Arsenic

Sources

Arsenic is found in a variety of places, including rocks, soil, water, plants, animals, and the food that we eat. It can be found in its pure form, but it’s most commonly seen in combination with other chemical compounds. These compounds can be organic or inorganic.  

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Watch the video below to learn more about arsenic.

Three significant groups of arsenic compounds  

• Organic: Arsenic + carbon 
• Inorganic: Arsenic + other elements (not carbon)  
• Arsine gas  

Arsenic is found in the following foods: 

• Rice 
• Cereal 
• Seafood 
• Chicken 
• Mushrooms  

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Watch the video below to learn more about arsenic in food.

Arsenic can be found in drinking water.   

• Levels vary widely across countries 
• Water in rural communities are more likely to have higher arsenic levels
• Higher in groundwater sources than surface sources 

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Other sources of arsenic 

• Industrial fumes 
• Pressure-treated lumber (prior to 2004)  

(Arsenic and Cancer Risk; Arsenic and Arsenic Compounds)

Biotransformation 

Methylation

• Inorganic arsenic (the toxic form) becomes methylated and turns into methylarsonic acid (MMA) and dimethylarsinic acid (DMA)
• Diets low in methionine or protein can result in decreased methylation of arsenic
• Age and pregnancy can impact arsenic methylation in humans

Reduction

• Arsenic becomes reduced in the blood  
• Glutathione serves as the reducing agent 

(Mechanisms of arsenic biotransformation).   

Toxicokinetics 

• Absorption: primarily small intestine  
• Distribution: kidneys, liver, heart, lungs, muscle, nervous system, gastrointestinal tract, spleen, and deposits in keratin-rich areas
• Metabolism: hepatic  
• Excretion: urine  

Carcinogenicity 

The International Agency for Research on Cancer (IARC) classifies arsenic and inorganic arsenic compounds as “carcinogenic to humans.” Cancer of the lung, bladder, skin, kidney, liver, and prostate is linked to arsenic exposure.

Organic arsenic compounds are less dangerous, as the IARC classifies them as “possibly carcinogenic to humans.” (Arsenic and Cancer Risk).  

Mechanism of Action

From a toxicological standpoint, the trivalent and pentavalent states of arsenic are of the most concern. Each will be discussed separately.  

Pentavalent arsenic MOA 

• Inhibition of hexokinase in glycolysis 
• Replacement of phosphate in the sodium pump of human erythrocytes 
• Uncoupler of adenosine-5′-triphosphate (ATP) via arsenolysis and subsequent depletion of ATP 

Trivalent arsenic MOA 

• Has the ability to bind strongly to thiol groups which could result in toxicity 
• Inhibition of pyruvate dehydrogenase, which has downstream effects in the citric acid cycle  

(Arsenic toxicity and potential mechanisms of action).  

Image link: Arsenic Exposure and Toxicology: A Historical Perspective. Figure 2.

Target organs 

Arsenic impacts nearly all organ systems, including the skin, gastrointestinal, cardiovascular, neurological, genitourinary, respiratory, endocrine, and hematological systems (Acute and chronic arsenic toxicity).  

Signs and symptoms of toxicity 

Acute poisoning signs and symptoms 

• Vomiting 
• Diarrhea (dominant feature) 
• Abdominal pain 
• Hypersalivation 
• Psychosis 
• Diffuse skin rash 
• Seizures  
• Hemoglobinuria 
• Pancytopenia  
• Anemia 
• Respiratory failure 
• Pulmonary edema 
• Peripheral neuropathy 

Chronic signs and symptoms  

• Abdominal pain 
• Diarrhea  
• Sore throat 
• Cancer and other malignancies  

(Acute and chronic arsenic toxicity)

How is arsenic poisoning diagnosed? 

If arsenic poisoning is suspected, samples should be taken from hair, urine, and blood. 

• Acute poisoning: 1.0-3.0 mg/kg in a hair sample.
• Chronic poisoning: 0.1-0.5 mg/kg in a hair sample  

(Acute and chronic arsenic toxicity)

How is arsenic poisoning treated?

If arsenic poisoning is suspected, contaminated clothes should be removed immediately. The skin should be rinsed to remove leftover arsenic that may be present. Treatment for acute arsenic poisoning includes gastric lavage, hemodialysis, and dimercaprol (British anti-Lewisite; pictured below) (Acute and chronic arsenic toxicity).

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Genetic susceptibility or heritable traits 

Studies have shown there is variability in genetic susceptibility to arsenic toxicity. Some genetic polymorphisms in enzymes responsible for arsenic metabolism include: 

• Arsenic (III) methyltransferase 
• Glutathione S-transferase  
• Methylenetetrahydrofolate reductase  

Please click here to see more on the genetic polymorphisms involved in arsenic toxicity by going to page 1533, Table 2.  

Some individuals possess single nucleotide polymorphisms which render them less likely to repair oxidative damage. This includes the following genes:  

• HOGG1 
• APE1 
• XRCC1 
• XRCC3 

In simpler terms, individuals who have variation in these enzymes or genes can be more susceptible to arsenic toxicity if and when they encounter it.

Historical or unique exposures 

• Arsenic has been commonly used as a homicidal and suicidal poison 
• It has been used for these reasons since the Middle Ages 
• It is sometimes called the “poison of kings” as it was used to remove members of the ruling class; it was used to kill Napoleon Bonaparte in 1851 
• Arsenic was used as a pigment in the 1800s and caused many accidental arsenic poisonings  

Please click here and go to page 307, Table 2 to learn more about historical events related to arsenic toxicity.  

Arsenic Exposure and Toxicology: A Historical Perspective.

Biomarkers of Exposure

Arsenic can be quantified using samples from hair, nails, blood, or urine.  

• Arsenic levels in keratin-rich areas such as nails may indicate chronic or past exposure 
• Arsenic levels in blood or urine may indicate recent or acute exposures  
• Urine levels typically range from 5-20 µg/L 

(Arsenic and Arsenic Compounds)

Essentiality

Although it is up for debate, some studies suggest that arsenic is an essential nutrient that plays a role in methionine metabolism. Methionine (pictured below) metabolism is vital during pregnancy, lactation, and vitamin B6 deprivation (Evidence for arsenic essentiality). 

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Deficiency

Arsenic deprivation studies have demonstrated that rats deprived of arsenic had changes in their coats and growth rate compared to the control group. Some studies show that arsenic deprivation manifests similarly to vitamin B6 deficiency (Evidence for arsenic essentiality).  

Disclaimer: I do not own any of these images. Each image has been cited with its corresponding link. 

References 

1. Arsenic and Cancer Risk. https://www.cancer.org/cancer/cancer-causes/arsenic.html. Accessed June 7, 2019.
2. Ng J, Gomez-Caminero A, International Programme on Chemical Safety, eds. Arsenic and Arsenic Compounds. 2. ed. Geneva: World Health Organization; 2001.
3. Hughes MF, Beck BD, Chen Y, Lewis AS, Thomas DJ. Arsenic Exposure and Toxicology: A Historical Perspective. Toxicological Sciences. 2011;123(2):305-332. doi:10.1093/toxsci/kfr184
4. Ratnaike RN. Acute and chronic arsenic toxicity. Postgraduate Medical Journal. 2003;79(933):391-396. doi:10.1136/pmj.79.933.391
5. Uthus EO. Evidence for arsenic essentiality. Environmental Geochemistry and Health. 1992;14(2):55-58. doi:10.1007/BF01783629
6. Vahter M. Mechanisms of arsenic biotransformation. Toxicology. 2002;181-182:211-217. doi:10.1016/S0300-483X(02)00285-8
7. Arsenic poisoning: Causes, symptoms, and treatment. Medical News Today. https://www.medicalnewstoday.com/articles/241860.php. Accessed June 7, 2019.
8. Hughes MF. Arsenic toxicity and potential mechanisms of action. Toxicology Letters. 2002;133(1):1-16. doi:10.1016/S0378-4274(02)00084-X
9. Faita F, Cori L, Bianchi F, Andreassi M. Arsenic-Induced Genotoxicity and Genetic Susceptibility to Arsenic-Related Pathologies. International Journal of Environmental Research and Public Health. 2013;10(4):1527-1546. doi:10.3390/ijerph10041527
10. Hughes MF, Beck BD, Chen Y, Lewis AS, Thomas DJ. Arsenic Exposure and Toxicology: A Historical Perspective. Toxicological Sciences. 2011;123(2):305-332. doi:10.1093/toxsci/kfr184