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Toxicity of arsenic species


Arsenic toxicity varies significantly among different arsenic species, and understanding these differences is crucial for assessing health risks associated with arsenic exposure. The major arsenic species include inorganic forms, such as arsenite (iAsIII) and arsenate (iAsV), as well as various organic forms. Surprisingly, synthetic organoarsenicals are extremely toxic  molecules which created interest in their development as chemical warfare agents (CWAs) during World War I.

Biotransformation of inorganic arsenic has been shown to occur in many organisms including animals and humans. Over 300 species of naturally occurring organoarsenicals have been identified with the development of modern analytical techniques. The discussions on the toxicity of arsenic species are mainly in reference to inorganic arsenic and methylated arsenicals (MMA and DMA) since their toxicity mechanism is well established and understood unlike for more complex organoarsenicals such as arsenosugars (AsS) and arsenolipds (AsL) which are yet to be fully elucidated.

Here's a brief overview of the toxicity of different arsenic species:

  • Inorganic arsenic species are generally more toxic than organoarsenicals:
    • Arsenite (iAsIII): Arsenite is generally considered more toxic than arsenate. It can interfere with cellular processes and enzyme functions, leading to oxidative stress and DNA damage. Chronic exposure to arsenite has been linked to various health issues, including skin lesions, cardiovascular diseases, and cancer.
    • Arsenate (iAsV): While arsenate is generally less toxic than arsenite, it still poses health risks. It can disrupt cellular energy production by interfering with phosphate metabolism. Chronic exposure to arsenate has been associated with similar health issues as arsenite, including cancer and cardiovascular diseases.
  • Organoarsenicals have not demonstrated acute toxicity; therefore, their toxicity may arise from metabolic transformations that lead to formation of highly toxic metabolites :
    • Monomethyl Arsenic (MMA) and Dimethyl Arsenic (DMA): These are common organic arsenic species found in seafood, as well as in rice and other plants. MMA and DMA are generally considered less toxic than their inorganic counterparts. The human body can efficiently convert inorganic arsenic into these organic forms, which are then rapidly excreted. However, recent studies suggest that DMA may be a precursor to more toxic species, such as dimethylmonothioarsenate (DMMTA), under certain conditions.
    • Trimethyl Arsenic (TMA): TMA is another organic form of arsenic. It is often found in marine organisms. Similar to MMA and DMA, TMA is generally less toxic than inorganic arsenic species.
    • Arsenobetaine (AsB), Arsenocholine (AsC), Arsenosugar (AsS): These organic arsenic species are commonly found in seafood. They are generally considered non-toxic and are efficiently excreted from the body without undergoing significant metabolism.
    • Arsenolipids (AsLs)): Over 260 arsenolipids have been discovered thus far, which can be categorized into four major families: arsenic-containing fatty acids (AsFAs), arsenic-containing hydrocarbons (AsHCs), arsenic-containing phospholipids (AsPLs) and cationic trimethyl fatty alcohols (TMAsFOHs). Unfortunately, toxicity studies on arsenolipids are still very rare with most reports discussing the toxicity of AsHCs and AsFAs, while reports on other complex AsLs are relatively less common. AsHCs exhibit toxicity to human liver and bladder cells similar to that of iAsIII and much higher than that of AsFAs. Also an experimental validation suggests that AsHCs can penetrate the BBB and migrate to the brain tissues. The toxicity of AsHCs in brain cells has been shown to be 5–19 times greater than that of iAsIII when applied to human neuronal astrocytes.
  • Thioarsenates:
    • Dimethylmonothioarsenate (DMMTA) and Others: Thioarsenates are a group of arsenic species that contain sulfur. Recent studies have indicated the presence of thioarsenates in rice plants. DMMTA, a thioarsenate, has been identified as having high cytotoxicity in humans.

In summary, inorganic arsenic species are generally more toxic than organic forms and the toxicity of arsenic compounds decreases in the following order:
iAsIII> iAsV> MMA > DMA > TMA > AsS > AsC > AsB. However, the toxicity also depend on factors such as dosage, duration of exposure, cell/tissue
type, metabolism, bioavailability, co-exposure with other toxins and individual susceptibility.

Ongoing research continues to enhance our understanding of the health effects associated with different arsenic species, especially in the context of environmental exposure and dietary intake.

Reviews discussing the toxicity of arsenic species

Caiyan Li, Jing Chen, Zhuo Wang, Bingbing Song, Kit-Leong Cheung, Jianping Chen, Rui Li, Xiaofei Liu, Xuejing Jia, Sai-Yi Zhong, Speciation analysis and toxicity evaluation of arsenolipids — an overview focusing on sea food, Arch. Toxicol., 98 (2024) 409–424. DOI: 10.1007/s00204-023-03639-5

Ravidarshdeep Kaur, Atul Garkal, Lopmudra Sarode, Priyanka Bangar, Tejal Mehta, Dhirendra Pratap Singh, Rakesh Rawal, Understanding arsenic toxicity: Implications for environmental exposure and human health, J. Hazard. Mater. Lett., 5 (2024) 100090. DOI: 10.1016/j.hazl.2023.100090

Suhail Muzaffar, Jasim Khan, Ritesh Srivastava, Marina S. Gorbatyuk, Mohammad Athar, Mechanistic understanding of the toxic effects of arsenic and warfare arsenicals on human health and environment, Cell Biol. Toxicol., 39 (2023) 85–110. DOI: 10.1007/s10565-022-09710-8

David J. Thomas, Arsenic methylation – Lessons from three decades of research, Toxicology, 457 (2021) 152800. DOI: 10.1016/j.tox.2021.152800

Xi-Mei Xue, Chan Xiong, Masafumi Yoshinaga, Barry Rosen, Yong-Guan Zhu, The enigma of environmental organoarsenicals, Crit. Rev. Environ. Sci. Technol., 52/21 (2022) 3835-3862. DOI: 10.1080/10643389.2021.1947678

Caleb Luvonga, Catherine A. Rimmer, Lee L. Yu, Sang B. Lee, Organoarsenicals in Seafood: Occurrence, Dietary Exposure, Toxicity, and Risk Assessment Considerations – A Review, J. Agric. Food Chem., 68/4 (2020) 943-960. DOI: 10.1021/acs.jafc.9b07532

Vivien Taylor, Britton Goodale, Andrea Raab, Tanja Schwerdtle, Ken Reimer, Sean Conklin, Margaret R. Karagas, Kevin A. Francesconi, Human exposure to organic arsenic species from seafood, Sci. Total Environ., 580 (2017) 266–282. DOI: 10.1016/j.scitotenv.2016.12.113

Marianne Molin, Stine Marie Ulven, Helle Margrete Meltzer, Jan Alexander, Arsenic in the human food chain, biotransformation and toxicology – Review focusing on seafood arsenic, J. Trace Elem. Med. Biol., 31 (2015) 249–259. DOI: 10.1016/j.jtemb.2015.01.010

David C. Bellinger, Inorganic Arsenic Exposure and Children's Neurodevelopment: A Review of the Evidence, Toxics, 1/1 (2013) 2-17. DOI: 10.3390/toxics1010002

S.M. Cohen, B.D. Beck, A.S. Lewis, M. Eldan, Evaluation of carcinogenicity of inorganic arsenic, Crit. Rev. Toxicol.,43/9 (2013) 711-752. DOI: 10.3109/10408444.2013.827152

J. Feldmann, E.M. Krupp, Critical review or scientific opinion paper: Arsenosugars - a class of benign arsenic species or justification for developing partly speciated arsenic fractionation in foodstuffs ?, Anal. Bioanal. Chem., 399 (2011) 1735-1741. DOI: 10.1007/s00216-010-4303-6

U. Schuhmacher-Wolz, H.H. Dieter, D. Klein, K. Schneider, Oral exposure to inorganic arsenic: evaluation of its carcinogenic and non-carcinogenic effects, Crit. Rev. Toxicol., 39/4 (2009) 271-298. DOI: 10.1080/10408440802291505

L. Irvine, I.J. Boyer, J.M. DeSesso, Monomethylarsonic Acid and Dimethylarsinic Acid: Developmental Toxicity Stdies With Risk Assessment, Birth Def. Res. B, 77 (2006) 53-68. DOI: 10.1002/bdrb.20065

M. Styblo, Z. Drobna, I. Jaspers, S. Lin, D.J. Thomas, The role of biomethylation in toxicity and carcinogenicity of arsenic: A reserach update, Environ. Health Perspect., 110/S.5 (2002)767-771. DOI: 10.1289/ehp.110-1241242

E.M. Kenyon, M.F. Hughes, A concise review of the toxicity and carcinogenicity of dimethylarsinic acid, Toxicology, 160 (2001) 227-236. DOI: 10.1016/S0300-483X(00)00458-3

T. Kaise, S. Fukui, The chemical form and acute toxicity of arsenic compounds in marine organisms, Appl. Organomet. Chem., 6/2 (1992) 155-160. doi: 10.1002/aoc.590060208

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