The Blood Exposome and Its Role in Discovering Causes of Disease.

BACKGROUND: Since 2001 researchers have mainly examined the human genome (G) to discover causes of disease despite evidence that G explains relatively little risk. We posit that unexplained disease risks are caused by the exposome (E, representing all exposures) and G×E interactions. It follows that etiologic research has been hampered by scientists' continuing reliance on low-tech methods to characterize E as contrasted with high-tech omics for characterizing G.

OBJECTIVES: Because exposures are inherently chemical in nature and arise from both endogenous and exogenous sources, blood specimens can be used to characterize exposomes. To explore the 'blood exposome' and its connection to disease we sought human-blood concentrations of many chemicals along with their sources, evidence of chronic-disease risks and numbers of metabolic pathways.

METHODS: From the literature we obtained human-blood concentrations for 1,561 small molecules and metals, derived from foods, drugs, pollutants and endogenous processes. Chemical similarities were mapped after weighting by blood concentrations, disease-risk citations and numbers of human metabolic pathways.

RESULTS: Blood concentrations spanned 11 orders of magnitude and were indistinguishable for endogenous and food chemicals and drugs while those of pollutants were 1,000-times lower. Chemical similarities mapped by disease risks were equally distributed by source categories while those mapped by metabolic pathways were dominated by endogenous molecules and essential nutrients.

CONCLUSIONS: The complexity of human exposures motivates characterization of the blood exposome, which includes all biologically active chemicals, for studies of disease etiology. Because most small molecules in blood are not human metabolites, investigations of causal pathways should expand beyond the endogenous metabolome.