Risk assesment of Estragole, Aristolochic acids, and Pyrrolizidine alkaloids in selected natural products and herbal tea in Malaysia

In Malaysia, natural products (NPs) and herbal tea are widely used due to factors such as affordability, accessibility, and traditional beliefs, but the lack of stringent regulation presents significant health challenges. Adverse effects from NPs and herbal tea, ranging from mild gastrointestinal disturbances to serious outcomes like hepatotoxicity, nephrotoxicity, and carcinogenicity, may arise from naturally-occurring toxic compounds or phytochemicals. Estragole, found in the alkenylbenzene group, is prevalent in many herbs and spices used in cooking and is also present in NPs and herbal teas. Exposure to estragole has been associated with hepatotoxicity. Aristolochic acids (AAs) found in Aristolochia species, are known to cause kidney disease and are classified as Group 1 carcinogens by the International Agency for Research on Cancer (IARC). AAs cause nephropathy and cancer of the kidney and urinary tract in humans and animals. 1,2-unsaturated pyrrolizidine alkaloids (PAs), produced by various plants, are hepatotoxic and carcinogenic, with lasiocarpine, riddelliine, and monocrotaline classified as 2B carcinogens, indicating potential carcinogenicity to humans. This study is the first to use an integrated approach by combining the Margin of Exposure (MOE), physiologically-based kinetic (PBK) modelling-based reverse dosimetry, and the RISK21 framework to assess the health risk of these compounds in Malaysian NPs. Ninety (90) NP samples (30 samples each for estragole, AAs and PAs) were collected through targeted sampling from the Malaysian market to quantify the concentrations of estragole, AAs, and PAs. This selection criteria aligned with those used in previous studies. Estimated Daily Intake (EDI) and MOE approaches were applied to assess lifetime and short-term exposure risks, while PBK modelling-based reverse dosimetry predicted acute toxicity from risk exposure, and the RISK21 approach characterized the health risk. Analysis showed that 30% contained estragole (55.0 – 418.0 µg/g), 16.7% contained AAs (8.7 – 2256.3 µg/g), and 36.7% contained PAs (0.02 – 21.1 µg/g). EDI values of estragole ranged from 0.99 - 9.44 μg/kg bw/day, for AAs from 0.52 – 67.66 μg/kg bw/day, and for PAs from 8.0 x 10-4 to 1.6 μg/kg bw/day. Lifetime consumption of samples containing estragole, AAs, and eight NP samples containing PAs, resulted in MOE values less than 10,000, indicating high priority for risk management. The MOE values for short-term exposure were above 10,000, suggesting low priority for risk management for estragole and PAs. PBK modelling showed BMDL10 values for acute toxicity of estragole in humans were 4.8 – 4.9 times lower than in rats, indicating higher human sensitivity. While for AAI, human BMDL10 values were 1.2 – 2.2 times higher, suggesting lower sensitivity compared to rats. RISK21 characterization showed that Malaysians face low to medium acute risk from estragole, AAs, and PAs though NPs and herbal teas. In conclusion, Malaysians are at risk of developing health issues due to estragole, AAs and PAs in NPs and herbal teas. The integrated approach provides a valuable method for assessing and characterizing these risks. Further research should include exposure from various food types, along with a more accurate assessment of exposure duration for short-term periods to corroborate and expand upon these findings.

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