The exposome is a term used to characterize exposure to all exogenous environmental agents, socioeconomic conditions, lifestyle, and diet along with markers of endogenous processes across the lifetime of an organism or community of interest. It integrates exposures with molecular or apical responses over time. Measures of the exposome enable data-driven discovery or hypothesis-free research, identifying associations between exposures and biologic endpoints of importance. Two strategies for linking the exposome to health outcomes have been described, and both can be useful. A “top-down” approach adopts untargeted analytic including omic methods to measure features of exogenous and endogenous exposures in biologic specimens. This approach allows contrasts of profiles between diseased and healthy populations. Omic profiles can be used to generate hypotheses to identify particularly relevant exposures, develop biomarkers for high-throughput screens, and determine sources of exposure. A “bottom-up” approach starts with a set of exposures from multiple sources to determine pathways or networks by which those exposures lead to disease. This is laborious and if confined to external sources of exposure, it misses chemical features of the internal environment associated with, for example, metabolism, gender, inflammation, obesity, stress, and discrimination. Most kinds of cancer are multifactorial in origin, and a causal pie model is often used to depict this complexity. Various combinations of component causes accumulate over a lifetime before becoming sufficient to initiate tumor formation and growth. Key events, alone and in combination, initiate adverse outcome pathways. Early biologic changes at low dose levels, exposures during critical windows of vulnerability during various life stages, interactions between exposures and components of mixtures, and gene-environment and internal-external interactions must be considered. In addition to technological challenges, this presentation will briefly raise four issues that must be considered when applying the concept of the exposome to the origins and prevention of cancer: 1) Biologic assumptions: Which signatures, biomarkers, key events, or adverse outcome pathways are important in the pathogenesis of cancer and what determines their variability among individuals or communities? 2) What biologic changes associated with measures of the exposome are adaptive or adverse? When do adaptive responses become adverse? 3) Multilevel variables—individual, family, community, and societal—influence disease risk. Which chemical and nonchemical stressors should be included in exposome assessment? 4) For purposes of prevention, what are the various sources of relevant exposures and their relative ranking in aggregated exposure pathways associated with adverse outcome pathways related to cancer?

Citation Format: Ted Schettler. The exposome and cancer [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA18.