Biomonitoring Xenobiotics in Human Biospecimens: Challenges, Advances, and the Future of Exposome Characterization

Xenobiotics, defined as foreign chemical substances not normally produced by or expected to be present in an organism, are pervasive throughout the human body system. While some xenobiotics have known adverse health effects, the impact of many remains unclear, particularly when considering the potential synergistic or additive effects of chemical mixtures. Human biomonitoring, using biospecimens such as blood, urine, placenta, umbilical cord blood, stool, milk, sweat, saliva, tears, teeth, hair, nails, breath, and cerebrospinal fluid, is a common approach to assess xenobiotic exposure. However, these matrices have inherent limitations in accurately measuring the vast array of chemicals constituting the human chemical exposome-the entirety of chemical exposures an individual experiences over time. This comprehensive review critically analyzes the advantages and limitations of both invasive and noninvasive biospecimens used in human biomonitoring. We outline major classes of detectable xenobiotics in these matrices, compare their qualitative and quantitative feasibility, and discuss challenges in using biospecimens to monitor the internal chemical exposome. The review highlights the importance of integrating complementary external monitoring methods alongside biospecimen analysis, given the short half-lives and trace levels of some xenobiotics in accessible biospecimens. We also discuss emerging technologies and methodologies in biomonitoring, including advanced analytical techniques, wearable sensors, and multi-omics approaches. Additionally, we discuss the ethical, legal, and social implications of biomonitoring and external monitoring. By synthesizing current knowledge and identifying research gaps, this review provides a comprehensive overview of xenobiotics in human biospecimens and outlines future directions for better characterizing the human chemical exposome. These insights are crucial for advancing our understanding of xenobiotic exposures and their health impacts, ultimately informing more effective strategies for disease prevention and intervention.