative impact of multiple extrinsic and intrinsic factors on individual and population health. New research methods increasingly facilitate the measurement of multifactorial and interactive effects in epidemiological and toxicological studies. Tiered or indicator-based approaches can guide the selection of potentially relevant I and E factors for study and quantification, and exposomics methods may eventually produce results that can be used to generate a response function over the life course. Quantitative data on I×E interactive effects should generate a better understanding of the variability in human response to environmental factors. The proposed I×E concept highlights the role for broader study design in order to identify extrinsic and intrinsic factors amenable to interventions at the individual and population levels in order to enhance resilience, reduce vulnerability and improve health.

Keywords: Epidemiology; Exposome; Gene-environment interactions; Risk; Social determinants of health; Toxic chemical exposure.

Fig. 1

Higher vs. lower cumulative disease risk of hypothetical individuals at a single point in time based on combinations of multiple risk factors.

Fig. 2

Extrinsic (E, upper panel) and intrinsic (I, middle panel) factors interact throughout the lifespan, enhancing vulnerability or resilience in a cumulative manner. Intrinsic genome and sex are fixed I factors whereas the other I factors are modifiable. Many E factors act on and influence the I factors, whereas E factors are modulated to a lesser degree by I factors (indicated by thick and thin arrows between the upper and middle panels). I×E interactions can vary over the lifespan beginning before conception via maternal and paternal effects (background schematic in middle panel). In a given individual, I×E interactions influence vulnerability and resilience, and consequentially health status, throughout life, as indicated by the fluctuating curves in the lower panel. The curves shown are not based on actual data and are hypothetical trajectories indicative of negative and positive effects on resilience and health status over the lifespan. Scenarios that could contribute to these fluctuations are described in the text in Section 3. Occ., occupational; Env., environmental.