Mercury exposure at low levels induces autoimmunity

Environmental Health PerspectivesToxicity from high levels of mercury and other xenobiotics is less widespread a problem than autoimmunity induced by lower levels generally considered to be safe. The largest public health burden is not toxicity but loss of immune tolerance. A study recently published in the journal Environmental Health Perspectives illustrates this in the case of mercury exposure among females of reproductive age. The authors state:

“Autoimmunity, which can include autoantibody formation, represents a breakdown of tolerance against self-antigens. Self-reactive lymphocytes may occur in healthy individuals, and in the absence of related pathology, autoimmunity represents pre- or sub-clinical immune dysregulation. Thus, the term autoimmunity should be distinguished from autoimmune disease, as it does not denote clinical or symptomatic disease…autoantibodies may precede autoimmune diagnoses by several years, and nearly all autoimmune diseases are characterized by circulating autoantibodies. Antinuclear antibodies (ANAs) are highly sensitive for a variety of autoimmune conditions, including systemic lupus erythematosus (SLE), scleroderma, and Sjögren’s syndrome.”

Investigating the effect of low levels of mercury

Mercury is ubiquitous and a top priority pollutant with seafood consumption and dental amalgam as common sources of exposure with abundant data on concentrations exceeding what is considered safe by regulatory agencies.

“However, immune effects associated with low levels of exposure to each type of mercury in the general population are not well characterized…Utilizing NHANES data, we explored the associations between three types of biomarkers of mercury exposure and the presence, strength, and patterns of antinuclear antibodies in a representative sample of reproductive-age females from the US population.’

They used hair mercury for predominantly organic (methyl) mercury; total blood mercury, a combination of organic and inorganic mercury; and urinary mercury, mainly the inorganic/elemental form from the US National Health and Nutrition Examination Survey (NHANES) for 1932 adult females  ages 16-49 years correlating these with the level of antinuclear antibodies. Their data show a manifest correlation with subclinical autoimmunity:

“16% of females were ANA-positive; 96% of ANA-positives had a nuclear staining pattern of speckled. Mercury geometric means (standard deviations) were: 0.22 (0.03) ppm hair, 0.92 (0.05) µg/L blood, and 0.62 (0.04) µg/L urinary. Hair and blood, but not urinary, mercury were associated with ANA positivity (sample sizes 452, 1352, and 804, respectively), adjusting for confounders: hair odds ratio (OR)=4.10; blood OR=2.32 comparing highest versus lowest quantiles. Magnitudes of association were strongest for high-titer (≥1:1280) ANA: hair OR=11.41; blood OR=5.93.”

This reveals an association of organic mercury exposure (at levels not considered toxic) and antinuclear antibodies.

Pertinent for a wide variety of autoimmune disorders

The authors comment on their findings:

“In this population-based study, we found that mercury exposure is associated with increased risk of high-titer ANA positivity among reproductive-age females in the general US population. Specifically, this association appears to be driven by organic (methyl) mercury, the predominant species in hair and total blood. Notably, a dose-response relationship was observed for low methylmercury exposure levels (<0.37 ppm hair mercury; <1 μg/L total blood mercury), in the range generally considered safe for women of childbearing potential by regulatory agencies (Mergler et al. 2007). The predominant nuclear staining pattern of speckled found in our population is a marker of autoimmunity with a wide variety of clinical associations, including SLE, mixed connective tissue disease, Sjögren’s syndrome, and idiopathic inflammatory myopathies. The methylmercury association was robust across models, whereas other suspected risk factors in the multivariable models, including age and smoking, were not found to be associated with ANA risk.”

Regarding the gender of their study subjects…

“Our study focused on females, ages 16-49 years. It is well recognized that females have a higher risk of autoimmune diseases, and that risk among females may also correlate with reproductive stage. Moreover, estrogenic hormones may promote autoimmunity (Somers and Richardson 2014). Mercury metabolism may also contrast between sexes, and differences in mercury excretion and distribution have been observed between sexes in mouse models, as well as immunotoxic effects at lower internal doses in females.”

The role of oxidative stress

Oxidative stress can promote autoimmunity which the authors comment on in the case of mercury:

Oxidative stress has been shown to contribute to the induction of autoimmune phenotypes in animal models, such as through epigenetic mechanisms converting normal “helper” T cells to autoreactive lymphocytes sufficient to cause lupus in the absence of added antigen. Mercury induces oxidative stress through sulphydryl reactivity and depletion of cellular antioxidants. In human T cells treated with methylmercury, reductions in intracellular glutathione (GSH) concentration, glutathione S-transferase activity and mitochondrial transmembrane potential have been observed, followed by generation of reactive oxygen species; intracellular GSH depletion has further been linked to susceptibility of T cells to undergo methylmercury-induced apoptosis.”

Low levels of mercury considered safe can induce autoimmunity

Practitioners should recall that binding of mercury and native proteins creates a hapten that can induce loss of immune tolerance to the self-antigen in the bound complex. This can result as undifferentiated autoimmunity with an array of diverse symptoms years before evolving into a well-defined autoimmune disease due to extensive tissue damage already having occurred. The authors conclude on a note of vast importance to clinical practice:

Methylmercury, at low levels generally considered safe, was associated with subclinical autoimmunity among reproductive-age females. Autoantibodies may predate clinical disease by years, thus methylmercury exposure may be relevant to future autoimmune disease risk.”

Environmental risk factors for neurodevelopmental, learning and behavioral disorders

Brain development, structure and function can suffer from a number of adverse environmental influences. A paper published in the journal Acta Pædiatrica review some of the environmental risk factors for ADHD.

“Converging evidence from epidemiologic, neuropsychology, neuroimaging, genetic and treatment studies shows that ADHD is a valid medical disorder…The majority of studies performed to assess genetic risk factors in ADHD have supported a strong familial nature of this disorder…However, several biological and environmental factors have also been proposed as risk factors for ADHD, including food additives/diet, lead contamination, cigarette and alcohol exposure, maternal smoking during pregnancy, and low birth weight.

The authors review numerous studies that examine some these extraneous risk factors. They conclude by stating:

“Although a substantial fraction of the aetiology of ADHD is due to genes, the studies reviewed in this article show that many environmental risk factors and potential gene–environment interactions also increase the risk for the disorder.”

A study published in the journal Neuropediatrics investigates specifically the association between blood levels of mercury and ADHD in Hong Kong children:

Fifty-two children with ADHD aged below 18 years diagnosed by DSM IV criteria without perinatal brain insults, mental retardation or neurological deficits were recruited from a developmental assessment center. Fifty-nine normal controls were recruited from a nearby hospital. Blood mercury levels were measured by cold vapor atomic absorption spectrophotometry.”

The authors uncovered a significant difference in blood mercury levels between the children with ADHD and the controls (‘normal’ children) which remained apparent after adjusting for age, gender and parents’ occupations:

“Children with blood mercury level above 29 nmol/L had 9.69 times higher risk of having ADHD after adjustment for confounding variables.”

The average blood mercury levels were higher for both the inattentive and combined subtypes of ADHD. Let’s bear in mind that this is one possible causal factor among many, not ‘THE’ cause. The authors conclude by stating:

High blood mercury level was associated with ADHD. Whether the relationship is causal requires further studies.”

We can see a similar biological mechanism at play when we consider research recently published in Pediatric Allergy and Immunology that examines the association of heavy metals and Tourette syndrome. The authors state:

“Tourette syndrome (TS) is a childhood-onset and relapsing disorder characterized by involuntary simple or complex tics and high co-morbidity with behavioral anomalies…We investigated immunologic alternations and serum heavy metal levels in patients with TS to elucidate the unclarified mechanisms.”

Their findings illuminate a key point:

In exacerbation, there were reverse CD4/CD8 (in two), higher percentages of natural killer cells (in five) and memory T cells (in eight), diminished lymphocyte activation CD69 marker (in three) and impaired NK cytotoxicity (in six) that showed a trend of lower inhibitory CD94 (NKG2A), activating NKp46, and perforin expression compared to those of patients with stable TS and healthy controls…Serum ASLO, mycoplasma antibody and the levels of heavy metals were not significantly different.”

In other words, the levels of heavy metals were pretty much the same but the immune system reaction to them was different. This is why it is impossible to make absolute statements about sub-acute levels of any heavy metal or toxin. Whether it elicits a dysregulated immune response leading to brain inflammation depends on the individual. The authors note this in their conclusion:

“Our study demonstrated that, in some patients with TS, consistently higher memory T cells and lower cytotoxicity in exacerbation status reflect immune alterations and underscore the potential for immunomodulation or immunosuppressive treatment.”

A paper published not long ago in Annals of Clinical Psychiatry carries the point further. The authors summarize the laboratory findings and other data in evidence for an autoimmune pathogenesis for autism:

Autoimmune markers were analyzed in the sera of autistic and normal children, but the cerebrospinal fluid (CSF) of some autistic children was also analyzed. Laboratory procedures included enzyme-linked immunosorbent assay and protein immunoblotting assay.”

Their findings certainly revealed the fire behind the smoke:

Autoimmunity was demonstrated by the presence of brain autoantibodies, abnormal viral serology, brain and viral antibodies in CSF, a positive correlation between brain autoantibodies and viral serology, elevated levels of proinflammatory cytokines and acute-phase reactants, and a positive response to immunotherapy. Many autistic children harbored brain myelin basic protein autoantibodies and elevated levels of antibodies to measles virus and measles-mumps-rubella (MMR) vaccine. Measles might be etiologically linked to autism because measles and MMR antibodies (a viral marker) correlated positively to brain autoantibodies (an autoimmune marker)—salient features that characterize autoimmune pathology in autism. Autistic children also showed elevated levels of acute-phase reactants—a marker of systemic inflammation.”

Here again we see why it is impossible to argue for an environmental factor (heavy metal, virus, vaccine) as an absolute cause for autism or any other condition. Children at risk are those whose immune system is dysregulated and predisposed to an autoimmune triggering agent.

The authors state in their conclusion:

“The scientific evidence is quite credible for our autoimmune hypothesis, leading to the identification of autoimmune autistic disorder (AAD) as a major subset of autism. AAD can be identified by immune tests to determine immune problems before administering immunotherapy.”

We can also consider mild traumatic brain injury as a kind of ‘environmental risk factor’ for disorders neurodevelopment, learning and behavior. A study just published in the journal Pediatrics tests the link between postconcussion syndrome (PCS) and brain injury:

“Much disagreement exists as to whether postconcussion syndrome (PCS) is attributable to brain injury or to other factors such as trauma alone, preexisting psychosocial problems, or medicolegal issues. We investigated the epidemiology and natural history of PCS symptoms in a large cohort of children with a mild traumatic brain injury (mTBI) and compared them with children with an extracranial injury (ECI).”

The authors followed 670 children with mTBI and 197 children with ECI (non-cranial injury) and used the the Post Concussion Symptom Inventory, Rivermead Postconcussion Symptom Questionnaire, Brief Symptom Inventory, and Family Assessment Device to determine outcomes. Their data led to this conclusion:

“Among school-aged children with mTBI, 13.7% were symptomatic 3 months after injury. This finding could not be explained by trauma, family dysfunction, or maternal psychological adjustment. The results of this study provide clear support for the validity of the diagnosis of PCS in children.

Environmental factors can be so severe that anyone would be affected. For most, however, the response depends on the individual. A skilled and experienced clinician knows when and where to focus suspicion. In the functional medicine model there are numerous resources available to test objectively when a question about environmental factors needs an answer, followed by the appropriate therapies when indicated.

Why are autoimmune and allergic diseases on the rise?

An interesting paper just published in PLoS (Public Library of Science) clarifies one of the mechanisms that account for the recent increase in autoimmune disorders. The authors set out to investigate the possibility of an induced dysregulation of the immune system:

Repeated immunization with antigen causes systemic autoimmunity… Overstimulation of CD4+ T cells led to the development of autoantibody-inducing CD4+ T (aiCD4+ T) cell[s]…[which became] antigen-specific cytotoxic T lymphocytes (CTL). These CTLs could be further matured by antigen cross-presentation, after which they caused autoimmune tissue injury akin to systemic lupus erythematosus (SLE).”

This essentially means that overexposure to a potential antigen (increased amounts of gluten in hybridized wheat, higher environmental levels of mercury, etc.) can result in sensitization of the immune system with cross-reaction to our own tissues (autoimmune disease). The authors clearly state their conclusion drawn from the evidence:

Systemic autoimmunity appears to be the inevitable consequence of over-stimulating the host’s immune ‘system’ by repeated immunization with antigen, to the levels that surpass system’s self-organized criticality.”

Mercury levels found to be higher in restaurant sushi tuna than supermarket

Biology LettersAn innovative and alarming study was just published in the journal Biology Letters that not only confirms the high level of toxicity of certain tuna species and uses DNA ‘barcode’ technology to reveal that the type of tuna in most restaurant sushi is the most contaminated with mercury.

The authors remind us:

“Excessive ingestion of mercury—a health hazard associated with consuming predatory fishes—damages neurological, sensory-motor and cardiovascular functioning.”

It can be difficult to identify a specific tuna species and know where it came from using conventional methods. This is where DNA barcodes advances the science:

“Accurate identification of commercial fish species has many public health and legal applications. DNA barcodes—short nucleotide sequences used to identify species—can serve as an important tool allowing regulatory agencies to recognize ambiguous food items that are fraudulent or hazardous.”

The authors undertook an extensive study to match confirmed identity with mercury content:

“We tested the mercury content of 100 tuna sushi samples from 54 restaurants and 15 supermarkets collected from October 2007 to December 2009 in New York, New Jersey, and Colorado.”

What did they find?

The mean mercury concentrations of all samples exceed the concentration permitted by Japan, and the maximum daily consumption considered safe by the US Environmental Protection Agency. Mean mercury levels for bluefin akami exceed those permitted by the US Food and Drug Administration, Health Canada and the European Commission.On average, one order of Bigeye Tuna sushi—the species used most often for sushi—exceeds the safe maximum daily dose recommended by Health Canada and the safe limit established by the World Health Organization and FAO for women of childbearing age.”


“Because the mercury concentrations found in our sushi were significantly higher than levels documented by the Food and Drug Administration this could reflect that our samples came from larger fish (the FDA lacks bluefin data). We found significantly lower mercury levels in supermarket sushi because samples were dominated by Yellowfin Tuna, which comprised a minority of restaurant samples and was found to be the species with the lowest mercury concentration.”

Science NowAt this time health agencies are  not using these findings that place Bigeye and bluefin tuna in the category that the FDA and EPA advise should be totally avoided by pregnant or nursing women and children. You may also like to read a report on this study published in Science Now by the American Academy of Sciences. How do you find out if mercury is a problem for you? Not by provoked chelation (see the earlier post), and inquire about or ‘stay tuned’ for posts on porphyrin profiles, anti-mercury antibodies and MELISA test technology.

Chelation to test for toxic metals? Read this first.

Annals of Clinical BiochemistryWhatever their persuasion, doctors have to be alert to the hazards of cognitive dissonance and confirmation bias (automatic opposition to views that differ from one’s dogma, ignoring data contrary to prejudice ). For some practitioners the evidence against using  chelation to test for toxic metals such as mercury may require a hard swallow. What does the science show?

One study published in the journal Annals of Clinical Biochemistry first notes…

“Oral chelation tests have been used to try to define mercury toxicity in individuals with dental amalgams, who are suffering from a variety of non-specific symptoms.”

In their study healthy individuals submitted to an oral chelation challenge with DMSA (dimercaptosuccinic acid). The result was an elevated excretion of mercury giving the false impression of toxicity inconsistent with their healthy condition. Moreover, one study volunteer suffered a serious reaction (more on this at the end of the post). The authors concluded:

“The oral chelation test using DMSA may lead to misleading diagnostic advice regarding potential mercury toxicity and can be associated with serious side effects.”

Environmental Health PerspectivesThe authors of another paper published in the journal Environmental Health Perspectives set out to answer the question ‘is a diagnostic chelation challenge with DMSA a reliable indicator of long-term mercury toxicity?’

“This study assessed diagnostic chelation challenge with dimercaptosuccinic acid (DMSA) as a measure of mercury body burden among mercury-exposed workers.”

Their data painted a very clear picture:

“There was no association between past occupational mercury exposure and the urinary excretion of mercury either before or after DMSA administration. There was also no association between urinary mercury excretion and the number of dental amalgam surfaces...”

This doesn’t mean that dental amalgams are good for you, but it shows that a chelation challenge is not the tool to find out how you’re handling them. In their conclusion they pinpoint the reason why the results of a chelation challenge can be completely misleading as to the actual body burden of the metals in question:

“We believe the most likely reason that DMSA chelation challenge failed to reflect past mercury exposure was the elapsed time (several years) since the exposure had ended. These results provide normative values for urinary mercury excretion both before and after DMSA challenge, and suggest that DMSA chelation challenge is not useful as a biomarker of past mercury exposure.”

Archives of Pathology & Laboratory Medicine 0109The authors of a study published in the Archives of Pathology & Laboratory Medicine weigh in with their findings that compare DMSA challenge in fish eaters and non-fish eaters, all of whom were doctors in good health. The baseline (pre-DMSA) levels of mercury excretion, and the post-DMSA levels corresponded to the immediate amount of mercury in the blood (recent fish dinners), leading to their conclusion:

“In this study of healthy physicians, oral DMSA produced a rise in urine mercury excretion both in non–fish eaters and fish eaters. The increase in chelated mercury excretion was higher in fish eaters. A simple rise in chelated mercury excretion over baseline excretion is not a reliable diagnostic indicator of mercury poisoning.”

Annals of Internal MedicineAnnals of Internal Medicine published this letter that explains the chemistry behind the misleading elevation in provoked chelation specimens:

“Both EDTA and DMPS attach to divalent cations, such as lead and mercury, trace amounts of which circulate harmlessly in the blood. This causes them to be excreted. Provocation has been shown to artificially increase the 24-hour average urine mercury…Because most extra excretion occurs toward the beginning of the test, one can extrapolate that provoked levels would be 2 to 3 times higher than baseline levels if only a 6-hour collection period had been used. Reference ranges for provoked specimens do not exist. Instead, the laboratory performing the tests compares the reported levels to unprovoked reference ranges for 24-hour specimens. Provocation, shortened collection time, and inappropriate reference range comparisons result in laboratory reports commonly showing 1 or more metal concentrations to be elevated.”


“Patients who ask about provoked urine test results should be advised that they are not trustworthy.”

Journal of Medical ToxicologyWhat does the American College of Medical Toxicology say about the matter? In a recently published position statement, they begin by observing…

“Heavy metals, such as lead and mercury, are ubiquitous in the environment. Exposure in human populations is constantly occurring, and detectable levels of lead and mercury are commonly found in blood and urine of individuals who have no clinical signs or symptoms of toxicity and may be considered background or reference values. Although urine testing for various metals in an appropriate clinical context, using proper and validated methods, is common and accepted medical practice, the use of post-challenge (a.k.a., post-provocation) urine metal testing, wherein specimens are typically collected within 48 hours of chelation agent administration, is fraught with many misunderstandings, pitfalls and risks.”

They go on to note…

Chelating agents have been found to mobilize metals in healthy individuals who have a body burden considered normal…urine specimens collected in relatively close temporal proximity to administration of chelating agents, i.e., post-challenge specimens, are expected to have increased concentrations of metallic elements. This includes elements, such as zinc, that are essential to normal physiologic functions and maintenance of good health.”

They further state:

“Currently available scientific data do not provide adequate support for the use of post-challenge urine metal testing as an accurate or reliable means of identifying individuals who would derive therapeutic benefit from chelation…Unfortunately, the practice of post-challenge urine metal testing and its application to assessment of metal poisoning often leads to unwarranted and prolonged oral and/or intravenous administration of chelating agents…Chelation therapy based on such laboratory values, in addition to being of no benefit to patient outcome, may actually prove harmful…”

These scientists apply their entire professional lives to understanding how best to evaluate toxicity in patients. Here is how they sum up their view:

“It is, therefore, the position of the American College of Medical Toxicology that post-challenge urinary metal testing has not been scientifically validated, has no demonstrated benefit, and may be harmful when applied in the assessment and treatment of patients in whom there is concern for metal poisoning.”

But what do you do if you have a legitimate concern about heavy metal toxicity? Are there valid, scientific, evidence-based ways to test? Indeed there are, but I’m surprised you’ve read this far; it’s a topic for future posts about the lab tests I use to evaluate the two ways that toxic metals can harm: disruption of biochemical pathways (poisoning) and instigating autoimmune phenomena due to allergic sensitivity (which accounts for many of the catastrophic outcomes due to ill-advised chelation testing).

Environmental Health PerspectivesBut to end this post on a positive note, I’ll conclude with one more paper also published in the journal Environmental Health Perspectives. They begin with the concern that we all share…

“Many people, by means of consumption of seafood or other anthropogenic sources, are exposed to levels of methylmercury (MeHg) that are generally considered to be quite low, but that may nevertheless produce irreversible brain damage, particularly in unborn babies. The only way to prevent or ameliorate MeHg toxicity is to enhance its elimination from the body.”

This doesn’t address the immune hypersensitivity component, but is valid nonetheless. They devised a test to see whether N-acetylcysteine (NAC), a normal constituent of the body, could reduce mercury levels in a developing embryo (!, rodent). It worked surprisingly well:

“In pregnant rats, NAC markedly reduced the body burden of MeHg, particularly in target tissues such as brain, placenta, and fetus.”

And here is the really interesting point:

“Because NAC causes a transient increase in urinary excretion of MeHg that is proportional to the body burden [because it is NOT a chelating agent, but supports the body’s own pathways of elimination], it is promising as a biomonitoring agent for MeHg in adult animals. In view of this and because NAC is effective at enhancing MeHg excretion when given either orally or intravenously, can decrease brain and fetal levels of MeHg, has minimal side effects, and is widely available in clinical settings, NAC should be evaluated as a potential antidote and biomonitoring agent in humans.”

OK, but what can we legitimately do for humans right now? More to come in future posts…

Oral DMSA for elimination of toxic metals with autistic spectrum disorders

This research  on the safety and efficacy of oral DMSA (dimercapto succinic acid) therapy for children with autistic spectrum disorders was recently published in BMC Clinical Pharmacology in two parts:

  1. Part A—Medical results
  2. Part B—Behavioral results

The authors conclude in Part A: “Overall, DMSA therapy seems to be reasonably safe, effective in removing several toxic metals (especially lead), dramatically effective in normalizing RBC glutathione, and effective in normalizing platelet counts. Only 1 round (3 days) was sufficient to improve glutathione and platelets. Additional rounds increased excretion of toxic metals.”

They further state in their conclusion to Part B: “Overall, both one and seven rounds of DMSA therapy seems to be reasonably safe in children with ASD who have high urinary excretion of toxic metals, and possibly helpful in reducing some of the symptoms of autism in those children.” [RBC = red blood cell; ASD = autistic spectrum disorder]

This is how metals and chemicals can provoke autoimmune disease

This review published in the International Archives of Allergy and Immunology gives a good description of how certain chemicals and metal ions can interact with proteins in our body to become recognizable to white blood cells, triggering inflammatory allergic or autoimmune disease. Key point: it doesn’t have to be enough of a chemical or metal like mercury to cause a toxic (metabolically poisonous) effect—in a susceptible individual a relatively small amount of something in our food, environment or vaccine can set in motion a chronic disease. What makes a person susceptible? Various factors are evaluated in the functional medicine model.