INTRODUCTION
As we all know, the Internet, the mass media, and published research has made it clear that there is no shortage of reasons to fear a large variety of food sources due to the fact that they are tainted by various environmental toxins. Therefore, given the constant barrage of these warnings that are constantly coming our way from the above-mentioned information resources, it is not surprising that mercury content of fish is being thrown into the “Oh my God, avoid as much as possible!!” category like all the rest. Hopefully, in part I of this series, the research-based evidence I presented established credence to the hypothesis that, despite the mercury content, fish are still part of the solution to environmental mercury concerns, not part of the problem. Why? The underappreciated, almost completely ignored variable, selenium.
In part II of this series I am going to present still more research that firmly supports the hypothesis that, due to the high selenium content, fish, despite the amount of mercury currently found in most fish in the American food supply, presents net opportunities for improvements in health, as evidenced by the first study reviewed in part I, “Fish consumption and omega-3 polyunsaturated fatty acids from diet are positively associated with cognitive function in older adults even in the presence of exposure to lead, cadmium, selenium and methylmercury, a cross-sectional study using NHANES 2011-2014 data” by Sasaki et al (1)that was published in The American Journal of Clinical Nutrition in February 2024.
The third study which I only began to review in part I that supported the above mentioned hypothesis was “Dietary selenium’s protective effects against methylmercury toxicity” by Ralston and Raymond (2). Therefore, I would like to now finish my review of the Raymond and Ralston (2) paper by highlighting key quotes from the important section that discusses the distinction in terms of selenium content between ocean and freshwater fish.
IS THERE A CLINICALLY IMPORTANT DISTINCTION IN TERMS OF SELENIUM CONTENT BETWEEN DIFFERENT OCEAN FISH?
Raymond and Ralston (2) begin this section by emphasizing what was stated previously in their paper about the evidence that the selenium content in ocean fish tends to negate the adverse impact in health of the methylmercury also found in ocean fish:
“MeHg toxicity has been counteracted by providing supplemental dietary Se from yellowfin tuna, menhaden, swordfish, and rockfish. Most recently Ralston showed that Se supplied from delipidated proteins of yellowfin tuna, swordfish, and mako shark were all effective in preventing the onset of growth inhibition and neurotoxic effects of high dietary MeHg exposures. Although there were substantial amounts of additional MeHg in diets prepared with these protein isolates, MeHg from these ocean fish did not accentuate MeHg toxicity, but fish Se prevented it. Therefore, the organic forms of Se present in ocean fish are bioavailable and effective in counteracting MeHg toxicity.”
With the above in mind, Ralston and Raymond (2) conclude the following, which is in contrast to prevailing assumptions among the general public, much of the medical community, and all too many in the nutritional/functional medicine community:
“This may explain why studies that examined effects of maternal exposure to MeHg from typical varieties of ocean fish have not found the adverse effects that had been expected, but have, instead, found substantial beneficial effects accompanying increasing seafood consumption, including increases of up to 10 IQ points.”
What, then, might be the explanation for the studies that have reported adverse cognitive effects from ingestion of seafood that contains MeHg? The simple answer is that, as the authors point out, not all seafood is the same in terms of MeHg:selenium ratios. Unlike the seafood mentioned above that was correlated with a decrease in adverse effects from MeHg, others have such a high MeHg:selenium ratio that it is no surprise that adverse effects were noted:
“In contrast, the studies that have found increasing MeHg exposure from seafood consumption were associated with neurodevelopmental impairments uniformly involved consumption of food that contained Hg in molar excess of Se such as pilot whale (5:1 reported by Julshamm et al., 1987) or varieties of shark (>2:1 reported by Kaneko and Ralston, 2007). The New Zealand population had extremely poor dietary Se status at the time of this study. This would have accentuated their vulnerability to MeHg exposure.”
Therefore, as I hope you can see, painting the mercury-related neurologic dangers of seafood ingestion in broad, generalized brushstrokes yields a picture that is misleading, inaccurate, and, most importantly, creates a completely unnecessary and detrimental sense of fear and concern in the general population. The fact of the matter is that, when discussing potential adverse health effects of mercury in seafood, the most important factor to discuss goes against what many, if not most, would consider to be a logical extrapolation. While it may seem inherently logical to focus on mercury when discussing the health effects of mercury in seafood, the facts, in contrast, dictate that the focus needs to be on selenium.
Ralston and Raymond (2), in the next quote, again emphasize this important relationship that is profoundly in contrast with what is usually assumed among the general public, the mass media, conventional health care practitioners, and, all too often, members of the nutritional/functional medicine community:
“Since the Se present in fish protects against the concurrent Hg exposures, risks of MeHg exposure from fish consumption need to assess both elements.”
Before continuing, please note again the key concept in the above quote – any discussion that only focuses on the mercury content of fish is both incomplete and misleading. Both mercury and selenium levels need to be considered to get a true picture of the risks of mercury ingestion from seafood.
In the next quote, the authors emphasize that any discussion about seafood and mercury in general terms is worthless in terms of ascertaining risk to health. To truly understand and appreciate risks for any particular patient, both overall selenium status and types of seafood ingested must be evaluated:
“…variation between individuals in their intakes and status of Se and Hg is highly sensitive to differences in amounts and types of fish consumed.”
In the next quote Ralston and Raymond (2) discuss a methodology that, compared to a simple measurement of mercury content, can more accurately evaluate mercury-based health risks for any type of seafood. It is called “Selenium-Health Benefit Values” (Se-HBV):
“The Selenium-Health Benefit Values (Se-HBV) of seafoods reflect not only the Hg that is present, but also the Se content of the seafoods. This approach incorporates the molar ratios and absolute amounts of Hg and Se present to calculate an index that has proven to be more reliable for predicting risks associated with MeHg exposure. The pilot whales and shark meats whose consumption has been associated with causing harm to children have negative (Se-HBVs) of -80 and -11, respectively. In contrast, the ocean fish that have been associated with beneficial effects on child IQ have Se-HBVs that range between 40 and 250.”
WHAT ABOUT FRESH WATER FISH?
As I hope you realize by now, there is substantial research documentation that, in relation to health risks from mercury exposure, ingestion of many if not most ocean-derived fish present more opportunities for benefit as opposed to risk. However, can the same be stated about freshwater fish? Not necessarily. Why? As you might expect by the now, the answer lies with selenium:
“Ocean fish tend to be generally rich in Se relative to Hg. However, in freshwater fish, the health risks of MeHg exposure may vary in response to individual and regional differences in Se intake. Environmental availability of Se is highly variable, abundant in soils of one area, and dangerously low in regions only miles away. Although the overall Se status in the United States is good, certain populations of the world are severely Se-compromised. Variations in geologic distributions of Se in soils influence the amounts present in foods, potentially predisposing for or protecting against potential risks of Hg exposure.”
With the above in mind, Ralston and Raymond (2) focus in the next paragraph on some of the complexities of the relationship between Se and Hg in freshwater fish:
“Understanding Se’s bioavailability and the factors that influence its metabolism are especially important in Se-deficient regions. Although typical varieties of ocean fish are Se-rich, the Se status of freshwater fish is more variable and can be low in certain regions.”
How might this variability in Se affect MeHg status? The authors comment:
“Methylmercury accumulates at higher levels and at accelerated rates in fish growing in lakes where Se availability is limited, and Se supplementation to normal levels has resulted in MeHg levels in fish diminishing by more than 75% after 3 years. Therefore, fish from low-Se lakes would not only have low-Se contents, they would also tend to have higher MeHg contents, a dangerous combination for consumption by pregnant mothers and other vulnerable populations.”
Of course, you may be wondering, rightly so, how practical and safe is it to “supplement” a lake with selenium? Unfortunately, Ralston and Raymond (2) do not answer this question. However, it certainly is interesting to note that selenium can be used therapeutically in lake fish to reduce their MeHg body burden.
Nevertheless, the authors point out that, similar to the scenario witnessed in the oceans, the impact of abundant Se in fresh water will have a very positive impact on MeHg accumulation in freshwater fish:
“Research indicates that Se is also involved in decreasing Hg accumulation in lake fish. Selenium bioavailability in Hg-contaminated lakes is inversely related to bioaccumulation of MeHg in fish.”
WHY ISN’T THE RELATIONSHIP BETWEEN SELENIUM AND MERCURY CONSIDERED IN WARNINGS TO THE PUBLIC ABOUT FISH INGESTION?
In the discussion section of their paper Ralston and Raymond (2) lament that the selenium factor is rarely part of the mercury story being told by authors of public health advisories concerning fish ingestion in relationship to mercury exposure:
“The current seafood advisories fail to consider the effects of Hg:Se molar ratios in ocean fish and the beneficial effects of improved maternal nutritional status on child health outcomes. Although maternal consumption of ocean fish with Se present in molar excess of Hg appears to be without harmful consequences, many mothers currently avoid eating fish.”
What is the net impact? Unfortunately, according to the authors, it is a net negative:
“These mothers lose the benefits of improved nutritional Se, omega-3, and vitamin D status that improve health outcomes of both mothers and their children. Studies of risks associated with MeHg exposure should be broadened to include consideration of benefits of nutrients from ocean fish consumption and should prompt investigation of Hg:Se molar ratios in freshwater fish for food safety assessments.”
FINAL THOUGHTS FROM RALSTON AND RAYMOND (2)
Ralston and Raymond (2) conclude their thought provoking paper with the following “big picture” observations:
“Based on perceived risks of MeHg exposure from fish consumption, seafood consumption advisories were properly cautious in suggesting that pregnant women should limit their fish consumption to no more than two fish meals per week. However, new data indicate that reducing maternal seafood consumption below this level may actually be causing harm because of the loss of nutraceutical benefits. In contrast, consumption of freshwater fish with MeHg present in highly adverse molar ratios comprises accentuated risks that are not currently being recognized. Since the intention of public health policy makers is to protect children and other vulnerable population subgroups, the advisories will need to be reassessed based on current information and responsibly adjusted to not only properly protect but actively improve child health.”
THE OTHER SIDE OF THE COIN: HOW MERCURY ADVERSLY AFFECTS SELENIUM BIOCHEMISTRY
Up to now I have been focusing on published research that shows how optimal selenium nutriture can greatly diminish the adverse impact of mercury, and methylmercury in particular, on human health. However, in doing so, is selenium acting as a “sacrificial lamb” of sorts? Previously in this series I discussed the fact that mercury can negatively impact the ability of selenium to participate in its many other important functions in human physiology besides curbing mercury toxic outcomes.
Now I would like to review still another paper by Ralston and Raymond that examines the negative impact of mercury on selenium physiology in much more detail. The paper is entitled “Mercury’s neurotoxicity is characterized by its disruption of selenium biochemistry” (3). The first quotes I would like to feature from this paper address an interesting question – Why does mercury, and methylmercury in particular, seem to preferentially accumulate in the brain? Traditionally it has been hypothesized that the explanation lies with the affinity of mercury for thiol/sulfur compounds:
“Mercury’s affinity for thiols suggested this could be related to the mechanism of its toxicity.”
Ralston and Raymond (3) point out that this is incorrect:
“…interactions with thiols fail to provide compelling rationales for Hg’s brain specificity, the reactions responsible for their damage, why fetal brains are more vulnerable than their mother’s, nor the prolonged silent latency between toxic exposures and the onset of effects.”
In contrast, as you might expect by now, the explanation for mercury’s affinity for the brain lies with selenium:
“However, CH3Hg-dependent interruptions of Se-metabolism provide a coherent rationale that is consistent with these consequences.”
It is also interesting to note that the protective effect of selenium in relationship to mercury toxicity is not a recent discovery but was first discovered over 50 years ago:
“Although Se’s ‘protective effect’ against Hg toxicity was first noted by Parizek and Ostadalova over 50 years ago, the pivotal importance of this finding remained overlooked or widely misunderstood.”
In the next quote, Ralston and Raymond (3) address early misunderstandings about how selenium and mercury interact in the brain. It was first thought that the only benefit of selenium was to bind mercury, preventing its ability to adversely affect thiol/sulfur metabolism. In fact, while selenium can bind mercury, a more important function of selenium is its role in selenium dependent enzymes that have powerful antioxidant activities:
“The role of selenoenzyme dependent prevention and reversal of oxidative damage in the brain was generally overlooked in earlier studies of Hg toxicity.”
However, as I mentioned, the main focus of this paper is the other side of the coin – while selenoenzymes can offset the ability of mercury to increase oxidative stress in the brain, in the process mercury can adversely affect activity of selenoenzymes. In relation to this other side of the coin scenario, consider this quote which points out how mercury can decrease activity of key selenium-dependent enzymes:
“It has…been shown that maternal exposure to CH3Hg+ decreased Se concentration and impaired glutathione peroxidase and diiodothyronine deiodinase activities in the brain of neonatal mice.”
Fortunately, selenium supplementation can offset the adverse impact of mercury on glutathione peroxidase activity:
“Mercury dependent inhibition of glutathione peroxidase is well documented and supplemental Se has been shown to prevent interruption of these selenoenzyme activities in the brains of laboratory animals.”
With the above in mind, selenium supplementation is not only necessary to bind mercury and, thus, prevent it from affecting other key physiologic pathways, but it is also necessary to offset the fact that mercury can irreversibly render selenium enzymes completely inactive:
“…by biochemical definition, CH3Hg+ is a highly selective irreversible inhibitor of selenoenzymes.”
The next quote gets into the specifics of how mercury can adversely affect selenium-based physiologic pathways:
“Loss of selenoenzyme activities due to irreversible inhibition is augmented by CH3Hg’s uniquely insidious ability to induce a conditioned Se-deficiency in the brain. Methylmercury is the only environmental insult that has been shown to diminish brain Se below the otherwise impenetrable minimum threshold of ~60% of normal. Sequestration of Hg together with Se as the result of CH3Hg+ binding to the selenocysteine of thioredoxin reductase is particularly evident in kidney and liver. Following catastrophically high CH3Hg exposures, there is an ongoing attrition of Se in somatic and brain tissues due to the continual formation of biologically unavailable mercury selenide (HgSe).”
The next quote I would like to feature from this Ralston and Raymond (3) paper explains why the antioxidant activity of selenoenzymes is so important in the brain:
“Oxygen consumption in the brain is ~10 fold higher than in other tissues, placing the brain at an increased risk of oxidative damage due to formation of reactive oxygen and nitrogen species. This risk is accentuated by the brain’s limited antioxidant enzyme pathways that are abundantly available in other tissues; its high iron contents could potentiate oxidative damage via the Fenton reaction; and the brain’s increased abundance of long chain polyunsaturated fatty acids, which are vulnerable to lipid oxidation. These factors emphasize the importance of selenoenzymes that prevent as well as reverse oxidative damage to the brain. To ensure these essential functions are not interrupted, brain Se concentrations are homeostatically controlled to maintain Se availability for selenoenzyme synthesis and activities.”
In fact, selenium is so important to the brain that, in scenarios of selenium deficiency, the body will begin to transfer selenium from other tissues to the brain:
“During extended periods of dietary Se deficiency in laboratory animals, the Se contents of somatic tissues such as liver, muscle, and blood, diminish to <2% of their normal contents. Selenium-transport molecules redistribute Se from somatic tissues to preferentially supply brain and endocrine tissues.”
Furthermore, because of the importance of selenium to optimal brain health, supplemental selenium will preferentially travel to the brain:
“When Se-deficient rats were provided radiolabeled 75SeO32-, brain was preferentially labelled before other tissues.”
What is it about the brain specifically that makes selenium so important for optimal brain health? Ralston and Raymond (3) provide a fascinating answer to this question that highlights a little known relationship between selenium and vitamin C:
“Because the distal compartments of dendrites and axons are remote from the soma of the neuron, it is difficult for the cell to repair damage to cellular components in the highly active regions of their synapses. Therefore, selenoenzyme-dependent maintenance of reduced ascorbate and other antioxidant molecules are essential for the prevention and reversal of oxidative damage in the synaptic interface, and homeostatic mechanisms have evolved to ensure their expression and activities proceed without interruption.”
What is the only environmental factor that can interfere with this important role of selenium in the brain? As you can probably guess by now – high levels of methylmercury:
“The only environmental insult known to severely impair brain selenoenzyme activities is high CH3Hg+ exposure.”
Therefore, as I hope I have made unmistakably clear, in a world where large scale avoidance of mercury exposure is often difficult, impractical, and/or cost prohibitive on a large scale basis, optimizing selenium status in our patients through diet, supplements, or both, is an important priority which, as of now, seems vastly underappreciated.
Why optimization of selenium status is particularly important in children.
In the next section of the Ralston and Raymond (3) paper the authors discuss both from a physiologic and clinical standpoint why it is particularly important to focus on selenium status in children in relationship to mercury. The first quote from this section I would like to feature highlights the high vulnerability of the fetus:
“The fetus is without significant tissue Se reserves, so loss of maternal Se imports to the rapidly growing brain can result in impaired selenoenzyme activities and damage. The three main families of selenoenzymes (iodothyronine diodinases, thioredoxin reductases, and glutathione peroxidases) have critical roles in fetal brain development growth, thyroid and calcium metabolism, protein folding, and prevention/reversal of oxidative damage, particularly in neuroendocrine tissues.”
How does this play out clinically? To answer this question Ralston and Raymond (3) discuss research conducted with two different populations. While both populations reported high dietary levels of seafood, there were stark differences in selenium status with attendant inevitable and expected differences in response to mercury exposure. The first populations discussed were residents of New Zealand and the Faroe Islands:
“…epidemiological studies in New Zealand, which is a Se deficient region, and the Faroe Islands reported associations of CH3Hg+ exposures with slight, concentration-dependent adverse effects on fetal development. These studies involved mothers eating seafoods during pregnancy with high Hg:Se ratios such as great white shark and pilot whale (~5:1) respectively. Although Se-rich cod fish was consumed in greater quantities, >95% of total CH3Hg+ exposure in the Faroe Islands originated from pilot whale consumption. The authors of this study later concluded that the cod fish offered substantial benefits that offset the otherwise expected neurodevelopmental damage from pilot whale consumption. Due to their high Hg content, advisories against pilot whale consumption have since been evoked and its meats removed from consumer markets.”
Before continuing, please note again that, while the high levels of mercury in pilot whales were certainly a concern in this study, an equally important issue was the low levels of selenium in the pilot whales.
Now, please consider the following quote that discusses the second study where neurodevelopmental benefits were seen in another population despite higher levels of mercury exposure from fish ingestion compared to that seen with the Faroe Island inhabitants:
“In the Seychelles study, mean prenatal CH3Hg+ exposure was higher than in the Faroe Islands study, but no adverse associations were found between CH3Hg+ and 21 endpoints. Instead, increasing prenatal CH3Hg+ was associated with improved scores on four neurological endpoints, as well as fewer reports of substance abuse and incidents of problematic behaviors in school.”
As you might expect, the key difference is the amount of selenium in the ingested seafood:
“The findings of these studies suggest that CH3Hg+ exposure from ocean fish which contain Se in excess of CH3Hg+ (a characteristic shared by nearly all commercial fish species) does not result in developmental harm, but diminished maternal consumption of ocean fish during pregnancy is associated with significant risks. Ocean fish are a significant source of Se and other important nutrients required for the health and development of children and avoiding ocean fish consumption during pregnancy is associated with the loss of these benefits.”
Have similar findings been noted in other populations that ingested high selenium ocean fish in contrast to the Faroe Island residents who were ingesting low selenium pilot whales? To answer this question please consider the following:
“…increasing maternal seafood consumption was shown to be associated with up to 5 points of child IQ benefits in the United Kingdom and nearly 10 points in the United States, even though MeHg exposures were greatest among mothers with the highest seafood intakes.”
In addition, contrary to what many, if not most, might expect, the mothers who avoided fish gave birth to children who demonstrated developmental inadequacies much more profound than those seen in children from the Faroe Islands whose mercury exposure was many times higher:
“Children of mothers who avoided fish consumption during pregnancy displayed developmental impairments of a magnitude ~60 times greater than the worse-case effects associated with the highest pilot whale consumption (thus the highest CH3Hg+ exposures) in the Faroes.”
Furthermore, additional research demonstrated similar patterns where low fish intake consistently correlated with lower academic performance compared with higher fish intake:
“Additionally, the children of mothers who complied with the 2004 U.S. Environmental Protection Agency reference dose (RfD) for CH3Hg+ exposure from fish consumption had an increased risk of scoring in the lowest quartile for verbal IQ, compared to children of mothers exceeding the recommended fish intake. Maternal compliance with diminished fish consumption also increased children’s risk for pathological scores in fine motor, communication, and social skills.”
With all of the above in mind, Ralston and Raymond (3) conclude:
“The findings of these studies suggest that CH3Hg+ exposure from ocean fish which contain Se in excess of CH3Hg+ (a characteristic shared by nearly all commercial marine fish species) does not result in developmental harm, but diminished maternal consumption of ocean fish during pregnancy is associated with significant risks. Ocean fish are a significant source of Se and other important nutrients required for the health and development of children and avoiding ocean fish consumption during pregnancy is associated with the loss of these benefits.”
In part III of this series I will finish my review of the Raymond and Ralston (3) paper. In this conclusion of my review, you will find a summary of a fascinating and detailed discussion on why the latency period between mercury exposure and development of mercury-related symptoms is, as I mentioned previously, directly related to mercury’s intimate association with selenium.
Moss Nutrition Report #313 – 04/15/2023 – PDF Version
REFERENCES
1. Sasaki N et al. Fish consumption and omega-3 polyunsaturated fatty acids from diet are positively associated with cognitive function in older adults even in the presence of exposure to lead, cadmium, selenium, and methylmercury: a cross-sectional study using NHANES 2011-2014 data. The American Journal of Clinical Nutrition. 2024;119(2):283-93.
2. Ralston NVC & Raymond LJ. Dietary selenium’s protective effects against methylmercury toxicity. Toxicology. 2010;278:112-23.
3. Ralston NVC & Raymond LJ. Mercury’s neurotoxicity is characterized by its disruption of selenium biochemistry. BBA – General Subjects. 2018;1862:2405-16.
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