Integrated Risk Characterization of Estragole, Aristolochic Acids, and Pyrrolizidine Alkaloids in Natural Products using Margin of Exposure and RISK21

Introduction: Natural products (NPs) including herbal teas are widely consumed in Malaysia but lack stringent regulation. Naturally occurring phytochemicals including estragole (genotoxic), aristolochic acids (AAs; Group 1 carcinogen) and certain pyrrolizidine alkaloids (PAs; Group 2B) pose severe hepatotoxic and nephrotoxic risk. Methodology: An integrated risk assessment using the Margin of Exposure (MOE) and the RISK21 framework was applied to 90 NPs (30 per compound). The samples were identified through National Pharmaceutical Regulatory Agency (NPRA) QUEST3 + database and analyzed using validated UPLC-DAD and LC-MS methods. Results and Discussion Estragole, AAs, and PAs were detected in 30% (55.0–418.0 µg/g), 16.7% (8.7–2256.3 µg/g), and 36.7% (0.02–21.1 µg/g) of samples, respectively. Lifetime exposure to estragole and AAs, and eight PA-positive samples, resulted in MOE values < 10 000, indicating high priority for risk management. RISK21 characterization placed AAs in the red zone, representing unacceptable risk. Notably, half of estragole-positive products targeted women’s health, raising concerns for vulnerable populations, including potential neonatal exposure via breast milk. Furthermore, simultaneous product use may result in potential cumulative effects. Conclusion Malaysians face significant long-term health risks from toxic phytochemicals in NPs, particularly AAs. The integrated framework provides a critical decision-support tool to strengthen regulatory oversight and enforce stricter quality control.