Implications of the exposome for exposure science.
ABSTRACT During the 1920s, the forerunners of exposure science collaborated with health professionals to investigate the causes of occupational diseases. With the birth of U.S. regulatory agencies in the 1970s, interest in the environmental origins of human diseases waned, and exposure scientists focused instead upon levels of selected contaminants in air and water. In fact, toxic chemicals enter the body not only from exogenous sources (air, water, diet, drugs, and radiation) but also from endogenous processes, including inflammation, lipid peroxidation, oxidative stress, existing diseases, infections, and gut flora. Thus, even though current evidence suggests that non-genetic factors contribute about 90% of the risks of chronic diseases, we have not explored the vast majority of human exposures that might initiate disease processes. The concept of the exposome, representing the totality of exposures received by a person during life, encompasses all sources of toxicants and, therefore, offers scientists an agnostic approach for investigating the environmental causes of chronic diseases. In this context, it is appropriate to regard the "environment" as the body's internal chemical environment and to define "exposures" as levels of biologically active chemicals in this internal environment. To explore the exposome, it makes sense to employ a top-down approach based upon biomonitoring (e.g. blood sampling) rather than a bottom-up approach that samples air, water, food, and so on. Because sources and levels of exposure change over time, exposomes can be constructed by analyzing toxicants in blood specimens obtained during critical stages of life. Initial investigations could use archived blood from prospective cohort studies to measure important classes of toxic chemicals, notably, reactive electrophiles, metals, metabolic products, hormone-like substances, and persistent organic compounds. The exposome offers health scientists an avenue for integrating research that is currently fractured along lines related to particular diseases and risk factors, and can thereby promote discovery of the key exposures responsible for chronic diseases. By embracing the exposome as its operational paradigm, exposure science can play a major role in discovering and mitigating these exposures.
Article: Categorizing biomarkers of the human exposome and developing metrics for assessing environmental sustainability.[show abstract] [hide abstract]
ABSTRACT: The concept of maintaining environmental sustainability broadly encompasses all human activities that impact the global environment, including the production of energy, use and management of finite resources such as petrochemicals, metals, food production (farmland, fresh and ocean waters), and potable water sources (rivers, lakes, aquifers), as well as preserving the diversity of the surrounding ecosystems. The ultimate concern is how one can manage Spaceship Earth in the long term to sustain the life, health, and welfare of the human species and the planet's flora and fauna. On a more intimate scale, one needs to consider the human interaction with the environment as expressed in the form of the exposome, which is defined as all exogenous and endogenous exposures from conception onward, including exposures from diet, lifestyle, and internal biology, as a quantity of critical interest to disease etiology. Current status and subsequent changes in the measurable components of the exposome, the human biomarkers, could thus conceivably be used to assess the sustainability of the environmental conditions with respect to human health. The basic theory is that a shift away from sustainability will be reflected in outlier measurements of human biomarkers. In this review, the philosophy of long-term environmental sustainability is explored in the context of human biomarker measurements and how empirical data can be collected and interpreted to assess if solutions to existing environmental problems might have unintended consequences. The first part discusses four conventions in the literature for categorizing environmental biomarkers and how different types of biomarker measurements might fit into the various grouping schemes. The second part lays out a sequence of data management strategies to establish statistics and patterns within the exposome that reflect human homeostasis and how changes or perturbations might be interpreted in light of external environmental stressors. The underlying concept is to identify probative outliers from the "unremarkable exposome" in individuals or subpopulations that could be used for discerning deviations from the healthy environment, much like current diagnostic medicine uses batteries of blood and urine tests to screen for preclinical disease conditions. Such empirically derived human in vivo data could subsequently be integrated into high-throughput in vitro and in silico testing of environmental and manufactured chemicals to support real-world toxicity evaluations.Journal of Toxicology and Environmental Health Part B 08/2012; 15(4):264-80. · 4.72 Impact Factor
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ABSTRACT: Benzene exposure is associated with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and probably lymphoma and childhood leukemia. Biological plausibility for a causal role of benzene in these diseases comes from its toxicity to hematopoietic stem cells (HSC) or progenitor cells, from which all leukemias and related disorders arise. The effect of this toxicity is manifest as lowered blood counts (hematotoxicity), even in individuals occupationally exposed to low levels of benzene. Benzene can induce AML/MDS via several well-characterized pathways associated with these diseases. Through its metabolites, benzene induces multiple alterations that likely contribute to the leukemogenic process, and appears to operate via multiple modes of action. To improve mechanistic understanding and for risk assessment purposes, it may be possible to measure several of the key events in these modes of action in an in vitro model of the bone marrow stem cell niche. Even though benzene is leukemogenic at relatively low occupational levels of exposure, it seems unlikely that it is a major cause of leukemia in the general population exposed to benzene in the ppb range. Other established non-genetic causes of AML, e.g. smoking, ionizing radiation and cancer chemotherapy, also only explain about 20% of AML incidence, leaving ∼80% unexplained. The question arises as to how to find the causes of the majority of de novo AMLs that remain unexplained. We propose that we should attempt to characterize the 'exposome' of human leukemia by using unbiased laboratory-based methods to find the unknown 'environmental' factors that contribute to leukemia etiology.Chemico-biological interactions 02/2011; 192(1-2):155-9. · 2.46 Impact Factor
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ABSTRACT: Primary biliary cirrhosis (PBC) is a chronic immune-mediated cholestatic liver disease of unknown aetiology which affects mostly women in middle age. Familial PBC is when PBC affects more than one member of the same family, and data suggest that first-degree relatives of PBC patients have an increased risk of developing the disease. Most often, these familial clusters involve mother-daughter pairs, which is consistent with the female preponderance of the disease. These clusters provide evidence towards a genetic basis underlying PBC. However, clusters of nonrelated individuals have also been reported, giving strength to an environmental component. Twin studies have demonstrated a high concordance for PBC in monozygotic twins and a low concordance among dizygotic twins. In conclusion, studies of PBC in families clearly demonstrate that genetic, epigenetic, and environmental factors play a role in the development of the disease.Autoimmune diseases. 01/2011; 2011:189585.