Arsenic: The Underrecognized Common Disease-inducing Toxin

Abstract

Arsenic toxicity is far more of a clinical problem than commonly recognized. At least 10% of the public water supplies contain levels of arsenic known to increase risk of many chronic diseases, such as cardiovascular disease, many cancers, peripheral neuropathy, and diabetes. Some parts of the country have very high arsenic levels, but because fewer than half of all private and public water supplies have been tested for this common toxin, those drinking or consuming food grown with such water will likely not be aware of their exposure. Several key single nucleotide polymorphisms (SNPs) and methylation deficits can significantly increase a patient’s susceptibility to arsenic toxicity. Reduction of arsenic toxicity starts, of course, with avoidance. This means evaluation of water contamination, avoidance of rice and chicken unless tested, cleaning up any old pressure treated wood in the environment, and other precautions. Excretion, neutralization, and protection from damage are facilitated through optimizing methylation processes and the use of natural health products such as turmeric and green tea, and liberally consuming cabbage family foods.

Arsenic exists in trivalent and pentavalent forms and is widely distributed in nature where it is present in soil and ground water. Humans experience additional exposure due to its use in industry and food production and the occasional intentional poisoning. Humans are exposed to both inorganic and organic forms, which have vastly different toxicity. Owing to its prevalence, toxicity and substantial contribution to human disease, arsenic is the most important toxin listed by the Agency for Toxic Substances and Disease Registry (ATSDR).¹ It has been number one for many years owing to its common use and presence in superfund sites.

One way we determine if a toxin was prevalent when we evolved as a species is to look at its half-life. Clearly, humans were regularly exposed to arsenic during evolution as we are normally good at eliminating both its organic and inorganic forms; both have half-lives measured in hours to days. Arsenic is very efficiently absorbed in the gastrointestinal and respiratory tracts, and quickly distributes throughout the body. As discussed later, the primary pathway for neutralization and excretion is through methylation and elimination through the kidneys. The primary forms of arsenic found in humans are inorganic, arsenobetaine, dimethylarsinic acid (DMA), and monomethylarsonic acid (MMA). The monomethylated arsenic (MMA) and inorganic arsenic are 30 to 300 times more toxic than the neutralized double methylated DMA, with arsenobetaine having little toxicity.

Sources

The most common sources of arsenic are groundwater, chicken, and rice, though other sources can be significant in specific populations. Surprisingly, many public and private water supplies are contaminated with arsenic, making groundwater the most common source of exposure. The average ground water level is 1 μg/L, but a number of sources are as high as 50 μg/L.² This is shown in Figure 1; however, only 50% of water supplies have been tested. Some water supplies have shown high levels of contamination, such as in Maine, where well samples as high as 3100 μg/L have been reported.³ The average amount of arsenic (primarily inorganic) from water in the United States is 3.2 μg/day with a range of 1–20 μg/day.

Figure 1.

Arsenic in Public Water Supplies⁴

Food sources of arsenic typically contain organic arsenic compounds such as arsenobetaine, arsenocholine, arsenosugars, and arsenolipids, which have very short half-lives and are considered to have low toxicity. Food can also contain the much more toxic MMA, but dosages are typically small. Table 1 shows the foods with the highest levels of arsenic, according to the US Food and Drug Administration Total Diet Study.⁵

Table 1.

Foods With the Highest Concentration of Arsenic Compounds

Food	mg/kg (PPM)
Haddock (pan cooked)	5.54
Tuna (canned in water)	0.878
Shrimp (boiled)	0.678
Fast food fish sandwich on bun	0.501
Salmon steaks	0.469
New England clam chowder	0.141
Tuna noodle casserole	0.112
Mushrooms raw	0.081
Fried rice, meatless, Chinese takeout	0.072
Infant rice cereal with whole milk	0.042
Chicken leg, fried, fast food	0.023

Although the table clearly shows that fish constitutes the greatest food source of arsenic, it is predominantly the very low toxicity arsenobetaine. Clinically, far more important are rice and, in the past, chicken. Consumption of 0.56 cups of cooked rice daily (the US average) is comparable to drinking 1 L/day of water containing 10 μg/L of arsenic.⁶ This level of rice consumption results in twice the level of urinary DMA than is present in persons who do not regularly consume rice.⁷ The levels of inorganic arsenic in rice vary greatly according to where and how it is grown.⁸ The arsenic content in rice is also affected by washing and cooking, as high levels of arsenic in the water will be absorbed by the rice.⁹ Cooking rice with excess water also has been shown to reduce arsenic content in the cooked rice between 35% and 45%.¹⁰ The chicken story is more complicated as in the past, the United States Department of Agriculture allowed the use of several arsenic-containing drugs in poultry husbandry, primarily for histoplasmosis. These organic arsenic compounds were considered relatively nontoxic until better quality research showed that they were converted into much more toxic inorganic arsenic, which showed up in the chickens and turkeys.¹¹ Most of these compounds have been either voluntarily withdrawn by the manufacturers or are in the process of being prohibited.

Other potentially significant sources of arsenic include cigarettes and hobbies/industrial exposure in glass artwork.^12,13,14,15 Arsenicals, often with lead, have been used for centuries as pesticides, initially as lead arsenate and more recently as monosodium methanearsonate. Although most of these are no longer used, orchard land is often contaminated and when the fields have been converted to housing, unexpected toxicity can occur.¹⁶ Nonetheless, water and dietary sources of arsenic remain the bulk of exposure sources.¹⁷ This may explain why Asians living in the United States have approximately 3 times the body load of total arsenic forms than non-Asians have, likely owing to their higher consumption of rice and fish.

Toxicity

Groundwater provides a continuous source of inorganic arsenic—with the actual form dependent on the source of the arsenic and the pH and oxidative status of the water. Foods provide primarily organic arsenicals along with the metabolites of inorganic arsenic. The various forms of arsenic have vastly different—and clinically significant—LD50s and half-lives, as shown in Table 2.

Table 2.

Half-Lives and LD50 of Arsenic Species

Species	Type	Half life	Primary source	LD50
MMA	Organic	10–20 h	Food	2 mg/kg
Arsenate (V)	Inorganic	2–4 d	Water	8 mg/kg
Arsenite (III)	Inorganic	2–4 d	Water	26 mg/kg
DMA	Organic	10–20 h	Food	648 mg/kg
Arsenobetaine	Organic	4–6 h	Seafood	>4000 mg/kg

Abbreviations: MMA, monomethylarsonic acid; DMA, dimethylarsinic acid;

The trivalent forms of arsenic are thiol-reactive, thus inhibiting enzyme systems or altering proteins with such sulfur groups. Pentavalent arsenic uncouples mitochondrial oxidative phosphorylation, probably by competition phosphate in the formation of adenosine triphosphate. Inorganic arsenic and MMA also cause cellular damage through oxidative stress and DNA methylation.^18,19 Oxidative damage to the DNA results in increased urinary excretion of nucleoside metabolites such as 8-hydroxy-2’-deoxyquanosine (8-OHdG), which is a useful measure for oxidative stress, total toxic load, and disease risk, especially several cancers.²⁰ Urinary 8-OHdG levels correlate with arsenic in groundwater as well as those occupationally exposed. ²¹

Chronic arsenic poisoning results in the classic skin lesions of hyperpigmentation, hypopigmentation, and basal and squamous cell cancers; peripheral neuropathy; and bladder, lung, and liver cancers.²² The vast majority of human studies on the adverse health effects of daily arsenic exposure are based on groundwater consumption rather than from food.

Clinical Significance

Elevated levels of arsenic exposure in ground water have been shown to significantly increase the risk of peripheral neuropathy, cardiovascular disease, myocardial infarction, stroke, chronic obstructive pulmonary disease (COPD), gout, lung cancer, and diabetes.

Due to the large amount of epidemiological data showing arsenic as a common cause of disease, a number of large studies have been conducted to better quantify the problem. A full review of these studies is beyond the scope of this editorial, which will focus on a few very large studies. One large study followed more than 165 000 adults from 17 municipalities in the Viterbo region of Italy for 20 years to determine the influence of the elevated groundwater arsenic on chronic disease.²³ The groundwater arsenic in this region varied from 0.5 μg/L to 80.4 μg/L, with a mean level of 19.3 μg/L. The average person in this study group lived in the area for 39.5 years. In men, the researchers found statistically significant increases (P < .001) for all-cause mortality, lung cancer, several measures of heart disease, myocardial infarction, and COPD. Of particular significance, those consuming groundwater with arsenic levels higher than 20 μg/L had an 83% increased risk of lung cancer, whereas those consuming water with arsenic levels slightly higher than the new US EPA of 10 μg/L had a 47% increase in risk. COPD risk was doubled in those with higher arsenic intake.

The Italian women showed a similarly elevated risk for lung cancer, although inexplicably the risk was higher in those with lower groundwater arsenic. The women also had 32% to 74% increased risk for myocardial infarcts, but they did not have increased risk for stroke or other circulatory disease issues. They also found that women drinking water with more than 10 μg/L of arsenic doubled their risk for diabetes mellitus.

A smaller US study (STRONG) followed 3575 Native Americans from Arizona, Oklahoma, North Dakota, and South Dakota between 1989 and 2008.²⁴ The groundwater arsenic levels ranged from less than 1 μg/L (North Dakota and South Dakota) to 61 μg/L (Arizona). Those with the higher levels of exposure were 65% more likely to have cardiovascular disease, 71% more likely to have coronary heart disease, and more than 3-fold more likely to have a fatal stroke.

Applying these findings to the CDC Exposure Report data would indicate that 25% of all US residents (those at and above the 75th percentile of arsenic, 13.7 μg/g creatinine) have significantly increased risk for cardiovascular disease, chronic heart disease, and stroke.

An interesting Canadian study of more than 2000 adults specifically excluded all seafood eaters and only monitored urinary arsenic levels rather than the levels of arsenic in the drinking water. ²⁵ The authors found that urinary arsenic higher than 5.71 μg As/L was associated with an increased risk for both prediabetes and diabetes. According to the CDC, 50% of people in the United States have higher levels than 8.10 μg As/L. Another way of assessing exposure to arsenic is to measure its level in toenails. As can be seen in Figure 2, arsenic levels clearly correlate with diabetes risk.

Figure 2.

Toenail Arsenic Correlates With Diabetes Risk²⁶

Another look at the data from the STRONG heart study focused on the association between drinking water arsenic intake and risk of various cancers.²⁷ The researchers showed no increased cancer risk below 6.91 μg/g creatinine. Those with arsenic levels higher than 13.22 μg/g creatinine had a 14% increased overall risk for cancer, with the worst being liver, lung, and especially prostate cancer, which showed a 3.3-fold increased risk.

Chronic low level groundwater arsenic exposure has also been linked to increased risk for zoster, diminished cognitive function, and reduced lung function.^28,29

Detoxification/Excretion Processes

The primary route of excretion of both inorganic and organic arsenic is via the urine, and the primary neutralization is through a double methylation process. However, this later process is affected by several polymorphic SNPs, and if only a single methylation occurs, arsenic is left in the far more toxic monomethylated form. The first methylation results in MMA (+3). Optimally, it is then quickly methylated a second time to form low toxicity DMA (+3).⁴ In general, the trivalent oxidative state of arsenic and arsenic metabolites are more toxic owing to increased reactivity with sulfur containing compounds (thiol groups) and greater generation of reactive oxygen species^.30 Methylation occurs enzymatically through the action of arsenic (+3 oxidation) methyltransferases (AS3MT), and nonenzymatically through either methylcobalamin or glutathione.³¹ The nonenzymatic methylation by methylcobalamin is enhanced by providing sodium selenite or 2,3-dimercapto-1-propanesulfonic acid. Single nucleotide polymorphisms of AS3MT, methyltetrahydrofolate reductase, and glutathione transferase omega 1 have all been shown to reduce the second methylation to DMA resulting in higher levels of MMA.³² S-adenosylmethionine (SAMe), folate, methionine, and choline all enhance full methylation of inorganic arsenic,³³ whereas deficiencies in those nutrients leads to lower levels of DMA and higher levels of MMA. Proper bowel flora will also methylate inorganic arsenic to arsenobetaine.³⁴ Persons who are unable to double methylate inorganic arsenic, which results in higher levels of MMA, typically also have elevated homocysteine levels.³⁵

Assessment

Random or first-morning urine arsenic levels can be submitted to various laboratories for measurement. For a more accurate measure of free arsenobetaine, no seafood should be consumed for 48 hours prior to sample collection. Levels lower than 6 μg As/g creatinine have little disease significance, whereas levels higher than 12 μg As/g creatinine indicate higher risk for cardiovascular disease, diabetes, respiratory problems, cancers, and neurological dysfunction. Total arsenic levels higher than 30 μg/g creatinine typically mean the MMA levels are high enough to cause genotoxicity. A number of laboratories offer genomic testing to determine key polymorphism have been discussed previously. Urinary 8-OHdG can be used to assess total body load of toxins and oxidative stress.²⁰ Toenail arsenic is an effective measure of body load and correlates well with disease risk.

Intervention

As with all toxins, careful avoidance is the first step. As discussed previously, this means looking for all sources, especially drinking water, contaminated rice and chicken, environmental exposure to old treated lumber, tobacco smoking, and others.

Tissue protection, neutralization, and excretion can be facilitated by a number of natural health products. As noted previously, SAMe, folate, methylfolate, methylcobalamin, and L-methionine have all been shown to enhance the methylation of inorganic arsenic.^5,7 Methylcobalamin and glutathione can be especially important for those with methylation deficits as they enhance neutralization without utilizing AS3MT.³ Folic acid supplementation at 800 μg daily has been shown to significantly lower blood arsenic levels.³⁶

Brassica family foods are rich sources of sulforaphanes, which help prevent cellular damage from arsenic.^37,38 Turmeric has multiple beneficial effects with regard to arsenic, as it facilitates methylation, excretion of inorganic arsenic, and reversal of cellular damage, including the DNA damage.^39,40 The epigallocatechin gallate and theaflavin constituents of green and black teas have also been shown to reverse arsenic-induced cytotoxicity and genotoxicity.^{41 42}

Conclusion

Arsenic toxicity is far more of a problem than commonly recognized. At least 10% of the public water supplies contain levels of arsenic known to increase the risk of many chronic diseases, such as cardiovascular disease, many cancers, peripheral neuropathy, and diabetes. Some parts of the country have very high arsenic levels, but because fewer than half of all private and public water supplies have been tested for this common toxin, those drinking or consuming food grown with such water will likely not be aware of their exposure. (While working on this editorial, I went digging to see if I could find the arsenic levels in drinking water in Washington State where I live. I was stunned to see a number water supplies higher than the known toxic level of 10 μg/L and some—within a few miles of where I live—with levels higher than 50!) Key to reduction of arsenic toxicity is, of course, avoidance. This means evaluation of water contamination, avoidance of rice and chicken unless tested, cleaning up any old pressure treated wood in the environment, and others.

Excretion, neutralization, and protection from damage are facilitated through optimizing methylation processes and the use of natural health products such as turmeric and green tea and liberally consuming cabbage family foods.

In This Issue

Associate Editor Jeffrey Bland, PhD, starts the issue discussing the how some dietary constituents and unhealthy gut bacteria are causing kidney disease. As I discussed in previous editorials (14.6 and 15.1), kidney disease and failure is an epidemic and huge cause of suffering and medical expense. As always, prevention is key. The good news is that a number of natural interventions can not only prevent but even reverse kidney damage.

In his update on the politics and business of integrative medicine, John Weeks writes about one of the most controversial issues: vaccination. Although the vast majority of practitioners and all the major professional associations support vaccination, there are definitely important areas of disagreement. Long-time readers of IMCJ will know that I am a very strong proponent of objective, scientific evaluation of all concepts, diagnostics, and interventions used in this field. Unfortunately, vaccination policy is like the “third rail” in politics and open discourse seems virtually impossible.

I remember vividly the first time I heard David Perlmutter, MD lecture at an IFM Symposium. His understanding of brain health and how the neurons and function are damaged by nutrient deficiencies and toxins was remarkable. He is also a very engaging and entertaining speaker. This interview by Managing Editor Craig Gustafson provides a great insight into his thinking and hope that much of brain degeneration is not only preventable, but even reversible. David will be a keynote speaker at the IFM Symposium in Los Angeles this Spring. I will be providing a workshop on environmental toxins and neurodegeneration.

Ruth McCaffrey, DNP, and Charles H. Hennekens, MD, DrPH, provide us the fourth installment of their excellent review on probiotics. This is issue covers their role in infectious disease. Patricia Hebert, PhD; E. Joan Barice, MD; Juyoung Park, PhD; Susan MacLeod Dyess, PhD; Ruth McCaffrey, DNP; and Charles H. Hennekens, MD, DrPH, provide us a review of the research on the use of topical copaiba in the treatments for inflammatory arthritis. Hopefully this will facilitate rigorous human trials.

Russell W. Margach, DC, introduces us to the chiropractic perspective on functional neurology. I very much applaud his discussion of the nervous system as pliable, actively adaptable, and trainable. Although the concept of “subluxations” has been subject to a growing amount of research and is controversial, speaking personally, good chiropractic care has been essential to my family’s health. So, I am delighted to see research and understanding continuing to evolve.

Dr Margach’s article is a great introduction for the case report by Laura A. Swingen, DC, DACNB; Rosi Goldsmith, LMT; Judith Boothby, MS, DC; Terry McDermott, DC; and Catherine Kleibel, BA. They show how chiropractic care, monitored with video nystagmography, is effective in the treatment of mild traumatic brain injury. I find very encouraging the concept that brain plasticity and adaptation provide much more opportunity for brain recovery from injury than thought possible in the past.

Under the expert guidance of Associate Editor David Riley, MD, we have another case report, “Collaborative Treatment of Juvenile Rheumatoid Arthritis,” by Judith Boothby, MS, DC, PC; Shelly Coffman, PT, DPT, OCS, FAAOMPT, CSCS; and Todd Turnbull, DC. This is struck a strong cord within me as a college friend of mine being cured of her supposedly “incurable” juvenile arthritis by a naturopathic doctor totally changed the course of my life.

In Back Talk, Bill Benda, MD addresses the huge challenge of bringing integrative medicine concepts into medical education and residencies. Very, very intriguing, creative and insightful recommendations Bill!

Joseph Pizzorno, ND, Editor in Chief

drpizzorno@innovisionhm.com

http://twitter.com/drpizzorno

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