Drug Doses Converge while Environmental and Occupational Thresholds Diverge: A Biological Paradox

High Resolution Image Download MS PowerPoint Slide The human body processes therapeutic drugs and environmental chemicals through the same biological systems, yet their regulatory treatment differs markedly. For most medicines, a single approved dose is applied across major jurisdictions, supported by internationally harmonized clinical trial requirements through the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). In contrast, health-based reference values for environmental and occupational chemicals─including reference doses, tolerable daily intakes, biomonitoring guidance values, and occupational exposure limits─often differ by one to several orders of magnitude across countries, despite relying on largely shared toxicological evidence. This review examines the scientific and institutional reasons for this divergence. The mechanisms governing absorption, distribution, metabolism, and excretion (ADME) are conserved across human populations, and pharmacogenomic exceptions are typically managed through individual clinical decisions rather than country-specific dosing frameworks. In environmental and occupational risk assessment, divergence arises partly from legitimate scientific uncertainty associated with chronic low-dose exposure, mixture effects, developmental susceptibility, and frequent reliance on animal data rather than prospective human trials. It is also strongly shaped by institutional history, regulatory sovereignty, and policy choices regarding precaution and acceptable risk. National biomonitoring programs often generate overlapping exposure datasets for the same compounds, while the thresholds used for their interpretation remain jurisdiction-specific. Converging methodological tools─including physiologically based pharmacokinetic and toxicokinetic modeling, in vitro-to-in vivo extrapolation, adverse outcome pathways, and biomonitoring equivalents─provide a shared scientific infrastructure for more harmonized and biologically grounded reference values. Their systematic application across pharmacology and toxicology offers the most practical path toward consistent human health protection across jurisdictions.