Ubiquitous presence of paracetamol in human urine: sources and implications

N-acetyl-4-aminophenol (acetaminophen/paracetamol, NA4AP) is one of the most commonly used over-the-counter analgesic and antipyretic drugs. Recent studies have reported anti-androgenic effects of NA4AP in vitro and possible associations between intrauterine exposure to NA4AP and the development of male reproductive disorders in humans. NA4AP is also a major metabolite of aniline (phenylamine), representing 75-86% of the aniline dose excreted in urine. Aniline is an important large-volume intermediate in several industrial processes. Besides individuals in various occupational settings with aniline exposure, the general population is also known to be ubiquitously exposed to aniline. In this article, we provide an overview of the recent literature concerning the intake of NA4AP during pregnancy and the possible anti-androgenic effects of NA4AP as well as literature concerning its known metabolic precursor aniline. We also present new research data, including the first human biomonitoring data on NA4AP excretion in urine, showing ubiquitous NA4AP body burdens in the general population at a wide range of concentrations. We found a small but significant impact of smoking on urinary NA4AP concentrations. We further present preliminary data on NA4AP excretion after therapeutic acetaminophen use, after aniline exposure in an occupational setting, and during a controlled fasting study (excluding oral exposure to both aniline and acetaminophen). Our findings indicate exposure to aniline (or aniline-releasing substances) as well as nutrition (next to the direct use of acetaminophen as medication) as possible sources of internal body burdens of NA4AP.