Beyond Tradition: An Integrated Toxicological, Ecological, and Public Health Perspective on Aristolochic Acids

Aristolochia species have long been used in traditional medicine for their presumed anti-inflammatory, analgesic and antimicrobial properties. However, extensive toxicological and epidemiological evidence now demonstrates that these plants contain aristolochic acids (AAs) I and II, highly potent nephrotoxic, genotoxic, and carcinogenic compounds. This review integrates findings from experimental models, clinical investigations, and environmental monitoring, emphasizing the persistence, mobility, and bioaccumulation of AAs in ecosystems and food chains. Compelling epidemiological data show that exposure to AAs is strongly associated with Balkan endemic nephropathy (BEN) and upper urinary tract carcinoma (UUC), conditions that exhibit some of the highest rates worldwide in regions of sustained environmental contamination. In Taiwan, UUC incidence is globally unmatched and closely linked to chronic ingestion of AA-containing herbal preparations, while in Balkan endemic areas, 30%-45% of individuals affected by BEN develop UUC. In these same regions, AA-derived DNA adducts are detected in the vast majority of exposed populations, serving as highly specific biomarkers of internal dose and demonstrating long-term mutagenic persistence. Environmental exposure levels further support these associations, with AAs detected in contaminated soils, wheat, and corn grains, and a variety of vegetables grown in endemic villages. Root crops in particular accumulate AAs from soil reservoirs influenced by pH-dependent solubility and hydrophobicity, while groundwater in affected areas contains AAs concentrations in the ng/L range, revealing an additional exposure pathway through drinking water. Together, these data illustrate a complex exposure landscape that results in preferential accumulation of AAs in renal, hepatic and urothelial tissues, leading to the formation of persistent DNA adducts, characteristic A:T → T:A transversions and subsequent malignant transformation. Despite the clarity of these risks, regulatory responses remain inconsistent across regions, allowing ongoing human exposure through traditional herbal remedies, contaminated food chains, and environmental reservoirs. This review identifies critical research gaps, including the need to better understand chronic low-dose exposure, interactions with individual genetic susceptibility and the development of more sensitive biomarkers capable of detecting both environmental and clinical exposure. Given the unequivocal risks associated with AAs, harmonized global regulation, strengthened toxicovigilance, and targeted public health education are urgently needed. The replacement of Aristolochia-based preparations with scientifically validated and safer therapeutic alternatives remains essential to reduce the growing global burden of AAs-related renal and urothelial diseases.