Skip to main content

Advertisement

SpringerLink
Log in

Hazardous or Advantageous: Uncovering the Roles of Heavy Metals and Humic Substances in Shilajit (Phyto-mineral) with Emphasis on Heavy Metals Toxicity and Their Detoxification Mechanisms

  • Review
  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Shilajit is a phyto-mineral diffusion and semi-solid matter used as traditional medicine with extraordinary health benefits. This study provides a comprehensive data on Shilajit with emphasis on heavy metal profile, associated toxicities, and metal detoxification mechanisms by humic substances present in Shilajit. Data was searched across papers and traditional books using Google Scholar, PubMed, Science Direct, Medline, SciELO, Web of Science, and Scopus as key scientific databases. Findings showed that Shilajit is distributed in almost 20 regions of the world with uses against 20 health problems as traditional medicine. With various humic substances, almost 11 biological activities were reported in Shilajit. This phyto-mineral diffusion possesses around 65 heavy metals including the toxic heavy metals like Cu, Al, Pb, As, Cd, and Hg. However, humic substances in Shilajit actively detoxify around 12 heavy metals. The recommended levels of heavy metals by WHO and FDA in herbal drugs is 0.20 and 0.30 ppm for Cd, 1 ppm for Hg, 10.00 ppm for As and Pb, 20 ppm for Cu, and 50 ppm for Zn. The levels of reported metals in Shilajit were found to be lower than the permissible limits set by WHO and FDA, except in few studies where exceeded levels were reported. Shilajit consumption without knowing permissible levels of metals is not safe and could pose serious health problems. Although the humic substances and few metals in Shilajit are beneficial in terms of chelating toxic heavy metals, the data on metal detoxification still needs to be clarified.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data Availability

All the supporting data has been included in the manuscript.

Code Availability

Not applicable.

References

  1. Puri HS (2002) Rasayana Ayurvedic herbs for longevity and rejuvenation, 1st Ed, Taylor & Francis London, England. https://doi.org/10.4324/9780203216569

  2. Carrasco-Gallardo C, Guzmán L, Maccioni RB (2012) Shilajit: a natural phytocomplex with potential procognitive activity. Int J Alzheimers Dis 2012:674142. https://doi.org/10.1155/2012/674142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ghosal S (2006) Shilajit in perspective, Ist. Alpha Science International Ltd, Oxford, United Kingdom

    Google Scholar 

  4. Agarwal SP, Khanna R, Karmarkar R, Anwer MK, Khar RK (2007) Shilajit: a review. Phytother Res 21(5):401–405

    Article  PubMed  Google Scholar 

  5. Kamgar E, Kaykhaii M, Zembrzuska J (2023) A comprehensive review on Shilajit: what we know about its chemical composition. Crit Rev Anal Chem 1–13. https://doi.org/10.1080/10408347.2023.2293963

  6. Marcinčák S, Semjon B, Marcinčáková D, Reitznerová A, Mudroňová D, Vašková J, Nagy J (2023) Humic substances as a feed supplement and the benefits of produced chicken meat. Life 13(4):927. https://doi.org/10.3390/life13040927

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  7. Stohs SJ, Singh K, Das A, Roy S, Sen CK (2017) 12-Energy and health benefits of Shilajit. In: Bagchi, D., Editor. Sustained energy for enhanced human functions and activity. Academic press 187–204. https://doi.org/10.1016/B978-0-12-805413-0.00012-0

  8. Abd Elnabi MK, Elkaliny NE, Elyazied MM, Azab SH, Elkhalifa SA, Elmasry S, Mouhamed MS, Shalamesh EM, Alhorieny NA, Abd Elaty AE, Elgendy IM, Etman AE, Saad KE, Tsigkou K, SS, Kornaros M, Mahmoud YAG, (2023) Toxicity of heavy metals and recent advances in their removal: a review. Toxics 11(7):580. https://doi.org/10.3390/toxics11070580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ali B, Gill RA (2022) Editorial: Heavy metal toxicity in plants: recent insights on physiological and molecular aspects, volume II. Front Pl Sci 13:1016257. https://doi.org/10.3389/fpls.2022.1016257

    Article  Google Scholar 

  10. Yates LM, Wandruszka RV (1999) Decontamination of polluted water by treatment with a crude humic acid blend. Environ Sci Technol 33:2076–2080. https://doi.org/10.1021/es980408k

    Article  CAS  ADS  Google Scholar 

  11. Perminova IV, García-Mina JM, Knicker H, Miano T (2019) Humic substances and nature-like technologies. J Soils Sedim 19:2663–2664. https://doi.org/10.1007/s11368-019-02330-6

    Article  Google Scholar 

  12. Tang WW, Zeng GM, Gong JL, Liang J, Xu P, Zhang C, Huang BB (2014) Impact of humic/fulvic acid on the removal of heavy metals from aqueous solutions using nanomaterials: a review. Sci Total Environ 468–469:1014–1027. https://doi.org/10.1016/j.scitotenv.2013.09.044

    Article  CAS  PubMed  ADS  Google Scholar 

  13. Chopra RN, Chopra IC, Handa KL, Kapoor DK (1958) In: indigenous drugs of India. India UN Dhar and Sons, Calcutta

    Google Scholar 

  14. Hill CA, Forti P (1997) Cave minerals of the World, 2nd edn. National Speleological Society, United States of America, p 463

  15. Linnik P, Vasilchuk T (2005) Role of humic substances in the complexation and detoxification of heavy metals: case study of the Dnieper reservoirs. In: Perminova IV, Hatfield K, Hertkorn N (eds) Use of humic substances to remediate polluted environments: From theory to practice. NATO Science Series, 52. Springer, Dordrecht. https://doi.org/10.1007/1-4020-3252-8_6

  16. Thomas DR (2017) Shilajit: resin of life. Kindle Edition Amazon, p 88

  17. Chopra A (2019) Shilajit: the healer of the Himalayas. Kindle Edition Amazon, p 36

  18. Mikhail S (2022) Encyclopedia of mumiyo (in Russian). Litres. https://books.google.com.pk/books?id=dPI-DwAAQBAJ

  19. Paulman F (2023) Shilajit: a beginner’s quick start guide and overview on its use cases, with a potential 3-step plan on getting started. Mindplusfood, p 52

  20. Windmann W (2023) Shilajit: the ayurvedic adaptogen for anti-aging and immune power. Earthdancer Books, p 160

  21. Acharya SB, Frotan MH, Goel RK, Tripathi SK, Das PK (1988) Pharmacological actions of Shilajit. Ind J Exp Biol 26:775–777

    CAS  Google Scholar 

  22. Ghosal S (1990) Chemistry of Shilajit, an immunomodulatory Ayurvedic rasayan. Pure Appl Chem 62(7):1285–1288

    Article  CAS  Google Scholar 

  23. Ghosal S, Mukherjee B, Bhattacharya SK (1995) Shilajit— a comparative study of the ancient and the modern scientific findings. Ind J Indus Med 17:1–10

    Google Scholar 

  24. Frolova LN, Kiseleva TL (1996) Chemical composition of mumijo and methods for determining its authenticity and quality (a review). Pharma Chem J 30(8):543–547. https://doi.org/10.1007/bf02334644

    Article  Google Scholar 

  25. Schepetkin I, Khlebnikov A, Kwon B (2002) Medical drugs from humus matter: focus on Mumie. Drug Develop Res 57(3):140–159. https://doi.org/10.1002/ddr.10058

    Article  CAS  Google Scholar 

  26. Choudhary SP, Singh AK, Dwivedi KN (2016) Medicinal properties of Shilajit – a review. Ind J Agri Allied Sci 2:103–106

    Google Scholar 

  27. Rahmani Barouji S, Saber A, Torbati M, Fazljou SMB, Yari Khosroushahi A (2020) Health beneficial effects of Moomiaii in traditional medicine. Galen Med J 9:e1743. https://doi.org/10.31661/gmj.v9i0.1743

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ghosal S, Reddy JP, Lal VK (1976) Shilajit I: chemical constituents. J Pharma Sci 65(5):772–773

    Article  CAS  Google Scholar 

  29. Ghosal S, Lal J, Singh SK, Goel RK, Jaiwal AK, Bhattacharya SK (1991) The need for formulation of Shilajit by its isolated active constituents. Phytother Res 5(5):211–216

    Article  CAS  Google Scholar 

  30. Aiello A, Fattorusso E, Menna M, Vitalone R, Schröder HC, Müller WE (2011) Mumijo traditional medicine: fossil deposits from antarctica (chemical composition and beneficial bioactivity). Evid Based Compl Alt Med 2011:738131. https://doi.org/10.1093/ecam/nen072

    Article  Google Scholar 

  31. Saleem AM, Gopal V, Rafiullah MRM, Bharathidasan P (2006) Chemical and pharmacological evaluation of karpura Shilajit bhasma, an ayurvedic diuretic formulation. Afr J Trad Compl Alt Med 3:27–36. https://doi.org/10.4314/ajtcam.v3i2.31154

    Article  CAS  Google Scholar 

  32. Rao SKR, Sudarshan SR, Parameshvara V (2005) Encyclopedia of Indian medicine: Materia medica – Metallic and mineral drugs. Popular Prakashan 5:125. https://books.google.com.pk/books?id=qmxFAAAAYAAJ

  33. Schepetkin IA, Khlebnikov AI, Ah SY, Woo SB, Jeong CS, Klubachuk ON, Kwon BS (2003) Characterization and biological activities of humic substances from Mumie. J Agri Food Chem 51(18):5245–5254. https://doi.org/10.1021/jf021101e

    Article  CAS  Google Scholar 

  34. Jafari M, Forootanfar H, Ameri A, Foroutanfar A, Adeli-Sardou M, Rahimi HR, Najafi A, Zangiabadi N, Shakibaie M (2019) Antioxidant, cytotoxic and hyperalgesia-suppressing activity of a native Shilajit obtained from Bahr Aseman mountains. Pak J Pharma Sci 32:2167–2173

    CAS  Google Scholar 

  35. Gupta SS (1966) Experimental studies on pituitary diabetes. Effects of Shilajit, Ficus bengalensis and anterior pituitary extract on glucose tolerance in rats. Ind J Med Res 54:354–362

    CAS  Google Scholar 

  36. Cornejo A, Jiménez JM, Caballero L, Melo F, Maccioni RB (2011) Fulvic acid inhibits aggregation and promotes disassembly of tau fibrils associated with Alzheimer’s disease. J Alzheim Dis 27(1):143–153. https://doi.org/10.3233/JAD-2011-110623

    Article  CAS  Google Scholar 

  37. Halpern M (2003) Clinical Ayurvedic medicine, 4th edn. California College of Ayurveda, Grass Valley, CA

    Google Scholar 

  38. Halpern M (2003) Principles of Ayurvedic medicine, 5th edn. California College of Ayurveda, Grass Valley, CA

    Google Scholar 

  39. Agzamov RA, Arifkhanova SI, Vakhidova GA (1988) Mumie kak patogeneticheskoe sredstvo dlia lecheniia tuberkuleza [Mumie as a pathogenetic agent in the treatment of tuberculosis]. Probl Tuberk 7:49–52

    Google Scholar 

  40. Aldakheel RK, Gondal MA, Alsayed HN, Almessiere MA, Nasr MM, Shemsi AM (2022) Rapid determination and quantification of nutritional and poisonous metals in vastly consumed ayurvedic herbal medicine (Rejuvenator Shilajit) by humans using three advanced analytical techniques. Biol Trace Elem Res 200(9):4199–4216. https://doi.org/10.1007/s12011-021-03014-4

    Article  CAS  PubMed  Google Scholar 

  41. Mao Z, Sun W, Fu L, Luo H, Lai D, Zhou L (2014) Natural dibenzo-α-pyrones and their bioactivities. Molecules 19(4):5088–5108. https://doi.org/10.3390/molecules19045088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sutradhar S, Fatehi P (2023) Latest development in the fabrication and use of lignin-derived humic acid. Biotechnology Biofuels Bioproduction 16(1):38. https://doi.org/10.1186/s13068-023-02278-3

    Article  CAS  Google Scholar 

  43. Ali M, Saharawat I, Singh O (2004) Phytochemical investigation of Shilajit. Ind J Chem 43B:2217–2222

    CAS  Google Scholar 

  44. Kong YC, But PPH, Ng KH, Cheng KF, Cambie RC, Malla SB (1987) Chemical studies on a Nepalese Panacea- Shilajit(I). Int J Crude Drug Res 25:179–182. https://doi.org/10.3109/13880208709060925

    Article  CAS  Google Scholar 

  45. Ali Himaidi AR, Mohammad U (2003) Safe use of Shilajit during pregnancy of female mice. Online J Biol Sci 3:681–684

    Article  Google Scholar 

  46. Assegid G, Fiest M, Schmolz E, Lamprecht I (2004) Thermal analysis of mumiyo, the legendary folk remedy from the Himalaya region. Thermochim Acta 417:301–309

    Article  Google Scholar 

  47. Khanna R, Witt M, Koch BP (2008) Spectroscopic characterisation of fulvic acids extracted from the rock exudate Shilajit. Organic Geochem 39:1719–1724. https://doi.org/10.1016/j.orggeochem.2008.08.009

    Article  CAS  ADS  Google Scholar 

  48. Schepetkin IA, Xie G, Julia MA, Quinn MT (2009) Complement fixing activity of fulvic acid from Shilajit and other natural sources. Phytother Res 23:373–384. https://doi.org/10.1002/ptr.2635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ghosal S, Lal J, Jaiswal AK, Bhattacharya SK (1993) Effects of Shilajit and its active constituents on learning and memory in rats. Phytother Res 7:29–34

    Article  CAS  Google Scholar 

  50. Jaiswal AK, Bhattacharya SK (1992) Effects of Shilajit on memory, anxiety and brain monoamines in rats. Ind J Pharmacol 24:12–17

    Google Scholar 

  51. Sharma P, Jha J, Shrinivas V, Dwivedi LK, Suresh P, Sinha M (2003) Shilajit: evalution of its effects on blood chemistry of normal human subjects. Anc Sci Life 23(2):114–119

    PubMed  PubMed Central  Google Scholar 

  52. Park JS, Kim GY, Han K (2006) The spermatogenic and ovogenic effects of chronically administered Shilajit to rats. J Ethnopharmacol 107(3):349–353. https://doi.org/10.1016/j.jep.2006.03.039

    Article  PubMed  Google Scholar 

  53. Biswas TK, Pandit S, Mondal S, Biswas SK, Jana U, Ghosh T, Tripathi PC, Debnath PK, Auddy RG, Auddy B (2009) Clinical evaluation of spermatogenic activity of processed Shilajit in oligospermia. Andrologia 42:48–56

    Article  Google Scholar 

  54. Kaur S, Kumar P, Kumar D, Kharya MD, Singh N (2013) Parasympathomimetic effect of Shilajit accounts for relaxation of rat corpus cavernosum. Amer J Mens Health 7:119–127. https://doi.org/10.1177/1557988312462738

    Article  Google Scholar 

  55. Khaksari M, Mahmmodi R, Shahrokhi N, Shabani M, Joukar S, Aqapour M (2013) The effects of Shilajit on brain edema, intracranial pressure and neurologic outcomes following the traumatic brain injury in rat. Iran J Basic Med Sci 16(7):858–864

    PubMed  PubMed Central  Google Scholar 

  56. Kececi M, Akpolat M, Gulle K, Gencer E, Sahbaz A (2016) Evaluation of preventive effect of Shilajit on radiation-induced apoptosis on ovaries. Arch Gynecol Obstet 293(6):1255–1262. https://doi.org/10.1007/s00404-015-3924-6

    Article  CAS  PubMed  Google Scholar 

  57. Trivedi N, Mazumdar B, Bhatt J, Hemavathi K (2004) Effect of Shilajit on blood glucose and lipid profile in alloxaninduced diabetic rats. Ind J Pharmacol 36(6):373–376

    CAS  Google Scholar 

  58. Bhattacharaya SK (1995) Shilajit attenuates streptozotocin induced diabetes mellitus and decreases pancreatic islet superoxide dismutase activity in rats. Phytother Res 9:41–44

    Article  Google Scholar 

  59. Saxena N, Dwivedi UN, Singh RK, Kumar A, Saxena C, Saxena RC, Saxena M (2003) Modulation of oxidative and antioxidative status in diabetes by Asphaltum panjabinum. Diabet Care 26(8):2469–2470. https://doi.org/10.2337/diacare.26.8.2469-a

    Article  Google Scholar 

  60. Bhattacharya SK, Sen AP (1995) Effects of Shilajit on biogenic free radicals. Phytother Res 9:56–59

    Article  Google Scholar 

  61. Bhattacharayya S, Pal D, Banerjee D, Auddy B, Gupta A, Ganguly P, Majumber UK, Ghosal S (2009) Shilajit dibenzo-apyrones: mitochondria targeted antioxidants. Pharmacologyonline 2:690–698

    Google Scholar 

  62. Vašková J, Veliká B, Pilátová M, Kron I, Vaško L (2011) Effects of humic acids in vitro. In Vitro Cell Devel Biol 47:376–382. https://doi.org/10.1007/s11626-011-9405-8

    Article  CAS  Google Scholar 

  63. Kotb-El-Sayed MK, Amin H, Al-kaf A (2012) Anti-microbial, anti-oxidant and anti-ulcerogenic effects of Shilajit on gastric ulcer in rats. Amer J Biochem Biotechnol 8:26–39

    Article  Google Scholar 

  64. Verma A, Kumar N, Gupta L, Chaudhary S (2016) Shilajitin cancer treatment: probable mode of action. Int J Pharm Bio Arch 7(1):12–16

    Google Scholar 

  65. Helbig B, Klöcking R, Wutzler P (1997) Anti-herpes simplex virus type 1 activity of humic acid-like polymers and their o-diphenolic starting compounds. Antiviral Chem Chemother 8(3):265–273

    Article  CAS  Google Scholar 

  66. Thiel KD, Helbig B, Klocking R, Wutzler P, Sprossig M, Schweizer H (1981) Comparison of the in vitro activities of ammonium humate and of enzymically oxidized chlorogenic and caffeic acids against type 1 and type 2 human herpes virus (author’s transl). Pharmazie 36(1):50–53

    CAS  PubMed  Google Scholar 

  67. Klöcking R, Helbig B, Schötz G, Schacke M, Wutzler P (2002) Anti-HSV-1 activity of synthetic humic acid-like polymers derived from p-diphenolic starting compounds. Antiviral Chem Chemother 13:241–249

    Article  Google Scholar 

  68. Gupta GD, Sujatha N, Dhanik A, Rai NP (2010) Clinical evaluation of Shilajatu Rasayana in patients with HIV infection. AYU 31(1):28–32. https://doi.org/10.4103/0974-8520.68205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Goel RK, Banerjee RS, Acharya SB (1990) Antiulcerogenic and anti-inflammatory studies with Shilajit. J Ethnopharmacol 29:95–103. https://doi.org/10.1016/0378-8741(90)90102-y

    Article  CAS  PubMed  Google Scholar 

  70. Lown JF, Gill K, Cutler SJ, Cutler HG, Pollock SH (2006) Anti-inflammatory humate compositions and methods of use thereof. Patent no. US-706755 B2. TBNI Inc, Dallas, TX, USA

  71. Van Rensburg CEJ, Snyman JR, Mokoele T, Cromarty AD (2007) Brown coal derived humate inhibits contact hypersensitivity; an efficacy, toxicity and teratogenicity study in rats. Inflammation 30(5):148–152. https://doi.org/10.1007/s10753-007-9031-5

    Article  CAS  PubMed  Google Scholar 

  72. Sabi R, Very P, Van Rensburg C (2012) Carbohydrate-derived fulvic acid (CHD-FA) inhibits carrageenan-induced inflammation and enhances wound healing: efficacy and toxicity study in rats. Drug Develop Res 73(1):18–23. https://doi.org/10.1002/ddr.20445

    Article  CAS  Google Scholar 

  73. Malekzadeh G, Dashti-Rahmatabadi MH, Zanbagh S, Akhavi Mirab-bashii A (2015) Mumijo attenuates chemically induced inflammatory pain in mice. Alter Ther Health Med 21(2):42–47

    Google Scholar 

  74. Shahrokhi N, Keshavarzi Z, Khaksari M (2015) Ulcer healing activity of Mumijo aqueous extract against acetic acid induced gastric ulcer in rats. J Pharm Bioallied Sci 7(1):56–59

    Article  PubMed  PubMed Central  Google Scholar 

  75. Winkler J, Ghosh S (2018) Therapeutic potential of fulvic acid in chronic inflammatory diseases and diabetes. J Diabet Res 2018:5391014. https://doi.org/10.1155/2018/5391014

    Article  CAS  Google Scholar 

  76. Kim KH, Jung JH, Chung WS, Lee CH, Jang HJ (2021) Ferulic acid induces keratin 6alpha via Inhibition of nuclear beta-catenin accumulation and activation of Nrf2 in wound-induced inflammation. Biomedicines 9. https://doi.org/10.3390/biomedicines9050459

  77. Yang HL, Hseu YC, Yi-Ting H, Luc FJ, Linb E, Laid JS (2004) Humic acid induces apoptosis in human premyelocytic leukemia HL-60 cells. Life Science 275(15):1817–1831. https://doi.org/10.1016/j.lfs.2004.02.033

    Article  CAS  Google Scholar 

  78. Hseu YC, Lin E, Chen JY, Liua R, Huang CY, Lu FJ, Liao JW, Chen SC, Yang HL (2008) Humic acid induces G1 phase arrest and apoptosis in cultured vascular smooth muscle cells. Environ Toxicol 24:243–258

    Article  ADS  Google Scholar 

  79. Vucskits AV, Hulla I, Bersenyi A, Andrasofszky E, Kulcsar M, Szabo J (2010) Effect of fulvic and humic acids on performance, immune response and thyroid function in rats. J Anim Physiol Anim Nutr 94:271–728

    Article  Google Scholar 

  80. Muela A, Garcia-Bringas JM, Barcina AI (2000) Humic materials offer photoprotective effect to Escherichia coli exposed to damaging luminous radiation. Microb Ecol 40:336–344. https://doi.org/10.1007/s002480000064

    Article  CAS  PubMed  ADS  Google Scholar 

  81. Clair TA, Ehrman J, Kaczmarska I, Locke A, Tarasick DW, Day KE, Maillet G (2001) Will reduced summer UV-B levels affect zooplankton populations of temperate humic and Clearwater lakes? Hydrobiologia 462:75–89

    Article  Google Scholar 

  82. Alkan U, Teksoy AA, Baskaya HS (2007) Influence of humic substances on the ultraviolet disinfection of surface waters. Water Environ J 21:61–68

    Article  CAS  Google Scholar 

  83. Calfio C, Gonzalez A, Singh SK, Rojo LE, Maccioni RB (2020) The emerging role of nutraceuticals and phytochemicals in the prevention and treatment of Alzheimer’s disease. J Alzheim Dis 77:33–51. https://doi.org/10.3233/JAD-200443

    Article  CAS  Google Scholar 

  84. Andrade V, Wong-Guerra M, Cortés N, Pastor G, González A, Calfío C, Guzmán-Martínez L, Navarrete LP, Ramos-Escobar N, Morales I, Santander R, Andrades-Lagos J, Bacho M, Rojo LE, Maccioni BR (2023) Scaling the Andean Shilajit: a novel neuroprotective agent for Alzheimer’s disease. Pharmaceuticals (Basel) 16(7):960. https://doi.org/10.3390/ph16070960

    Article  CAS  PubMed  Google Scholar 

  85. Kloskowski T, Szeliski K, Krzeszowiak K, Fekner Z, Kazimierski L, Jundzill A, Drewa T, Pokrywczynska M (2021) Mumio (Shilajit) as a potential chemotherapeutic for the urinary bladder cancer treatment. Sci Rep 11:22614. https://doi.org/10.1038/s41598-021-01996-8

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  86. Pant K, Gupta P, Damania P, Yadav AK, Gupta A, Ashraf A, Venugopal SK (2016) Mineral pitch induces apoptosis and inhibits proliferation via modulating reactive oxygen species in hepatic cancer cells. BMC Complement Altern Med 16:148. https://doi.org/10.1186/s12906-016-1131-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Atashbar J, Shahrokhi N, Khaksari HM, Asadi KG, Shahrokhi N, Ghazi F (2018) Mumijo protection against acetaminophen-induced acute hepatic injury: role of oxidative stress. J Kerm Univ Med Sci 25(1):44–56

    Google Scholar 

  88. Ghezelbash B, Shahrokhi N, Khaksari M, Ghaderi-Pakdel F, Asadikaram G (2020) Hepatoprotective effects of Shilajit on high fat-diet induced non-alcoholic fatty liver disease (NAFLD) in rats. Hormone Mol Biol Clin Invest 41. https://doi.org/10.1515/hmbci-2019-0040

  89. Jambi EJ, Abdulaziz AF (2022) Shilajit potentiates the effect of chemotherapeutic drugs and mitigates metastasis induced liver and kidney damages in osteosarcoma rats. Saudi J Biol Sci 29(9):103393. https://doi.org/10.1016/j.sjbs.2022.103393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Velmurugan C, Vivek B, Wilson E, Bharathi T, Sundaram T (2012) Evaluation of safety profile of black Shilajit after 91 days repeated administration in rats. Asian Pac J Trop Biomed 2(3):210–214. https://doi.org/10.1016/S2221-1691(12)60043-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Healthy Nutrition Group LLC. 2023. Certificates of analysis & lab tests: understanding heavy metal levels in natural Shilajit resin. Venice, CA 90294. Available from https://naturalshilajit.com/pages/shilajit-resin-certificates-of-analysis-lab-tests

  92. Sukhdolgor J, Orkhonselenge D (2014) Biochemical study of Mumijo in Uvs province, Mongolia. Mongol J Chem 12:56–59. https://doi.org/10.5564/mjc.v12i0.173

    Article  Google Scholar 

  93. Rahim M, Mohammadzei I, Hassan W, Ahmad N (2016) Heavy metal profile of Shilajit samples obtained from Gilgit and Chellas, Pakistan. J Phys Sci 27:139–144

    Article  CAS  Google Scholar 

  94. Mishra T, Sircar D, Dhaliwal SH, Singh N (2020) Spectroscopic and chromatographic characterization of crude natural Shilajit from Himachal Pradesh. India. The Nat Prod J 10(3):244–256. https://doi.org/10.2174/2210315509666190112111808

    Article  CAS  Google Scholar 

  95. Ghosal S, Singh SK, Kumar Y, Srivatsava R (1988) Antiulcerogenic activity of fulvic acids and 4-metoxy-6-carbomethyl biphenyl isolated from Shilajit. Phytother Res 2:187–191

    Article  CAS  Google Scholar 

  96. Garedew A, Feist M, Schmolz E, Lamprecht I (2004) Thermal analysis of mumiyo, the legendary folk remedy from the Himalaya region. Thermochim Acta 417(2):301–309. https://doi.org/10.1016/j.tca.2003.09.034

    Article  CAS  Google Scholar 

  97. Agarwal SP, Anwer MDK, Khanna R, Ali A, Sultana Y (2010) Humic acid from Shilajit – a physico-chemical and spectroscopic characterization. J Serb Chem Soc 75(3):413–422

    Article  CAS  Google Scholar 

  98. Ghorani-Azam A, Riahi-Zanjani B, Balali-Mood M (2016) Effects of air pollution on human health and practical measures for prevention in Iran. J Res Med Sci 21:65. https://doi.org/10.4103/1735-1995.18964

    Article  PubMed  PubMed Central  Google Scholar 

  99. Luo L, Wang B, Jiang J, Fitzgerald M, Huang Q, Yu Z, Li H, Zhang J, Wei J, Yang C, Zhang H, Dong L, Chen S (2020) Heavy metal contaminations in herbal medicines: determination, comprehensive risk assessments and solutions. Front Pharmacol 11:595335. https://doi.org/10.3389/fphar.2020.595335

    Article  CAS  PubMed  Google Scholar 

  100. Vahter M, Akesson A, Lidén C, Ceccatelli S, Berglund M (2007) Gender differences in the disposition and toxicity of metals. Environ Res 104(1):85–95. https://doi.org/10.1016/j.envres.2006.08.003

    Article  CAS  PubMed  Google Scholar 

  101. Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ (2012) Heavy metal toxicity and the environment. Exp Suppl 101:133–164. https://doi.org/10.1007/978-3-7643-8340-4_6

    Article  PubMed  Google Scholar 

  102. Balali-Mood M, Naseri K, Tahergorabi Z, Khazdair MR, Sadeghi M (2021) Toxic mechanisms of five heavy metals: mercury, lead, chromium, cadmium, and arsenic. Front Pharmacol 12:643972. https://doi.org/10.3389/fphar.2021.643972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gazwi HSS, Yassien EE, Hassan HM (2020) Mitigation of lead neurotoxicity by the ethanolic extract of Laurus leaf in rats. Ecotoxicol Environ Safe 192:110297. https://doi.org/10.1016/j.ecoenv.2020.110297

    Article  CAS  Google Scholar 

  104. Saper RB, Phillips RS, Sehgal A, Khouri N, Davis RB, Paquin J, Thuppil V, Kales SN (2008) Lead, mercury, and arsenic in US- and Indian-manufactured Ayurvedic medicines sold via the Internet. JAMA 300(8):915–923. https://doi.org/10.1001/jama.300.8.915.Erratum.In:JAMA300(14):1652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hayes RB (1997) The carcinogenicity of metals in humans. Can Causes Cont 8:371–385

    Article  CAS  Google Scholar 

  106. Järup L (2003) Hazards of heavy metal contamination. Brit Med Bullet 68:167–182

    Article  Google Scholar 

  107. Mcelroy JA, Shafer MM, Gangnon RE, Crouch LA, Newcomb PA (2008) Urinary lead exposure and breast cancer risk in a population-based case-control study. Can Epidemiol Biomark Prevent 17:2311–2317

    Article  CAS  Google Scholar 

  108. Moore LE, Smith AH, Eng C, Kalman D, DeVries S, Bhargava V, Chew K, Moore D, Ferreccio C, Rey OA, Waldman FM (2002) Arsenic-related chromosomal alterations in bladder cancer. J Nat Can Inst 94:1688–1696. https://doi.org/10.1093/jnci/94.22.1688

    Article  CAS  Google Scholar 

  109. Huang SL, Weng YM, Huang CH (2004) Lipid peroxidation in sarcoplasmic reticulum and muscle of tilapia is inhibited by dietary vitamin E supplementation. J Food Biochem 28:101–111

    Article  CAS  Google Scholar 

  110. Mazumder DNG (2008) Chronic arsenic toxicity & human health. Ind J Med Res 128(4):436–447

    Google Scholar 

  111. Saint-Jacques N, Parker L, Brown P, Dummer TJ (2014) Arsenic in drinking water and urinary tract cancers: a systematic review of 30 years of epidemiological evidence. Environ Health 13:44. https://doi.org/10.1186/1476-069X-13-44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Huang HW, Lee CH, Yu HS (2019) Arsenic-induced carcinogenesis and immune dysregulation. Int J Environ Res Pub Health 16(15):2746. https://doi.org/10.3390/ijerph16152746

    Article  CAS  Google Scholar 

  113. Ellingsen DG, Andersen A, Nordhagen HP, Efskind J, Kjuus H (1993) Incidence of cancer and mortality among workers exposed to mercury vapour in the Norwegian chloralkali industry. Brit J Ind Med 50(10):875–880. https://doi.org/10.1136/oem.50.10.875

    Article  CAS  Google Scholar 

  114. Bernhoft RA (2012) Mercury toxicity and treatment: a review of the literature. J Environ Pub Health 2012:460508. https://doi.org/10.1155/2012/460508

    Article  Google Scholar 

  115. Tsai MT, Huang SY (2017) Cheng SY (2017) Lead poisoning can be easily misdiagnosed as acute porphyria and nonspecific abdominal pain. Case Rep Emerg Med 2:1–4. https://doi.org/10.3109/10408444.2013.768596

    Article  CAS  Google Scholar 

  116. Chen Y, Mao X, Zhu D (1984) Synthesis of macroporous humic acid resins and their chelating properties for heavy metal ions. Pol Comm 1984:159–168

    Google Scholar 

  117. Winner RW (1985) Bioaccumulation and toxicity of copper as affected by interactions between humic acid and water hardness. Water Res 19:449–455. https://doi.org/10.1016/0043-1354(85)90036-3

    Article  CAS  ADS  Google Scholar 

  118. Ullah SM, Gerzabek MH (1991) Influence of fulvic and humic acids on Cu-toxicity and V-toxicity to Zea mays. Bodenkultur 42:123–134

    CAS  Google Scholar 

  119. Kezhong G, Jack P, Jeniffer J, Colin T, Colin T (1999) Interaction between peat, humic acid and aqueous metal ions. Environ Geochem Health 21:13–26

    Article  Google Scholar 

  120. Xue H, Sigg L (1999) Comparison of the complexation of Cu and Cd by humic or fulvic acids and by ligands observed in lake waters. Aqua Geochem 5:313–335. https://doi.org/10.1023/A:1009679819002

    Article  CAS  Google Scholar 

  121. Christl I, Metzger A, Heidmann I, Kretzschmar R (2005) Effect of humic and fulvic acid concentrations and ionic strength on copper and lead binding. Environ Sci Technol 39:5319–5326

    Article  CAS  PubMed  ADS  Google Scholar 

  122. Dobranskyte A, Jugdaohsingh R, McCrohan CR, Stuchlik E, Powell JJ, White KN (2006) Effect of humic acid on water chemistry, bioavailability and toxicity of aluminium in the freshwater snail, Lymnaea stagnalis, at neutral pH. Environ Pollut 140(2):340–347. https://doi.org/10.1016/j.envpol.2005.06.030

    Article  CAS  PubMed  Google Scholar 

  123. Sanmanee N, Areekijseree M (2010) The effects of fulvic acid on copper bioavailability to porcine oviductal epithelial cells. Biol Trace Elem Res 135:162–173. https://doi.org/10.1007/s12011-009-8508-5

    Article  CAS  PubMed  Google Scholar 

  124. Jones AM, Griffin PJ, Waite TD (2015) Ferrous iron oxidation by molecular oxygen under acidic conditions: the effect of citrate, EDTA and fulvic acid. Geochim Cosmochim Acta 160:117–131. https://doi.org/10.1016/j.gca.2015.03.026

    Article  CAS  ADS  Google Scholar 

  125. Mousavi MP, Gunsolus IL, Perez De Jesus CE, Lancaster M, Hussein K, Haynes CL, Bühlmann P (2015) Dynamic silver speciation as studied with fluorous-phase ion-selective electrodes: effect of natural organic matter on the toxicity and speciation of silver. Sci Tot Environ 537:453–461. https://doi.org/10.1016/j.scitotenv.2015.07.151

    Article  CAS  Google Scholar 

  126. Bi D, Yuan G, Wei J, Xiao L, Feng L, Meng F, Wang J (2019) A soluble humic substance for the simultaneous removal of cadmium and arsenic from contaminated soils. Int J Environ Res Pub Health 16(24):4999. https://doi.org/10.3390/ijerph16244999

    Article  CAS  Google Scholar 

  127. Wang Q, Wen J, Zheng J, Zhao J, Qiu C, Xiao D, Mu L, Liu X (2021) Arsenate phytotoxicity regulation by humic acid and related metabolic mechanisms. Ecotoxicol Environ Safe 207:111379. https://doi.org/10.1016/j.ecoenv.2020.111379

    Article  CAS  Google Scholar 

  128. Rong Q, Zhong K, Huang H, Li C, Zhang C, Nong X (2020) Humic acid reduces the available cadmium, copper, lead, and zinc in soil and their uptake by Tobacco. Appl Sci 10(3):1077. https://doi.org/10.3390/app10031077

    Article  CAS  Google Scholar 

  129. Sun Q, Wang G, Yin R, Zhang T, Zheng Y, Wu C, Liu C, Huang K, Wang F (2022) Effects of molecular-level component variation of fulvic acid on photodegradation of microcystin-LR under solar irradiation. Chem Engin J 449:137553. https://doi.org/10.1016/j.cej.2022.137553

    Article  CAS  Google Scholar 

  130. Wan K, Xiao Y, Fan J, Miao Z, Wang G, Xue S (2022) Preparation of high-capacity macroporous adsorbent using lignite-derived humic acid and its multifunctional binding chemistry for heavy metals in wastewater. J Clean Prod 363:132498. https://doi.org/10.1016/j.jclepro.2022.132498

    Article  CAS  Google Scholar 

  131. Xun L, Yajun Z, Xianglin F, Nian L (2022) Effects of environmental factor fulvic acid on AgNPs food chain delivery and bioavailability. Compl Biochem Physiol Part C: Toxicol Pharmacol 258:109369. https://doi.org/10.1016/j.cbpc.2022.109369

    Article  CAS  Google Scholar 

  132. Jolliffe DM, Budd AJ, Gwilt DJ (1991) Massive acute arsenic poisoning. Anaesthesia 46(4):288–290. https://doi.org/10.1111/j.1365-2044.1991.tb11500.x

    Article  CAS  PubMed  Google Scholar 

  133. Cheng JP, Wang WH, Jia JP, Zheng M, Shi W, Lin XY (2006) Expression of c-fos in rat brain as a prelude marker of central nervous system injury in response to methylmercury-stimulation. Biomed Environ Sci 19(1):67–72

    CAS  PubMed  Google Scholar 

  134. Strużyńska L, Dąbrowska-Bouta B, Koza K, Sulkowski G (2007) Inflammation-like glial response in lead-exposed immature rat brain. Toxicol Sci 95(1):156–162. https://doi.org/10.1093/toxsci/kfl134

    Article  CAS  PubMed  Google Scholar 

  135. Schutte R, Nawrot TS, Richart T, Thijs L, Vanderschueren D, Kuznetsova T, Hecke EV, Roels HA, Staessen JA (2008) Bone resorption and environmental exposure to cadmium in women: a population study. Environ Health Perspect 116(6):777–783. https://doi.org/10.1289/ehp.11167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Dongre NN, Suryakar AN, Patil AJ, Ambekar JG, Rathi DB (2011) Biochemical effects of lead exposure on systolic & diastolic blood pressure, heme biosynthesis and hematological parameters in automobile workers of north Karnataka (India). Ind J Clin Biochem 26(4):400–406. https://doi.org/10.1007/s12291-011-0159-6

    Article  CAS  Google Scholar 

  137. Pan C, Liu HD, Gong Z, Yu X, Hou XB, Xie DD, Zhu XB, Li HW, Tang JY, Xu YF, Yu JQ, Zhang L, Fang H, Xiao KH, Chen YG, Wang JY, Pang Q, Chen W, Sun JP (2013) Cadmium is a potent inhibitor of PPM phosphatases and targets the M1 binding site. Sci Rep 3:2333. https://doi.org/10.1038/srep02333

    Article  PubMed  PubMed Central  Google Scholar 

  138. Shen S, Li XF, Cullen WR, Weinfeld M, Le XC (2013) Arsenic binding to proteins. Chem Rev 113(10):7769–7792. https://doi.org/10.1021/cr300015c

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Wang J, Zhu H, Yang Z, Liu Z (2013) Antioxidative effects of hesperetin against lead acetate-induced oxidative stress in rats. Ind J Pharmacol 45(4):395–398. https://doi.org/10.4103/0253-7613.115015

    Article  CAS  Google Scholar 

  140. Pi H, Xu S, Reiter RJ, Guo P, Zhang L, Li Y, Li M, Cao Z, Tian L, Xie J, Zhang R, He M, Lu Y, Liu C, Duan W, Yu Z, Zhou Z (2015) SIRT3-SOD2- mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin. Autophagy 11(7):1037–1051. https://doi.org/10.1080/15548627.2015.1052208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Boskabady MH, Tabatabai SA, Farkhondeh T (2016) Inhaled lead affects lung pathology and inflammation in sensitized and control Guinea pigs. Environ Toxicol 31(4):452–460. https://doi.org/10.1002/tox.22058

    Article  CAS  PubMed  ADS  Google Scholar 

  142. Bottino C, Vázquez M, Devesa V, Laforenza U (2016) Impaired aquaporins expression in the gastrointestinal tract of rat after mercury exposure. J Appl Toxicol 36(1):113–120. https://doi.org/10.1002/jat.3151

    Article  CAS  PubMed  Google Scholar 

  143. Fay MJ, Alt LAC, Ryba D, Salamah R, Peach R, Papaeliou A, Zawadzka S, Weiss A, Patel N, Rahman A, Stubbs-Russell Z, Lamar PC, Edwards JR, Prozialeck WC (2018) Cadmium nephrotoxicity is associated with altered microRNA expression in the rat renal cortex. Toxics 6(1):16. https://doi.org/10.3390/toxics6010016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Wang Y, Mandal AK, Son YO, Pratheeshkumar P, Wise JTF, Wang L, Zhang Z, Shi X, Chen Z (2018) Roles of ROS, Nrf2, and autophagy in cadmium-carcinogenesis and its prevention by sulforaphane. Toxicol Appl Pharmacol 353:23–30. https://doi.org/10.1016/j.taap.2018.06.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chen R, Xu Y, Xu C, Shu Y, Ma S, Lu C, Mo X (2019) Associations between mercury exposure and the risk of nonalcoholic fatty liver disease (NAFLD) in US adolescents. Environ Sci Pollut Res 26(30):31384–31391. https://doi.org/10.1007/s11356-019-06224-5

    Article  CAS  Google Scholar 

  146. Deng Y, Wang M, Tian T, Lin S, Xu P, Zhou L, Dai C, Hao Q, Wu Y, Zhai Z, Zhu Y, Zhuang G, Dai Z (2019) The effect of hexavalent chromium on the incidence and mortality of human cancers: a meta-analysis based on published epidemiological cohort studies. Front Oncol 9:24. https://doi.org/10.3389/fonc.2019.00024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Pavesi T, Moreira JC (2020) Mechanisms and individuality in chromium toxicity in humans. J Appl Toxicol 40:1183–1197. https://doi.org/10.1002/jat.3965

    Article  CAS  PubMed  Google Scholar 

  148. Zhang C, Gan C, Ding L, Xiong M, Zhang A, Li P (2020) Maternal inorganic mercury exposure and renal effects in the Wanshan mercury mining area, southwest China. Ecotoxicol Environ Safe 189:109987. https://doi.org/10.1016/j.ecoenv.2019.109987

    Article  CAS  Google Scholar 

  149. Wang W, Yang H, Wang X, Jiang J, Zhu W (2010) Effects of fulvic acid and humic acid on aluminum speciation in drinking water. J Environ Sci 22(2):211–217. https://doi.org/10.1016/s1001-0742(09)60095-4

    Article  CAS  Google Scholar 

  150. Barabasz W, Albinska D, Jaskowska M, Lipiec J (2002) Ecotoxicology of aluminium. Pol J Environ Stud 11(3):199–204

    CAS  Google Scholar 

  151. Yokel RA (2012) Aluminum in Food – The nature and contribution of food additives. InTech Open 203–228. https://doi.org/10.5772/30847

  152. Jaishankar M, Tseten T, Anbalagan N, Mathew BB, Beeregowda KN (2014) Toxicity, mechanism and health effects of some heavy metals. Interdiscip Toxicol 7(2):60–72. https://doi.org/10.2478/intox-2014-0009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Shati AA, Alamri SA (2010) Role of saffron (Crocus sativus L.) and honey syrup on aluminum-induced hepatotoxicity. Saud Med J 31(10):1106–1113

  154. Wen YF, Zhao JQ, Nirala SK, Bhadauria M (2012) Aluminum-induced toxicity and its response to combined treatment of HEDTA and propolis in rats. Polish J Environ Stud 21(5):1437–1443

    CAS  Google Scholar 

  155. Afolabi OK, Wusu AD, Ugbaja R, Fatoki JO (2018) Aluminium phosphide-induced testicular toxicity through oxidative stress in Wistar rats: ameliorative role of hesperidin. Toxicol Res Appl 2018:2. https://doi.org/10.1177/2397847318812

    Article  Google Scholar 

  156. Romundstad P, Haldorsen T, Andersen A (2000) Lung and bladder cancer among workers in a Norwegian aluminium reduction plant. Occup Environ Med 57:495–499. https://doi.org/10.1136/oem.57.7.495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Exley C, Charles LM, Barr L, Martin C, Polwart A, Darbre PD (2007) Aluminium in human breast tissue. J Inorg Biochem 101:1344–1436

    Article  CAS  PubMed  Google Scholar 

  158. Gardner JL, Al-Hamdani SH (1997) Interactive effects of aluminum and humic substances on Salvania. J Aqua Pl Manage 35:30–34

    Google Scholar 

  159. Olsen V, Mørland J (2004) Arsenic poisoning Tidss Nor Laegef 124(21):2750–2753

    Google Scholar 

  160. Kuivenhoven M, Mason K (2022) Arsenic toxicity. [Updated 2023 Jun 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541125

  161. Tseng CH, Chong CK, Tseng CP, Centeno JA (2007) Blackfoot disease in Taiwan: its link with inorganic arsenic exposure from drinking water. Ambio 36(1):82–84. https://doi.org/10.1579/0044-7447(2007)36[82:bditil]2.0.co;2

    Article  CAS  PubMed  ADS  Google Scholar 

  162. Sage AP, Minatel BC, Ng KW, Stewart GL, Dummer TJB, Lam WL, Martinez VD (2017) Oncogenomic disruptions in arsenic-induced carcinogenesis. Oncotarget 8(15):25736–25755. https://doi.org/10.18632/oncotarget.15106

    Article  PubMed  PubMed Central  Google Scholar 

  163. Huang NC, Wann SR, Chang HT, Lin SL, Wang JS, Guo HR (2011) Arsenic, vinyl chloride, viral hepatitis, and hepatic angiosarcoma: a hospital-based study and review of literature in Taiwan. BMC Gastroenterol 11:142. https://doi.org/10.1186/1471-230X-11-142

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  164. Bolliger CT, van Zijl P, Louw JA (1992) Multiple organ failure with the adult respiratory distress syndrome in homicidal arsenic poisoning. Respiration 59(1):57–61. https://doi.org/10.1159/000196026

    Article  CAS  PubMed  Google Scholar 

  165. Abernathy CO, Ohanian EV (1992) Non-carcinogenic effects of inorganic arsenic. Environ Geochem Health 14(2):35–41. https://doi.org/10.1007/BF01783626

    Article  CAS  PubMed  Google Scholar 

  166. Pakulska D, Czerczak S (2006) Hazardous effects of arsine: a short review. Int J Occup Med Environ Health 19(1):36–44. https://doi.org/10.2478/v10001-006-0003-z

    Article  PubMed  Google Scholar 

  167. Cui YX, Dong L, Zhang M, Liu YN, Chen YH, Jia MZ, Chen K, Wang H, Shi Y, Ma T, Chen J (2023) Long-term exposure to arsenic in drinking water leads to myocardial damage by oxidative stress and reduction in NO. Toxicology 492:153529. https://doi.org/10.1016/j.tox.2023.153529

    Article  CAS  PubMed  Google Scholar 

  168. Buschmann J, Kappeler A, Lindauer U, Kistler D, Berg M, Sigg L (2006) Arsenite and arsenate binding to dissolved humic acids: influence of pH, type of humic acid and aluminum. Environ Sci Technol 40:6015–6020

    Article  CAS  PubMed  ADS  Google Scholar 

  169. Weng L, Williem H, Van R, Tjisse H (2009) Effects of fulvic and humic acids on arsenate adsorption to goethite: experiments and modeling. Environ Sci Technol 43:7198–7204. https://doi.org/10.1021/es9000196

    Article  CAS  PubMed  Google Scholar 

  170. Palmer NE, Wandruszka RV (2010) Humic acids as reducing agents: the involvement of quinoid moieties in arsenate reduction. Environ Sci Pollut 17:1362–1370. https://doi.org/10.1007/s11356-010-0322-2

    Article  CAS  Google Scholar 

  171. Fakour H, Lin TF (2014) Experimental determination and modeling of arsenic complexation with humic and fulvic acids. J Hazard Mater 279:569–578. https://doi.org/10.1016/j.jhazmat.2014.07.039

    Article  CAS  PubMed  Google Scholar 

  172. Sengupta S, Bhattacharyya K, Mandal J, Chattopadhyay AP (2022) Complexation, retention and release pattern of arsenic from humic/fulvic acid extracted from zinc and iron enriched vermicompost. J Environ Manage 318:115531. https://doi.org/10.1016/j.jenvman.2022.115531

    Article  CAS  PubMed  Google Scholar 

  173. Mandal J, Golui D, Datta SP (2019) Assessing equilibria of organo-arsenic complexes and predicting uptake of arsenic by wheat grain from organic matter amended soils. Chemosphere 234:419–426. https://doi.org/10.1016/j.chemosphere.2019.06.088

    Article  CAS  PubMed  ADS  Google Scholar 

  174. Rani A, Kumar A, Lal A, Pant M (2014) Cellular mechanisms of cadmium- induced toxicity: a review. Int J Environ Health Res 24:378–399. https://doi.org/10.1080/09603123.2013.835032

    Article  CAS  PubMed  Google Scholar 

  175. Patrick L (2003) Toxic metals and antioxidants: part II; The role of antioxidants in arsenic and cadmium toxicity. Altern Med Rev 8:106–128

    PubMed  Google Scholar 

  176. Gallagher CM, Chen JJ, Kovach JS (2010) Environmental cadmium and breast cancer risk. Aging 1:804–814

    Article  Google Scholar 

  177. Haghighi M, Kafi M, Fang P, Gui-Xiao L (2010) Humic acid decreased hazardous of cadmium toxicity on Lettuce (Lactuca Sativa L.). Veg Crops Res Bullet 72:49–61. https://doi.org/10.2478/v10032-010-0005-z

    Article  CAS  Google Scholar 

  178. Adhikari A, Aneefi AG, Sisuvanh H, Singkham S, Pius MV, Akter F, Kwon EH, Kang SM, Woo YJ, Yun BW, Lee IJ (2023) Dynamics of humic acid, silicon, and biochar under heavy metal, drought, and salinity with special reference to phytohormones, antioxidants, and melatonin synthesis in rice. Int J Mol Sci 24(24):17369. https://doi.org/10.3390/ijms242417369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Baker DE, Senef JP (1995) Copper. In: Allowa BJ (ed) Heavy metals in soils. Blackie Academic and Professional, London, pp 179–205

    Chapter  Google Scholar 

  180. Marschner H (1995) Mineral nutrition of higher plants, 2nd edn. Academic Press Inc, London

    Google Scholar 

  181. Blockhuys S, Wittung-Stafshede P (2017) Roles of copper-binding proteins in breast cancer. Int J Mol Sci 18(4):871. https://doi.org/10.3390/ijms18040871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Shanbhag V, Jasmer-McDonald K, Zhu S, Martin AL, Gudekar N, Khan A, Ladomersky E, Singh K, Weisman GA, Petris MJ (2019) ATP7A delivers copper to the lysyl oxidase family of enzymes and promotes tumorigenesis and metastasis. Proceed Nat Acad Sci USA 116(14):6836–6841. https://doi.org/10.1073/pnas.1817473116

    Article  CAS  ADS  Google Scholar 

  183. Wang Z, Jin D, Zhou S, Dong N, Ji Y, An P, Wang J, Luo Y, Luo J (2023) Regulatory roles of copper metabolism and cuproptosis in human cancers. Front Oncol 13:1123420. https://doi.org/10.3389/fonc.2023.1123420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Yarmohammadi A, Khoramivafa M, Honarmand SJ (2019) Humic acid reduces the CuO and ZnO nanoparticles cellular toxicity in rapeseed (Brassica napus). Cell Mol Biol 65(4):29–36. https://doi.org/10.14715/cmb/2019.65.4.5

    Article  PubMed  Google Scholar 

  185. Lane RE (1949) The care of the lead worker. British J Ind Med 6:125–143

    CAS  Google Scholar 

  186. Gidlow DA (2004) Lead toxicity. Occup Med 54(2):76–81. https://doi.org/10.1093/occmed/kqh019

    Article  CAS  Google Scholar 

  187. Malcová R, Gryndler M, Hrselova H, Vosatka M (2002) The effect of fulvic acids on the toxicity of lead and manganese to arbuscular mycorrhizal fungus Glomus intraradices. Fol Microbio (Praha) 47(5):521–526. https://doi.org/10.1007/BF02818792

    Article  Google Scholar 

  188. Zralý Z, Písaříková B, Trčková M, Navrátilová M (2008) Effect of humic acids on lead accumulation in chicken organs and muscles. Acta Vetern Brno 77:439–445. https://doi.org/10.2754/avb200877030439

    Article  Google Scholar 

  189. Guan Y, Gong J, Song B, Li J, Fang S, Tang S, Cao W, Li Y, Chen Z, Ye J, Cai Z (2022) The effect of UV exposure on conventional and degradable microplastics adsorption for Pb (II) in sediment. Chemosphere 286:131777. https://doi.org/10.1016/j.chemosphere.2021.131777

    Article  CAS  PubMed  Google Scholar 

  190. Perelomov LV, Sarkar B, Sizova OI, Chilachava KB, Shvikin AY, Perelomova IV, Atroshchenko YM (2018) Zinc and lead detoxifying abilities of humic substances relevant to environmental bacterial species. Ecotoxicol Environ Safe 151:178–183. https://doi.org/10.1016/j.ecoenv.2018.01.018

    Article  CAS  Google Scholar 

  191. Hassan MU, Chattha MU, Khan I, Chattha MB, Aamer M, Nawaz M (2019) Nickel toxicity in plants: reasons, toxic effects, tolerance mechanisms, and remediation possibilities-a review. Environ Sci Pollut Res 26(13):12673–12688. https://doi.org/10.1007/s11356-019-04892-x

    Article  CAS  Google Scholar 

  192. Grimsrud TK, Peto J (2006) Persisting risk of nickel related lung cancer and nasal cancer among Clydach refiners. Occup Environ Med 63(5):365–366. https://doi.org/10.1136/oem.2005.026336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Su CC, Lin YY, Chang TK, Chiang CT, Chung JA, Hsu YY, Lian IB (2010) Incidence of oral cancer in relation to nickel and arsenic concentrations in farm soils of patients’ residential areas in Taiwan. BMC Pub Health 10:1–10. https://doi.org/10.1186/1471-2458-10-67

    Article  CAS  Google Scholar 

  194. Manjula M, Angadi PV, Priya NK, Hallikerimath S, Kale AD (2019) Assessment of morphological parameters associated with neural invasion in oral squamous cell carcinoma. J Oral Maxillo Pathol 23(1):157. https://doi.org/10.4103/jomfp.JOMFP_178_18

    Article  CAS  Google Scholar 

  195. Agnew UM, Slesinger TL (2022) Zinc toxicity. [Updated 2022 Dec 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554548

  196. Rahimzadeh MR, Rahimzadeh MR, Kazemi S, Moghadamnia AA (2020) Zinc poisoning - symptoms, causes, treatments. Mini Rev Med Chem 20(15):1489–1498. https://doi.org/10.2174/1389557520666200414161944

    Article  CAS  PubMed  Google Scholar 

  197. Kim YH, Fazlollahi F, Kennedy IM, Yacobi NR, Hamm-Alvarez SF, Borok Z, Kim KJ, Crandall ED (2010) Alveolar epithelial cell injury due to zinc oxide nanoparticle exposure. Amer J Resp Crit Care Med 182(11):1398–1409. https://doi.org/10.1164/rccm.201002-0185OC

    Article  CAS  Google Scholar 

  198. Barceloux DG (1999) Zinc. J Toxicol Clin Toxicol 37(2):279–292. https://doi.org/10.1081/clt-100102426

    Article  CAS  PubMed  Google Scholar 

  199. Paun S, Tudosie M, Petris R, Macovei R (2012) The effects of zinc on human body, including on renal failure and renal transplantation. J Med Life 5:137–140

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Yanagisawa H, Miyazaki T, Nodera M, Miyajima Y, Suzuki T, Kido T, Suka M (2014) Zinc-excess intake causes the deterioration of renal function accompanied by an elevation in systemic blood pressure primarily through superoxide radical-induced oxidative stress. Int J Toxicol 33(4):288–296. https://doi.org/10.1177/1091581814532958

    Article  CAS  PubMed  Google Scholar 

  201. Krone CA, Harms LC (2003) Re: zinc supplement use and risk of prostate cancer. J Nat Can Inst 95(20):1556. https://doi.org/10.1093/jnci/djg088

    Article  Google Scholar 

  202. Gallus S, Foschi R, Negri E, Talamini R, Franceschi S, Montella M, Ramazzotti V, Tavani A, Maso LD, Vecchia CL (2007) Dietary zinc and prostate cancer risk: a case-control study from Italy. Europ Urol 52(4):1052–1056. https://doi.org/10.1016/j.eururo.2007.01.094

    Article  CAS  Google Scholar 

  203. Ho E, Song Y (2009) Zinc and prostatic cancer. Curr Opin Clin Nutr Metabol Care 12(6):640–645. https://doi.org/10.1097/MCO.0b013e32833106ee

    Article  CAS  Google Scholar 

  204. Mahmoud AM, Al-Alem U, Dabbous F, Ali MM, Batai K, Shah E, Kittles RA (2016) Zinc intake and risk of prostate cancer: case-control study and meta-analysis. PLoS ONE 11(11):e0165956. https://doi.org/10.1371/journal.pone.0165956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Paulauskis JD, Winner RW (1988) Effects of water hardness and humic acid on zinc toxicity to Daphnia magna Straus. Aqua Toxicol 12(3):273–290. https://doi.org/10.1016/0166-445x(88)90027-6

    Article  CAS  Google Scholar 

  206. Bunluesin S, Pokethitiyook P, Lanza GR, Julian FT, Maleeya K, Baoshan X (2007) Influences of cadmium and zinc interaction and humic acid on metal accumulation in Ceratophyllum demersum. Water Air Soil Pollut 180:225–235

    Article  CAS  ADS  Google Scholar 

  207. Ouyang K, Yu XY, Zhu Y, Gao C, Huang Q, Cai P (2017) Effects of humic acid on the interactions between zinc oxide nanoparticles and bacterial biofilms. Environ Pollut 231:1104–1111. https://doi.org/10.1016/j.envpol.2017.07.003

    Article  CAS  PubMed  Google Scholar 

  208. Velintine AV, Wee BS, Droepenu EK, Chin SF, Kok YK (2021) Effects of humic acid and natural sunlight irradiation on the behaviour of zinc oxide nanoparticles in the aqueous environment. Biointerf Res Appl Chem 11(4):11256–11271. https://doi.org/10.33263/BRIAC114.1125611271

    Article  CAS  Google Scholar 

  209. Bondareva L, Kudryasheva N (2021) Direct and indirect detoxification effects of humic substances. Agronomy 11(2):198. https://doi.org/10.3390/agronomy11020198

    Article  CAS  Google Scholar 

  210. Ismael MA, Elyamine AM, Zhao YY, Moussa MG, Rana MS, Afzal J, Imran M, Zhao XH, Hu CH (2018) Can selenium and molybdenum restrain cadmium toxicity to pollen grains in Brassica napus? Int J Mol Sci 19(8):2163. https://doi.org/10.3390/ijms19082163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Qu L, Jia W, Dai Z, Xu Z, Cai M, Huang W, Han D, Dang B, Ma X, Gao Y, Xu J (2022) Selenium and molybdenum synergistically alleviate chromium toxicity by modulating Cr uptake and subcellular distribution in Nicotiana tabacum L. Ecotoxicol Environ Safe 248:114312. https://doi.org/10.1016/j.ecoenv.2022.114312

    Article  CAS  Google Scholar 

  212. Zhang M, Hu C, Zhao X, Tan Q, Sun X, Cao A, Cui M, Zhang Y (2012) Molybdenum improves antioxidant and osmotic-adjustment ability against salt stress in Chinese cabbage (Brassica campestris L. Ssp. Pekinensis). Pl Soil 355:375–383. https://doi.org/10.1007/s11104-011-1109-z

    Article  CAS  Google Scholar 

  213. Yamane Y, Fukuchi M, Li C, Koizumi T (1990) Protective effect of sodium molybdate against the acute toxicity of cadmium chloride. Toxicology 60:235–243. https://doi.org/10.1016/0300-483X(90)90146-8

    Article  CAS  PubMed  Google Scholar 

  214. Hadi F, Ali N, Fuller MP (2016) Molybdenum (Mo) increases endogenous phenolics, proline and photosynthetic pigments and the phytoremediation potential of the industrially important plant Ricinus communis L. for removal of cadmium from contaminated soil. Environ Sci Pollut Res 23:20408–20430. https://doi.org/10.1007/s11356-016-7230-z

    Article  CAS  Google Scholar 

  215. Filek M, Zembala M, Hartikainen H, Miszalski Z, Kornaś A, Wietecka-Posłuszny R, Walas P (2009) Changes in wheat plastid membrane properties induced by cadmium and selenium in presence/absence of 2, 4-dichlorophenoxyacetic acid. Pl Cell Tiss Org Cult 96:19–28. https://doi.org/10.1007/s11240-008-9455-0

    Article  CAS  Google Scholar 

  216. Feng R, Wei C, Tu S (2013) The roles of selenium in protecting plants against abiotic stresses. Environ Exp Bot 87:58–68. https://doi.org/10.1016/j.envexpbot.2012.09.002

    Article  CAS  Google Scholar 

  217. Richard C, Guyot G, Trubetskaya O, Trubetskoj O, Grigatti M, Cavan L (2009) Fluorescence analysis of humic-like substances extracted from composts: influence of composting time and fractionation. Environ Chem Lett 7:61–65. https://doi.org/10.1007/s10311-008-0136-3

    Article  CAS  Google Scholar 

  218. Trubetskoj OA, Trubetskaya OE, Richard C (2009) Photochemical activity and fluorescence of electrophoretic fractions of aquatic humic matter. Water Res 36:518–524. https://doi.org/10.1134/S0097807809050042

    Article  CAS  Google Scholar 

  219. Orlov DS (1997) Humic substances in the biosphere. Soros Edu J 2:56–63

    Google Scholar 

  220. Gu B, Chen J (2003) Enhanced microbial reduction of Cr(VI) and U(VI) by different natural organic matter fractions. Geochim Cosmochim Acta 67:3575–3582

    Article  CAS  ADS  Google Scholar 

  221. Zhilin D, Schmitt-Kopplin P, Perminova I (2004) Reduction of Cr(VI) by peat and coal humic substances. Environ Chem Lett 2:141–145. https://doi.org/10.1007/s10311-004-0085-4

    Article  CAS  Google Scholar 

  222. Sachs S, Bernhard G (2011) Humic acid model substances with pronounced redox functionality for the study of environmentally relevant interaction processes of metal ions in the presence of humic acid. Geoderma 162:132–140. https://doi.org/10.1016/j.geoderma.2011.01.012

    Article  CAS  ADS  Google Scholar 

  223. Theng BKG (2012) Chapter 12: Humic substances. In: developments in clay science. In: Formation and properties of clay-polymer complexes, vol 4, 2nd edn. Elsevier, 391–456

  224. Tarasova AS, Kislan SL, Fedorova ES, Kuznetsov AM, Mogilnaya OA, Stom DI, Kudryasheva NS (2012) Bioluminescence as a tool for studying detoxification processes in metal salt solutions involving humic substances. J Photochem Photobiol B 117:164–170. https://doi.org/10.1016/j.jphotobiol.2012.09.020

    Article  CAS  PubMed  Google Scholar 

  225. Kudryasheva NS, Tarasova AS (2014) Pollutant toxicity and detoxification by humic substances: mechanisms and quantitative assessment via luminescent biomonitoring. Environ Sci Pollut Res 22(1):155–167. https://doi.org/10.1007/s11356-014-3459-6

    Article  CAS  Google Scholar 

  226. Burlakovs J, Kļaviņš M, Osinska L, Purmalis O (2013) The impact of humic substances as remediation agents to the speciation forms of metals in soil. In: APCBEE Procedia. 4th Int Conf Environ Sci Develop 5:192–196

    CAS  Google Scholar 

  227. Carlosa L, Mártirea DO, Gonzaleza MC, Gomisb J, Bernabeub A, Amatb AM (2012) Photochemical fate of a mixture of emerging pollutants in the presence of humic substances. Water Res 46:4732–4740

    Article  Google Scholar 

  228. Tchaikovskaya O, Sokolova I, Kondratieva L, Karetnikova E (2001) Role of photochemical and microbial degradation of phenol in water. Int J Photoen 3(4):177. https://doi.org/10.1155/S1110662X01000228

    Article  CAS  Google Scholar 

  229. Tchaikovskaya ON, Karetnikova EA, Sokolova IV, Sokolova TV, Fedorova ES, Kudryasheva NS (2008) Luminescence investigations of the degradation of 2-methylphenol and 4-methylphenol in water. Russ Phys Jo 51:1344–1355. https://doi.org/10.1007/s11182-009-9187-6

    Article  CAS  Google Scholar 

  230. Chaikovskaya ON, Sokolova IV, Sokolova TV, Yudina NV, Mal’tseva EV, Ivanov AA (2008) Effect of humic acids on phototransformation of methylphenols in water. J Appl Spectro 75:597–602

    Article  CAS  Google Scholar 

  231. Bryantseva NG, Fedorova ES, Sokolova IV, Kudryasheva NS, Khilya VP, Garazd YL (2008) Luminescent analysis of photoinduced detoxification of substituted furocoumarins. J Appl Spectro 75:236–240

    Article  CAS  Google Scholar 

  232. Havelcová M, Mizera J, Sýkorová I, Pekař M (2009) Sorption of metal ions on lignite and the derived humic substances. J Hazard Mat 161:559–564

    Article  Google Scholar 

  233. Al-Abri M, Dakheel A, Tizaoui C, Hilal N (2010) Combined humic substance and heavy metals coagulation, and membrane filtration under saline conditions. Desalination 253:46–50

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The anonymous valued reviewers are acknowledged for their precious comments to keep this manuscript on track.

Author information

Authors and Affiliations

  1. Food and Biotechnology Research Centre, Pakistan Council of Scientific and Industrial Research (PCSIR) Laboratories Complex, Ferozepur Road, Lahore, 54600, Punjab, Pakistan

    Adil Hussain & Asma Saeed

Authors
  1. Adil Hussain
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Asma Saeed
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AH: conceptualization, data collection, methodology, visualization, writing original draft—review and editing. AS: conceptualization, data collection, visualization, review, and editing.

Corresponding author

Correspondence to Adil Hussain.

Ethics declarations

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hussain, A., Saeed, A. Hazardous or Advantageous: Uncovering the Roles of Heavy Metals and Humic Substances in Shilajit (Phyto-mineral) with Emphasis on Heavy Metals Toxicity and Their Detoxification Mechanisms. Biol Trace Elem Res (2024). https://doi.org/10.1007/s12011-024-04109-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12011-024-04109-4

Keywords

Search

Navigation