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Linking Exposure To Health Effects Using A Systems
Biology Approach

Abstract:

Image of fish in a jarEnvironmental biomarker research is used to unambiguously connect levels of environmental contamination to the risk of adverse effects in the public's health with the ultimate goal of reducing this risk. This is accomplished by understanding the linkage among environmental exposures, the interactions with complex human biochemistry, and the eventual adverse health outcomes. Only then can the research community provide proper guidance to the public to optimize health through modification of their activities and through subsequent environmental regulation. As such, biomarker research for exposure assessment is more than just looking for a specific chemical in a biological matrix; rather, it is a complex, eclectic array of research tasks that are pieced together to eventually achieve an overall picture. In general, we first require some knowledge of the pollutant concentrations and variability, the exposure routes, and the demographics and numbers of the affected population. Then we address the distribution and levels of the native compounds within the biological system, most often in blood, urine, and breath, and link this to the environmental levels. Finally, we measure compounds of response in the biological system to assess the biological availability of the native compounds. These compounds can be chemically modified versions of the native compounds of exposure (phase 1 and phase 2 metabolites), or can be reflected as pattern shifts in endogenous compounds that are always present (e.g. alcohols, ketones, aldehydes, proteins, etc.). Further downstream in the biological progression, we can measure compounds indicative of (or precursors to) adverse health effects such as differentially expressed proteins, cell damage products, inflammation response, etc. The implementation of biomarkers research addresses the main shortcomings of traditional approaches using ecologic exposure assessment. Under an ecologic approach one would measure the amount of a specific pollutant in the air at any time and assign a single exposure level to the entire local population. Health outcome statistics such as emergency room admissions, asthma attacks, disease prevalence, morbidity, etc. are then associated with different pollutant levels in different locations; this effectively treats adverse effects as a stochastic events and thus restricts remediation efforts to broad reductions in overall exposure. In contrast, the biomarker approach provides specific links to individuals or groups of similar individuals. If we consider benzene exposure as an example, measurements of blood-borne benzene in a group of subjects are indicative of environmental uptake and can vary widely depending on activity patterns despite having the same nominal environmental exposure. Measurements of metabolites such as benzene oxide, phenol, hydroquinone, or phenyl-mercapturic acid are indicative of biologically available dose and can vary widely despite similar blood levels of benzene due to differences in enzyme levels, cardiac output, or phenotype. The risk of an adverse health outcome such as acute myologenous leukemia can vary greatly despite similar levels of metabolites due to genetic differences in susceptibility driven by DNA repair, metabolic activity, excretion efficiency, and detoxification processes. As such, the links between environmental levels of a pollutant and eventual health outcomes are quite complex and specific methods are required to determine the best approaches to protect public health. These endeavors require detailed sampling, analytical, modeling, and statistical methods before they can be broadly applied to population based studies. This task address a variety of contemporary environmental issues and develops specific methods for them. The intention is to use specific examples to demonstrate the utility of particular biomarker approaches and subsequently provide general guidance to address future environmental problems

Objective:

The main objective is to link environmental conditions to adverse health outcomes through an understanding of complex biological processes ranging from the systemic to the molecular level. Research results are to provide guidance for risk reduction and to establish the efficacy of intervention for demonstrating accountability. Specifically, environmental biomarker research is comprised of a hierarchy of activities that run the gamut from pollutant identification to adverse human effect. These are outlined below:

Obviously, not every item can be studied for every environmental pollutant within the confines of a single project such as this. Instead, we develop linkages among various steps for certain compounds and build an overall understanding of the systems biology. For instance, previous work has linked methyl tertiary butyl ether (MTBE) exposure to MTBE in blood and breath, and also measured the biomarker tertiary butyl ether (TBA). This allows the development of a simple classical pharmacokinetic model to understand precisely the relationship between exposure and production of a phase 1 metabolite. Such a model can be used to estimate previous average exposures based on a simple biomarker measurement. When applied to a number of subjects in a particular region or group, one could then use the model to estimate population based exposures and between/within group variance components. As another example, consider changes in patterns of endogenous compounds in blood, breath or urine as a result of diesel exhaust exposure. Pre- and post-exposure differential protein expression (proteomics) or differential production of aldehydes and ketones (metabolomics) could signal pre-clinical adverse changes, and when coupled to exposure assessment, could yield estimates of sensitive groups or individuals.

Pure biomarker measurements as reported by the Centers for Disease Control in their NHANES surveys serve only to identify trends and distributions. Our eventual objectives go further; with our research we hope to provide the knowledge to eventually intervene through regulation or advice to protect the public health. As such, all of our biomarker work requires environmental measurements (or at least good estimates) of exposures. To additionally determine variability of susceptibility through biomarkers of effects, we also require individual exposure measurements to supplement ecologic measures. Although the ostensible focus of this task is to measure biomarkers, it must be understood that accurate environmental exposure knowledge is of utmost importance to interpret the results.

Relevance/Significance/Impact:

The environmental framework under which population exposure is determined ecologically and health outcomes are linked statistically is no longer effective. A measurement with an air sampler on top of the downtown Post Office does not accurately assign the exposure for everyone in the city. With the increased understanding of the human genome and individual biochemistry, the interaction between specific patterns of environmental stimuli and an adverse health outcome in an individual can no longer be considered stochastic; in short, one does not get cancer due to bad luck. We may not yet know precisely how the cascade of biochemical events occur from the initial external insult to the final manifestation of disease, but we are confident that with more detailed study and collaborative work among different disciplines, we can elucidate these pathways and interrupt the series of events through avoidance or through biochemical intervention.

Principal Investigator: Dr. Joachim D Pleil

Human Exposure and Atmospheric Sciences

Research & Development | National Exposure Research Laboratory

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