Elemental impurity risk assessment in St. John's Wort supplements

Öz

The content of elemental impurities in herbal supplements often exceeds safety limits, particularly if they are grown or harvested in polluted areas. Therefore, numerous reports have focused on the health risk assessment of elemental impurities in herbal supplements. In this study, the levels of cadmium (Cd), lead (Pb), arsenic (As) and mercury (Hg) within herbal supplements containing St. John's Wort, and a carcinogenic and non-carcinogenic health risk assessment associated with elemental impurity exposure was conducted. Four elemental impurities in 10 herbal supplement capsules were analyzed by Inductively coupled plasma mass spectrometry (ICP-MS) using a Microwave Digestion system. Risk calculations were performed considering the recommended Daily intake (IR) dose advised for adult use on the supplement labels. The Estimated Daily Intake (EDI) was first determined for each elemental exposure. Subsequently, the calculated EDI value was used to compute the Target Hazard Quotient (THQ) and HI values for non-carcinogenic risk assessment, and the CR and TCR values for carcinogenic risk assessment. Upon evaluating both the HI values for non-carcinogenic effects and the TCR values for carcinogenic effects, it was determined that only two samples S1 and S3, among the 10 supplements studied, do not present any carcinogenic (the CR or TCR values were between 1×10-⁶ and 1×10-⁴) or non-carcinogenic health hazards (HI < 1). The consumption of S1 and S3 at the specified dosages in adults was deemed safe. These findings emphasize the necessity for more extensive data in the quality evaluation of herbal dietary supplements and accentuate the significance of regulatory supervision and policy formulation in this domain.

Anahtar Kelimeler

• Carcinogenic risk
• non-carcinogenic risk
• toxic element
• herbal supplement

Sarı kantaron takviyelerinde elementel safsızlık risk değerlendirmesi

Öz

Bitkisel takviyelerdeki elementel safsızlık içeriği, özellikle kirlenmiş bölgelerde yetiştiriliyor veya hasat ediliyorsa, genellikle güvenlik sınırlarını aşmaktadır. Bu nedenle, çok sayıda rapor, bitkisel takviyelerdeki elementel safsızlıkların sağlık risk değerlendirmesine odaklanmıştır. Bu çalışmada, sarı kantaron içeren bitkisel takviyelerdeki kadmiyum (Cd), kurşun (Pb), arsenik (As) ve cıva (Hg) seviyeleri ve elementel safsızlık maruziyetiyle ilişkili kanserojen ve kanserojen olmayan sağlık risk değerlendirmesi yapılmıştır. 10 bitkisel takviye kapsülündeki dört elementel safsızlık, mikrodalga sindirim sistemi kullanılarak İndüktif Olarak Eşleştirilmiş Plazma Kütle Spektrometresi (ICP-MS) ile analiz edilmiştir. Risk hesaplamaları, takviye etiketlerinde yetişkin kullanımı için önerilen Günlük Alım (IR) dozu dikkate alınarak yapılmıştır. Her bir elementel maruziyet için Tahmini Günlük Alım (EDI) ilk olarak belirlenmiştir. Daha sonra, hesaplanan EDI değeri, kanserojen olmayan risk değerlendirmesi için Hedef Tehlike Katsayısı (THQ) ve HI değerlerini ve kanserojen risk değerlendirmesi için CR ve TCR değerlerini hesaplamak için kullanıldı. Hem kanserojen olmayan etkiler için HI değerleri hem de kanserojen etkiler için TCR değerleri değerlendirildikten sonra, incelenen 10 takviyeden sadece iki örneğin (S1 ve S3), kanserojen (CR veya TCR değerleri 1×10-⁶ ile 1×10-⁴ arasında) veya kanserojen olmayan sağlık tehlikesi (HI < 1) göstermediği belirlendi. S1 ve S3'ün belirtilen dozlarda yetişkinlerde tüketimi güvenli kabul edildi. Bu bulgular, bitkisel besin takviyelerinin kalite değerlendirmesinde daha kapsamlı verilere duyulan ihtiyacı vurgulamakta ve bu alanda düzenleyici denetim ve politika oluşturmanın önemini ortaya koymaktadır.

Anahtar Kelimeler

• Kanserojenik risk
• kanserojenik olmayan risk
• toksik element
• bitkisel takviye

Kaynakça

1. Acar İ, Canbolat F, Ayata F (2025). Determination of the elemental impurity levels in different mushroom species and probabilistic risk sssessment. Environmental Toxicology 41: 5-17. https://doi.org/10.1002/tox.24556
2. Agapouda A, Booker A, Kiss T, Hohmann J, Heinrich M, Csupor D (2019). Quality control of Hypericum perforatum L. analytical challenges and recent progress. Journal of Pharmacy and Pharmacology 71(1): 15-37. https://doi.org/10.1111/jphp.12711
3. Barnes J, Anderson LA, Phillipson JD (2001). St John's wort (Hypericum perforatum L.): a review of its chemistry, pharmacology and clinical properties. Journal of pharmacy and pharmacology 53(5): 583-600. https://doi.org/10.1211/0022357011775910
4. Canbolat F (2023). Analysis of non-carcinogenic health risk assessment of elemental impurities in vitamin C supplements. Iranian Journal of Basic Medical Sciences 26(2): 216-227. https://dx.doi.org/10.22038/IJBMS.2022.67487.14789
5. Canbolat F (2024). Elemental impurity analysis in five different types of coffee: Assessment of carcinogenic and non-carcinogenic risks. Sakarya University Journal of Science 28(4): 866-875. https://doi.org/10.16984/saufenbilder.1488500
6. Cansever I, Söğüt O (2025). An analytical approach for determining macro-and micro-elements in two different growing periods of Artemisia abrotanum L. BioMetals 38(5):1535-1550. https://doi.org/10.1007/s10534-025-00718-1
7. Ćwieląg‐Drabek M, Piekut A, Szymala I, Oleksiuk K, Razzaghi M et al. (2020). Health risks from consumption of medicinal plant dietary supplements. Food Science & Nutrition 8(7): 3535-3544. https://dx.doi.org/10.1002/fsn3.1636
8. Çolak S, Yazıco K, Akca SB (2020). Determination of heavy metal contents in St. John’s Wort (Hypericum spp) in Zonguldak, Turkey. Fresenius Environmental Bulletin 29(5): 3571-3578

9. Derkach T, Khomenko V (2018). Elemental composition of the medicinal plants Hypericum perforatum, Urtica dioica and Matricaria chamomilla grown in Ukraine: a comparative study. Pharmacognosy Journal 10(3): 486-491. https://dx.doi.org/10.5530/pj.2018.3.80
10. De Wit L, Jeurissen S, Chen W (2021). Risk assessment of herbal preparations containing St John's wort. Netherland: National Institute for Public Health and the Environment.
11. EMA (2021). European Union herbal monograph on Hypericum perforatum L., herba (well-established and traditional use), Amsterdam: European Medicines Agency Committee on Herbal Medicinal Products (HMPC).
12. Farasati Far B, Gouranmohit G, Naimi‐jamal MR, Neysani E, El‐Nashar H A et al., (2024). The potential role of Hypericum perforatum in wound healing: A literature review on the phytochemicals, pharmacological approaches, and mechanistic perspectives. Phytotherapy Research 38(7): 3271-3295. https://dx.doi.org/10.1002/ptr.8204
13. Gasser U, Klier B, KuhnAV, Steinhoff B (2009). Current findings on the heavy metal content in herbal drugs. Pharmeuropa 1: 37-49.
14. ICH (2022). Guideline for elemental impurities Q3D(R2) Guidance for Industry. Rockville: U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER).
15. Irshad M, Ahmed M, Ramzan M, Fatima M, Aftab F et al. (2024). Appraisal of potentially toxic metals contamination in protein supplements for muscle growth: A chemometric approach and associated human health risks. Journal of Trace Elements in Medicine and Biology 85: 1-13. https://doi.org/10.1016/j.jtemb.2024.127481
16. Islam N, Zamir R, Faruque MO (2024). Health risk assessment of metals in antidiabetic herbal preparations: a safety screening. Evidence‐Based Complementary and Alternative Medicine 2024(1): 1-12. https://doi.org/10.1155/2024/6507185
17. Jurowski K, Fołta M, Tatar B, Krośniak M (2022). The level of cadmium impurities in traditional herbal medicinal products with Plantago lanceolata L., folium (Ribwort plantain leaves) available in Polish pharmacies—comprehensive toxicological risk assessment including regulatory point of view and ICH Q3D Elemental Impurities Guideline. Biological Trace Element Research 200(6): 2963-2969. https://doi.org/10.1007/s12011-021-02861-5
18. Kandić I, Kragović M, Petrović J, Janaćković P, Gavrilović M (2023). Heavy metals content in selected medicinal plants produced and consumed in Serbia and their daily intake in herbal infusions. Toxics 11(2): 198. 1-19. https://doi.org/ 10.3390/toxics11020198
19. Kenny CR, Ring G, Sheehan A, Mc Auliffe MA, Lucey B et al. (2022). Novel metallomic profiling and non-carcinogenic risk assessment of botanical ingredients for use in herbal, phytopharmaceutical and dietary products using HR-ICP-SFMS. Scientific Reports 12(1): 1-24. https://doi.org/10.1038/s41598-022-16873-1
20. Liu H, Tang J, Chen T, Zhu P, Sun D et al. (2023). Assessment of heavy metals contamination and human health risk assessment of the commonly consumed medicinal herbs in China. Environmental Science and Pollution Research 30(3): 7345-7357. https://doi.org/10.1007/s11356-022-22647-z
21. Luo L, Wang B, Jiang J, Fitzgerald M, Huang Q et al. (2021). Heavy metal contaminations in herbal medicines: Determination, comprehensive risk assessments, and solutions. Frontiers in pharmacology 11: 1-14. https://dx.doi.org/10.3389/fphar.2020.595335
22. Magna EK, Koranteng SS, Donkor A, Gordon C (2021). Health risk assessment and levels of heavy metals in farmed Nile Tilapia (Oreochromis niloticus) from the Volta Basin of Ghana. Journal of Chemistry 2021(1): 1-10. https://doi.org/10.1155/2021/2273327
23. Masarovičová E, Kráľová K, Kummerová M (2010). Principles of classification of medicinal plants as hyperaccumulators or excluders. Acta Physiologiae Plantarum 32(5): 823-829. https://doi.org/10.1007/s11738-010-0474-1
24. Muhammad, MAA, Abdullahi SUR, Sulaiman M, Abba A, Olaleye A et al. (2024). Carcinogenic and noncarcinogenic health risk assessment of heavy metals on some selected traditional herbal drugs. Research Journal of Food Science and Quality Control (RJFSQC), 9(32024): 66-79. https://dx.doi.org/10.56201/rjfsqc.v10.no3.2024.pg66.79
25. Meng C, Wang P, Hao Z, Gao Z, Li Q et al. (2022). Ecological and health risk assessment of heavy metals in soil and Chinese herbal medicines. Environmental geochemistry and health 44(3): 817-828. https://doi.org/10.1007/s10653-021-00978-z
26. Miletić A, Lučić M, Onjia A (2023). Exposure factors in health risk assessment of heavy metal (loid) s in soil and sediment. Metals 13(7): 1-28. https://doi.org/10.3390/met13071266
27. Nobakht SZ, Akaberi M, Mohammadpour AH, Moghadam AT, Emami SA (2022). Hypericum perforatum: Traditional uses, clinical trials, and drug interactions. Iranian Journal of Basic Medical Sciences 25(9): 1045-1058. https//dx.doi.org/10.22038/IJBMS.2022.65112.14338
28. Okumuş E, Canbolat F, Acar İ (2025). Evaluation of antioxidant activity, anti-lipid peroxidation effect and elemental impurity risk of some wild Agaricus species mushrooms. BMC Plant Biology 25(1): 1-12. https://doi.org/10.1186/s12870-025-06520-y
29. Özyiğit İİ, Yalcin B, Turan S, Saracoglu IA, Karadeniz S et al. (2018). Investigation of heavy metal level and mineral nutrient status in widely used medicinal plants’ leaves in Turkey: Insights into health implications. Biological trace element research 182(2): 387-406. https://dx.doi.org/10.1007/s12011-017-1070-7
30. Popović S, Pantelić A, Milovanović Ž, Milinkov J, Vidović M (2017). Analysis of tea for metals by flame and graphite furnace atomic absorption spectrometry with multivariate analysis. Analytical Letters 50(16): 2619-2633. https://doi.org/10.1080/00032719.2017.1307849
31. Ring G, Sheehan A, Lehane M, Furey A (2021). Development, validation and application of an ICP-SFMS method for the determination of metals in protein powder samples, sourced in Ireland, with risk assessment for Irish consumers. Molecules 26(14): 1-20. https://doi.org/10.3390/molecules26144347
32. Rojas P, Ruiz-Sánchez E, Rojas C, García-Martínez BA, López-Ramírez AM et al. (2023). Human health risk assessment of arsenic and other metals in herbal products containing St. John’s Wort in the metropolitan area of Mexico City. Toxics 11(9): 801. 1-20. https:// doi.org/10.3390/toxics11090801
33. Suljić A, Bečić E, Husejnović MŠ, Ademović Z (2024). St John’s Wort as a possible tool for remediation of the soil contaminated with heavy metals. In: Arslanagić-Kalajdžić M, Ademović N, Tufek-Memišević T (eds) Interdisciplinary Advances in Sustainable Development II. BHAAAS 2023. Lecture Notes in Networks and Systems, vol 804. Cham: Springer, Pp. 61-69. https://doi.org/10.1007/978-3-031-46692-2_6
34. Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ (2012). Heavy metal toxicity and the environment. In: Luch A (edt.) Molecular, clinical and environmental toxicology. Experientia Supplementum 101. pp: 133-164 Basel: Springer. https://doi.org/10.1007/978-3-7643-8340-4_6
35. USP (2017). Elemental impurities – limits. In USP 40 e NF 35, First supplement. The United States Pharmacopeia Convention, https://www.usp.org/sites/default/files/usp/document/our-work/chemical-medicines/key-issues/232-40-35-1s.pdf / [accessed 03 June 2025].
36. USEPA (2010) Risk-based concentration table. Washington: United State Environmental Protection Agency. http://www.epa. gov/reg3hwmd/risk/human/index.htm. / [accessed 15 May 2025].