Grantee Research Project Results
2013 Progress Report: Fish Selenium Health Benefit Values in Mercury Risk Management
EPA Grant Number: R834792Title: Fish Selenium Health Benefit Values in Mercury Risk Management
Investigators: Ralston, Nicholas V.C. , Raymond, Laura
Institution: University of North Dakota
EPA Project Officer: Hahn, Intaek
Project Period: April 1, 2011 through March 31, 2013 (Extended to March 31, 2015)
Project Period Covered by this Report: April 1, 2013 through March 31,2015
Project Amount: $490,089
RFA: Exploring Linkages Between Health Outcomes and Environmental Hazards, Exposures, and Interventions for Public Health Tracking and Risk Management (2009) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Human Health
Objective:
The intention of this project was to establish, evaluate, and demonstrate the utility of the selenium (Se) Health Benefit Value (HBVSe) as criteria for predicting benefits versus risks associated with fish consumption. The reliability of risk assessments based on MeHg alone (the current approach) was compared to a variety of criteria that concurrently consider dietary MeHg exposures and Se intakes. The accuracy and statistical reliability of net Se content (Se-Hg), Hg:Se molar ratios, Se-HBV (the earlier version of the index) and the updated HBVSe criterion were compared to the “MeHg only” criteria currently used in risk assessments. The results of this project indicate that risk assessments based on MeHg alone are unable to differentiate exposures that result in toxicity from those that do not. Criteria that are based on concurrent consideration of dietary MeHg exposures and Se intakes were far more accurate and statistically robust. The results of human, animal, and cell culture studies will continue to be evaluated using “Physiologically Oriented Interactions of Nutrients and Toxins” (POINT) models to refine understanding of the biochemical responses associated with Hg exposure-dependent diminishments of bioavailable Se and selenoenzyme activities in brain and related tissues.
Progress Summary:
The Hg, Se, and HBVSe results on over 13,000 ocean and freshwater fish and shellfish have been examined and reported in earlier annual reports. The past year has been spent on mathematical assessments and statistical comparisons of the different risk assessment criteria. These comparisons have been used to test the hypothesis that HBVSe provides more reliable and accurate predictions of health risks associated with MeHg toxicity than criteria based on Hg alone. Thus far, the results of these comparisons have uniformly supported the hypothesis. Now that the biochemical mechanism of MeHg toxicity has been confirmed (Raymond and Ralston, 2004; Carvalho, et al., 2008; Ralston and Raymond, 2010), the relationship between the severity of neurotoxic effects and Hg:Se molar ratios in tissues and other previously unexplained aspects of MeHg toxicity have become easier to understand. When MeHg tissue concentrations in the brain approach or exceed an equimolar stoichiometry with the concentration of Se present in the biochemically active form of selenocysteine (Sec), MeHg binding of Sec and subsequent sequestration in the form of insoluble mercury selenides (HgSe) tend to diminish the “free” Se concentration to levels that significantly or severely compromise selenoenzyme synthesis.
The first comparison examined relative effects of dietary MeHg and Se on growth of weanling male Long-Evans rats from the study reported in Ralston, et al. (2007). Using the standard approach of assessing treatment groups as parallel cohorts assessed by t-tests provided important insights regarding the importance of dietary Se in relation to MeHg toxicity. However, in the current assessment, all data were considered in relation to regressions using HBVSe, Se-HBV, Hg:Se, Se-Hg, or Hg only as the regressor (See Table 1).
Table 1. Data from Ralston, et al. (2007)
Regressors in Relation to F Values of MeHg Effects on Growth |
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Criteria | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 | Week 9 |
HBVSe | 4.3 | 11.0 | 15.7 | 21.3 | 31.9 | 35.1 |
Se-HBV | 4.3 | 10.8 | 15.6 | 21.2 | 31.7 | 35.3 |
Hg:Se | 4.5 | 11.2 | 15.9 | 21.6 | 32.9 | 35.3 |
Se-Hg | NS | NS | 6.1 | 9.8 | 14.1 | 16.4 |
Hg Only | NS | NS | 4.5 | 7.5 | 10.7 | 12.4 |
Regressors in Relation to p Values of MeHg Effects on Growth |
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Criteria | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 | Week 9 |
HBVSe | 0.04 | <0.01 | <0.001 | 2.4 x 10-5 | 5.5 x 10-7 | 2.0 x 10-7 |
Se-HBV | 0.04 | <0.01 | <0.001 | 2.4 x 10-5 | 6.1 x 10-7 | 1.9 x 10-7 |
Hg:Se | 0.04 | <0.01 | <0.001 | 2.1 x 10-5 | 4.0 x 10-7 | 1.9 x 10-7 |
Se-Hg | NS | NS | 0.02 | <0.01 | 4.2 x 10-4 | 1.5 x 10-4 |
Hg Only | NS | NS | 0.04 | <0.01 | <0.01 | <0.001 |
Regressors in Relation to Adjusted R2 of MeHg Effects on Growth |
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Criteria | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 | Week 9 |
HBVSe | 0.05 | 0.14 | 0.20 | 0.26 | 0.35 | 0.37 |
Se-HBV | 0.05 | 0.15 | 0.20 | 0.26 | 0.35 | 0.38 |
Hg:Se | 0.06 | 0.15 | 0.21 | 0.27 | 0.36 | 0.38 |
Se-Hg | NS | NS | 0.08 | 0.13 | 0.19 | 0.21 |
Hg Only | NS | NS | 0.06 | 0.10 | 0.14 | 0.17 |
We predicted that risk assessment criteria based on Hg alone will be capable of identifying effects of MeHg toxicity, but that criteria based on the difference in their molar concentrations in diet (Se-Hg) will be superior, and those based on dietary molar ratios (Hg:Se) will be better still. However, because of the improved discrimination between diets that have similar Hg:Se molar ratios but different absolute intakes, we predicted that the Se-HBV would be better still. Since it further differentiates seafood benefits versus risks, the HBVSe criterion was expected to be slightly superior to the Se-HBV criterion, but only in regard to providing an improved reflection of the beneficial effects of dietary Se from Se-rich foods. Based on their relative importance in the biochemical mechanism of MeHg toxicity, the reliability and statistical robustness of these seafood safety criteria were predicted to be HBVSe ≈ Se-HBV > Hg:Se > Se-Hg >>Hg only. To test this prediction and establish the relative merits of these seafood safety criteria for reflecting benefits versus risks associated with seafood consumption, the outcomes of a series of animal studies were used as dependent variables examined in relation to these criteria as independent variables. The accuracy and reliability of these indices were compared in relation to the statistical robustness of their ability to sensitively identify harmful effects, differentiate harmful from harmless exposures, and demonstrate a consistent relationship between the risk index and the observed outcome.
As shown in Table 1, predictions of risk based on Hg only provide highly significant data; the reliability of criteria involving Se are far better. Predictions based on the net Se excess or deficit (Se-Hg) are more reliable, and criteria based on the Hg:Se molar ratio and either HBVSe or Se-HBV are both far superior to the predictions of risk based on Hg only. The observed relationship between reliability and statistical robustness of the indices tested in this study were HBVSe ≈ Se-HBV ≈ Hg:Se > Se-Hg >Hg only. These analyses indicate that the HBVSe, Se-HBV, and Hg:Se molar ratio criteria are better indictors of risk than those based on Hg only. The Hg only approach cannot accurately predict the accentuated toxicity that high MeHg exposures have when dietary Se intakes are relatively low, such as occurs when eating pilot whale or shark meats. Similarly, the Hg only approach has no way to differentiate those hazardous exposures from the effects observed when high MeHg exposures are accompanied by rich dietary Se intakes. This lack of adequate discrimination explains the confusion caused by studies that have found toxic effects at levels of MeHg exposure where other studies have supposedly failed to find toxicity. Although unintentional, such descriptions clearly reveal the existence of an informal bias and lack of proper objectivity. Now that increasing numbers of studies are finding that increasing MeHg exposures are associated with beneficial effects on child neurodevelopment, it is urgently important to be able to reliably predict which foods will or will not be associated with benefits or risks.
Furthermore, the Hg only approach ignores the potentially accentuated risk of maternal MeHg exposures from sources with high MeHg and low Se levels, such as freshwater fish that originate from watersheds with poor environmental Se availability but high Hg inputs. The Hg only approach also lacks the ability to differentiate hazardous high Hg, low Se exposures from those that are accompanied by rich Se intakes. The inability of Hg only criteria to adequately discriminate between hazardous exposures and exposures that will not be associated with adverse outcomes has prompted confusion among pregnant mothers and their physicians and has alarmed consumers that are not pregnant or likely to become pregnant.
Relevance to the agency’s mission: The goal of this project is to develop, compare, and demonstrate the most reliable, accurate, and consistent assessments of MeHg exposure risks in support of EPA’s mission to protect and improve human and environmental health. Now that the biochemical mechanisms of MeHg toxicity are becoming better understood, its previously unexplained and widely misunderstood features are much easier to understand. Because adverse child neurodevelopmental outcomes were found in association with increasing maternal MeHg exposures in certain studies while others found no such associations, an informal bias arose that assumed the latter groups had failed to find the effect, implying the effect was present but the study must have been flawed. Not understanding the pivotal role of the MeHg:Se molar relationship in the biochemical mechanism of MeHg toxicity and not recognizing that the observed outcomes were entirely consistent with predictions based on this improved understanding, considerable controversy arose. That controversy could have been largely avoided if the biochemical mechanisms of MeHg-dependent inhibition of selenoenzymes and sequestration of Se had been more widely understood. Now that studies are confirming that increasing ocean fish consumption is associated with beneficial effects on child neurodevelopment, it is urgently important to reliably differentiate foods that are versus are not associated with risks. This will clarify advisories and provide the public with the information they need to understand why maternal MeHg exposures from pilot whale and shark meats can be harmful while lower MeHg exposures from Se-rich ocean fish are not.
Assessments based on the HBVSe criterion coincide with and support the 2014 U.S. Environmental Protection Agency (EPA)–U.S. Food and Drug Administration (FDA) advisories for pregnant women regarding the four types of fish that should be avoided. Recommendations based on the HBVSe criteria are more understandable because they enable consumers to recognize that foods with a positive value are beneficial to eat during pregnancy, while those with negative values need to be avoided. Since consumption of fish with negative HBVSe poses risks to humans and piscivorous wildlife that may not be recognized when using criteria that reflect Hg only, this subject urgently requires further study. Because consumption of freshwater fish with negative HBVSe poses greater risks to humans and piscivorous wildlife, and since poor environmental Se availability greatly increases MeHg bioaccumulation in freshwater fish, studies are needed in order to examine MeHg and Se contents of fish from low-Se areas.
Future Activities:
Articles describing work from this project are currently being written for environmental and health-related journals. We also are informing organizations that assess Hg concentrations in ocean or freshwater fish that it is important for them to include Se assessments and consider employing HBVSe criteria in their future Hg risk assessments.
References:
Carvalho, C.M.L.; Chew, E-H.; Hashemy, S.I.; Lu, J.; and Holmgren, A. 2008 Inhibition of the human thioredoxin system: A molecular mechanism of mercury toxicity. Journal of Biological Chemistry. 283;18:11913-11923.
Kaneko, J.J. and Ralston, N.V.C. 2007. Selenium and mercury in pelagic fish in the central north Pacific near Hawaii. Biol. Trace Elem. Res. 119: 242–54.
Ralston, N.V.C.; Blackwell; J.L.; Raymond, L.J. (2007) Importance of Molar Ratios in Selenium-Dependent Protection Against Methylmercury Toxicity. Biol. Trace Element Res. 119(3) 255-268.
Ralston, N.V.C.; Ralston C.R.; Blackwell III J.L.; and Raymond, L.J. (2008) Dietary and Tissue Selenium in Relation to Methylmercury Toxicity. Neurotoxicology. 29(5):802-811.
Ralston, N.V.C., Raymond, L.J. (2010) Dietary selenium's protective effects against methylmercury toxicity. Toxicology 278:112-123. 19.
Raymond, L.J. and Ralston, N.V.C. (2004) Mercury:Selenium Interactions and Health Implications. Seychelles Medical and Dental Journal, Special Issue, 7(1):72-77.
Journal Articles on this Report : 2 Displayed | Download in RIS Format
Other project views: | All 25 publications | 6 publications in selected types | All 5 journal articles |
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Type | Citation | ||
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Raymond LJ, Deth RC, Ralston NVC. Potential role of selenoenzymes and antioxidant metabolism in relation to autism etiology and pathology. NeuroToxicology 2014;2014:164938, doi:10.1155/2014/164938. |
R834792 (2013) |
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Soon R, Dye T, Ralston NVC, Berry MJ, Sauvage LM. Seafood consumption and umbilical cord blood mercury concentrations in a multiethnic maternal and child health cohort. BMC Pregnancy and Childbirth 2014;14(1):209. |
R834792 (2013) |
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Supplemental Keywords:
Risk management, ecological effects, marine, estuary, bioavailability, metabolism, vulnerability, sensitive populations, dose-response, susceptibility, aquaticRelevant Websites:
Fish, Mercury, and Nutrition: The Net Effects ExitProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.