Risk assessment of plant food supplements and other herbal products containing aristolochic acids using the margin of exposure (MOE) approach

Abstract

After the incidences of induction of aristolochic acid nephropathy after consumption of herbal weight loss preparations that accidentally contained aristolochic acids (AAs), several countries defined national restrictions on the presence of AAs in food, including plant food supplements (PFS) and herbal products. This study investigates whether the risks associated with exposure to AAs via PFS and herbal products are at present indeed negligible. Data reported in literature on AA levels in PFS and other herbal products and also obtained from a new series of PFS in the present study were used to calculate the estimated daily intakes (EDIs) and corresponding margins of exposure (MOEs). Available literature data revealed that 206 out of 573 samples were found to contain aristolochic acid I (AAI) and/or aristolochic acid II (AAII). The results obtained from recently collected PFS revealed that both AAI and AAII were detected in three out of 18 analysed PFS at levels up to 594.8 and 235.3 µg g -1 , respectively, being in line with the levels reported in literature. The EDIs resulting from intake of these PFS resulted in MOEs that were generally below 10,000, corroborating the priority for risk management. Although these results refer to PFS collected by targeted sampling strategies, the data reveal that AA-containing PFS are still freely available. When considering that the use of these samples may be limited to shorter periods of time, the EDIs might be lower, but MOE values would still be lower than 10,000 for more than 50% of the AA-containing PFS and herbal products. In conclusion, the presence of AAs in PFS and herbal products even several years after instalment of the legal restrictions still raises concern, especially for people who frequently use the respective PFS and herbal products. ARTICLE HISTORY

Recognition of the toxicity of aristolochic acid

“…Previous studies have reported that AA exerts therapeutic effects, including antitumour, anti‐infective, anti‐inflammatory, analgesic, antifertility and blood pressure‐regulatory effects. Thus, AA has been commonly used to treat a variety of illnesses, such as eczema, pneumonia, stroke, hepatitis, snake bites, arthritis, gout and coronary artery diseases, and is widely used in traditional and local medicines and herbal products . Aristolochia fangchi , but not Stephania tetrandra , contains AA.…”

“…In addition to differences in the accumulated dose of AA and the duration of AA intake, individual differences in the activities of enzymes that catalyse the biotransformation of AA could be responsible for the observed discrepancy in susceptibility levels. Thus, the identification of the enzymes involved in AA metabolism is of particular relevance . In the liver, the AA mixture is metabolized under anaerobic conditions to the corresponding aristolactam I and II, whereas under aerobic conditions, the only metabolite obtained is the O‐demethylated derivative aristolochic acid Ia (AA Ia), which is a biotransformation product from aristolochic acid I (AA I).…”

“…9 In 2001, the US FDA advised consumers to stop using products containing AA, and the sale of AA-containing botanical products has also been prohibited in several other countries, including Canada, New Zealand, Australia and many Asian countries. 2 In addition, AA exposure has been frequently linked to urothelial malignancies, and AA was classified as a human class I carcinogen by the WHO's International Agency for Research on Cancer (IARC) in 2002. 10 In 2012, AA was classified by the IARC as a human carcinogen (group 1) that acts via a genotoxic mechanism.…”

“…Thus, the identification of the enzymes involved in AA metabolism is of particular relevance. 2 In the liver, the AA mixture is metabolized under anaerobic conditions to the corresponding aristolactam I and II, whereas under aerobic conditions, the only metabolite obtained is the O-demethylated derivative aristolochic acid Ia (AA Ia), which is a biotransformation product from aristolochic acid I (AA I). AA I is considered to be responsible for the nephrotoxic and carcinogenic effects of AA.…”

Efeito do tratamento com extrato etanólico de Aristolochia cymbifera sobre a regeneração nervosa periférica

“…Devido essas informações, a Agência Européia de Medicamento vem proibindo a comercialização de produtos à base de plantas que sabidamente contém estes ácidos aristolóquicos(RAUBER, 2006). Além disso, a agência Americana Food and Drug Administration (FDA) vem advertindo consumidores em relação a continuidade do uso de produtos que contenham ácidos aristolóquicos(TABACH et al, 2013;ROZAINI ABDULLAH et al, 2017). Nesse estudo, o extrato da planta reduziu 20 significativamente o tempo de crise epilética em todos os tempos analisados (24, 48 e 72 horas após a administração da solução).…”