Routes of exposure

 

Arsenic (As) is found in the air, soil and water. We breathe it and come into contact with it through our skin, but the major routes of exposure include drinking water and diet, with the most common source being rice.

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Health effects

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Arsenic is a well-established class I human carcinogen. Chronic exposure to high levels of arsenic (>300 µg/L) is associated with substantial increase in risk for a wide array of diseases including cancers of the lung, bladder, liver, skin, and kidney, as well as neurological and cardiovascular diseases and diabetes. Emerging evidence suggests that arsenic may have adverse effects on health even at concentrations as low as 10–50 µg/L, as recent studies in Bangladesh have observed dose-response relationships with mortality and arsenical skin lesion risk in populations with low to moderate arsenic exposure over many years. Arsenical skin lesions are a classical sign of arsenic toxicity, an indicator of susceptibility to arsenic-related disease, and a precursor to arsenic-induced skin cancers. Once individuals are chronically exposed to arsenic, risk for arsenic-related diseases and mortality remains high for several decades even after cessation of exposure.

Women who are highly exposed to arsenic have an earlier onset of menopause.

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Children

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Studies in animals and in children showed that arsenic affects the immune system and increases infant morbidity and mortality. Arsenic crosses the placenta during pregnancy and causes inflammation, reduced immune capacity and damage to the thyroid gland of the newborn.

In Bangladesh and in the United States, the risk of upper and lower respiratory tract infections and diarrhea in infants increased with higher maternal arsenic during pregnancy.

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Epidemiology

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Over 100 million individuals worldwide are exposed to arsenic through drinking water, with approximately 13 million in the United States and many more in developing countries. 56 million people in Bangladesh are exposed to high levels of arsenic in their water. 

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On top of genetic makeup, additional factors such as age, sex and low-protein intake have shown associations with cancer risk in conjunction with iAs exposures. Smokers show greater levels of arsenic. Pregnant women show lower and lower arsenic levels, as week of gestation progresses. 

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Metabolism

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Inorganic arsenic enters the body as arsenite or arsenate. Methylation and additional reduction reactions then produce monomethylarsonic acid (MMA) and then dimethylarsinic acid (DMA). MMA is more toxic than DMA and less readily excreted in urine.

 

Relative concentrations of these arsenic metabolites measured in urine represent an individual’s capacity to metabolize arsenic. The efficiency of arsenic metabolism determines the susceptibility to arsenic toxicity.

 

Methylation of arsenic is catalyzed by the arsenic methyltransferase (AS3MT) enzyme.

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Genetic sensitivity to arsenic

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Certain genetic makeups are associated with metabolism, secretion and levels of arsenic in body tissues, making some people more sensitive to its deleterious effects.

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Genetic variants in the gene encoding for the enzyme Arsenic (+3 oxidation state) Methyltransferase (AS3MT) play a key role in arsenic methylation capacity.

 

It was found that among some populations exposed to high arsenic levels, improved metabolism of arsenic has developed over the years. It seems that natural selection has favored certain AS3MT makeups that associate with more efficient arsenic metabolism in populations that have lived with arsenic exposure for many generations.

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Adopted from "Human Adaptation to Arsenic-Rich Environments"

Mol Biol Evol. 2015;32(6):1544-1555

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Indigenous populations in the Andes are exposed to high Arsenic levels in their water for generations over generations. However, they show uniquely low urinary excretion of MMA.

Individuals from these populations have higher frequencies of the inferred protective AS3MT haplotypes than other closely related populations who are not exposed to high Arsenic load in their environment.

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Selection for a protective AS3MT makeup is probably caused by adverse effects of arsenic such as hepatoxicity, cardiovascular disease, and impaired lung function which may result in reduced reproduction. Given the severe deleterious health effects of arsenic in both children and adults, individuals who carry the arsenic-tolerance makeup and thus can metabolize arsenic faster with reduced exposure to toxic metabolites could have a very strong selective advantage in high-arsenic environments. Thus, individuals with these genotypes tend to bring more children, and healthier children, which in turn will reproduce with more success as well in an arsenic-ridden environment.

 

For this specific indigenous population, the arsenic-related selective pressure is estimated at about 11,000 years ago, when they have settled in the arsenic-rich environment. 

 

At a more global view, a protective set-up tend to be more frequent in East Asians and Native Americans.

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Adopted from "Human Adaptation to Arsenic-Rich Environments"

Mol Biol Evol. 2015;32(6):1544-1555

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The number of protective makeups is visualized by the differences in the form of violin plots for the different comparative populations from the 1000 Genome project. It is evident that East-Asian and indigenous American populations show higher prevalence of the protective genotype (the large base on this violin plot)

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Selenium (Se) and arsenic are both trace elements and share some metabolism pathways. Studies have found that selenium may serve to decrease arsenic toxicity via formation of an As-Se compound and its excretion. However, selenium itself can be toxic at high levels, and in addition it also boosts arsenic levels at high concentration. It seems that normal intake of selenium improves antioxidant capacity and counteracts chronic arsenic toxicity.

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Genetic association studies have found that a certain variant in the INMT gene, involved in selenium metabolism, affects both selenium and arsenic levels. This variant promotes urinary excretion of arsenic, while slowing loss of selenium. SEPP1 is another gene involved in selenium metabolism. This gene might be responsible for some of the extracellular antioxidant defense properties of selenium or might be involved in the transport of selenium to tissues such as brain and testis.

The GSTP1 gene plays a significant role in antioxidant defense mechanisms. Its variants were associated with levels of trace elements such as mercury and arsenic.

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How to reduce the risk from exposure to arsenic

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• Find out what are the arsenic levels in your drinking water. The Environmental Protection Agency (EPA) standard for arsenic in drinking water is 0.01 mg/l or 10 parts per billion (ppb), replacing the old standard of 50 ppb. You can look for water filters that further reduce arsenic levels.

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• Rice is the main dietary contributor (excluding drinking water) of inorganic arsenic exposure in the population. In general, brown rice has much more arsenic then its white version. Removal of the grain’s outer layers removes much of the arsenic, but with the cost of losing many nutrients. Basmati rice is usually the healthiest when arsenic levels are measured. Organic rice takes up arsenic from the water ant soil the same way as conventional rice does. Try to diversify your grains intake. Buckwheat, quinoa and millet have much less arsenic and may serve as a substitute for rice. When you do want rice in your plate, make sure you rinse it well before cooking. Using more water when cooking and draining afterwards may further reduce arsenic levels. ​​Remember that rice is an ingredient in products such as cereals, rice milk, infant rice formulas

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• Randomized trials have provided strong evidence that folate supplementation increases arsenic methylation capacity, allowing faster excretion.

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• Carriers of the INMT and SEPP1 risk variants should make sure they meet the recommended daily intake for selenium.

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     The safe upper limit for selenium is 400 micrograms a day in adults. Anything above that is considered           an overdose.

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