Reducing Periconceptional Methylmercury Exposure: Cost-Utility Analysis for a Proposed Screening Program for Women Planning a Pregnancy in Ontario, Canada.

BACKGROUND: The assessment of neurodevelopmental effects in children associated with prenatal methylmercury exposure, from contaminated fish and seafood in the maternal diet, has recently been strengthened by adjustment for the negative confounding resulting from co-exposure to beneficial polyunsaturated fatty acids (PUFAs). OBJECTIVES: We aimed to determine the cost-effectiveness of a periconceptional screening program of blood mercury concentration for women planning to become pregnant in Ontario, Canada. Fish intake recommendations would be provided for those found to have blood mercury levels above the intervention threshold. METHODS: Analysis was conducted using a combined decision tree/Markov model to compare the proposed screening intervention with standard care from a societal perspective over a lifetime horizon. We used the national blood mercury distributions of women 20-49 years of age reported in the Canadian Health Measures Survey from 2009 through 2011 to determine the cognitive deficits associated with prenatal methylmercury exposure for successful planned pregnancies. Outcomes modeled included the loss in quality of life and the remedial education costs. Value of information analysis was conducted to assess the underlying uncertainty around the model results and to identify which parameters contribute most to this uncertainty. RESULTS: The incremental cost per quality-adjusted life year (QALY) gained for the proposed screening intervention was estimated to be Can$18,051, and the expected value for a willingness to pay of Can$50,000/QALY to be Can$0.61. CONCLUSIONS: Our findings suggest that the proposed periconceptional blood mercury screening program for women planning a pregnancy would be highly cost-effective from a societal perspective. The results of a value of information analysis confirm the robustness of the study's conclusions.

Associations of methylmercury and inorganic mercury between human cord blood and maternal blood: a meta-analysis and its application.

Considering the different ability of placental transfer, an assessment of the cord:maternal blood ratio for both methylmercury (MeHg) and inorganic mercury (IHg) is needed especially for interpreting the low-level prenatal exposure. In this study, we conducted a Monte Carlo-based meta-analysis to comprehensively estimate that ratio for MeHg (RMeHg) and IHg (RIHg). The obtained values followed log-normal distributions, with a mean (standard deviation) of 1.89 (0.98) and 1.01 (0.55) for RMeHg and RIHg, respectively. We also estimated the percentage of MeHg in the blood by means of THg in cord and maternal blood using the RMeHg and RIHg, and obtained a value very close to the measured one (relative deviation, -0.4%). In conclusion, the fetus is exposed to approximately twice as much MeHg and to the same level of IHg as in maternal blood; the introduced model provides a rough but reasonable estimate of the percentage of MeHg in the blood.

A simple method for methylmercury, inorganic mercury and ethylmercury determination in plasma samples by high performance liquid chromatography-cold-vapor-inductively coupled plasma mass spectrometry.

A simple and sensitive method with a fast sample preparation procedure is proposed for the determination of mercury species in plasma/serum. The method combines online high-performance liquid chromatography separation, Hg cold-vapor formation and inductively coupled plasma mass spectrometry detection. Prior to analysis, plasma (250 µL) was accurately pipetted into 15 mL conical tubes. Then, an extractant solution containing mercaptoethanol, L-cysteine and HCl was added to the samples following sonication for 10 min. Quantitative mercury extraction was achieved with the proposed procedure. Separation of mercury species was accomplished in less than 8 min on a C8 reverse phase column with a mobile phase containing 3% v/v methanol + 97% v/v (0.5% v/v 2-mercaptoethanol + 0.05% v/v formic acid). The method detection limits were found to be 12 ng L(-1), 5 ng L(-1) and 4 ng L(-1) for inorganic mercury, ethylmercury and methylmercury, respectively. Method accuracy is traceable to Standard Reference Material (SRM) 966 Toxic Metals in Bovine Blood from NIST. Additional validation was provided by the analysis of a secondary reference serum sample from the INSQ-Canada. Finally, the method was successfully applied for the speciation of mercury in plasma samples collected from volunteers exposed to methylmercury through fish consumption. For the first time to our knowledge, levels of different species of Hg in plasma samples from riverside populations exposed to MeHg were determined.

Assessment of mercury and selenium concentrations in captive bottlenose dolphin's (Tursiops truncatus) diet fish, blood, and tissue.

Concentrations of total mercury (Hg) and selenium (Se) were determined in diet fish and whole blood and tissue samples from seven bottlenose dolphins (Tursiops truncatus) housed at the National Aquarium Baltimore (NAB). In addition, concentrations of monomethylmercury (CH(3)Hg(+)) were determined in diet fish and dolphins' tissue samples. The data were compared with the values found in wild populations to better understand how the dietary Hg and Se uptake rates affect the Hg and Se levels in dolphins. The diet fish total Hg concentrations ranged between 14 and 47 ng g(-1) and were markedly lower than for similar fish found in Florida, South Carolina, and other aquaria. CH(3)Hg(+) accounted for 85 to 91% of the total Hg found in diet fish. The diet fish Se concentrations ranged between 270 and 800 ng g(-1), indicating excess molar concentrations of Se over Hg. The Hg concentration range in the blood of NAB dolphins was 27-117 ng g(-1) and the concentrations were about one order of magnitude and several factors lower than the concentrations found in the blood of wild bottlenose dolphins in Florida and in South Carolina, respectively. The total Hg and CH(3)Hg(+) in tissue samples were also significantly lower than the reported values obtained from wild populations of bottlenose dolphins. The differences in the Hg concentrations in the dolphins' blood may be due to the different levels of Hg atmospheric deposition in the area where the dolphins' diet fish were found. The Se concentration range in the blood of NAB dolphins was 221-297 ng g(-1) which was two factors lower than the values found in wild populations. The lower Hg levels, as well as higher Se:Hg molar ratios in the blood of NAB dolphins, suggest that NAB dolphins may be less susceptible to the potential neurotoxicity from the CH(3)Hg(+) in their blood.

An exposure assessment of methyl mercury via fish consumption for the Japanese population.

The objective of this article was to propose an exposure assessment model to describe the relationship between fish consumption and body methyl mercury (MeHg) levels in the Japanese population. Individual MeHg intake was estimated by the summation of species-specific fish consumption multiplied by species-specific fish MeHg levels. The distribution of fish consumed by individuals and the MeHg level in each fish species were assigned based on published data from Japanese government institutions. The probability of MeHg intake for a population was accomplished through a Monte Carlo simulation by the random sampling of fish consumption and species-specific MeHg levels. Internal body MeHg levels in blood and hair were estimated using a one-compartment model. Overall, the mean value of MeHg intake for the Japanese population was estimated to be 6.76 microg/day or 0.14 microg/kg body weight per day (bw/day), while the mean value for the hair mercury level was 2.02 microg/g. Compared with the survey data that tabulated hair mercury levels in a cross-section of the Japanese population, the simulation results matched the hair mercury survey data very well for women, but somewhat underestimated for men and all of the population. This exposure assessment model is a useful attempt at further risk assessment with respect to a risk-benefit analysis.

Methylmercury exposure assessment using dietary and biomarker data among frequent seafood consumers in France CALIPSO study.

BACKGROUND: Seafood is considered by toxicologists as the main source of methylmercury (MeHg), but little data is available concerning contamination of seafood and MeHg status of French frequent consumers. OBJECTIVES: The objectives were to assess food exposure and biomarker of exposure of MeHg from a group of frequent consumers of seafood. METHODS: Two approaches to exposure assessment were used: the currently used food intake and the biomarker of exposure. A validated food frequency questionnaire (FFQ) was used to assess seafood consumptions for 80 products of 385 frequent consumers aged 18 and over in four French coastal areas. Seafood samples were collected in each region considering preservation methods and supply habits according to a total diet study sampling. Food samples were analyzed for MeHg. Exposure was assessed by combining consumptions with contamination data. Whole blood samples were collected from the volunteers and analyzed for MeHg. RESULTS: The mean dietary exposure to MeHg or weekly intake (WI FFQ) was 1.51+/-1.17 microg/kg bw/wk. Thirty-five percent of the subjects exceed the Joint Expert Committee on Food Additives (JECFA) provisional tolerable weekly intake (PTWI), whereas the use of the biological results with the JECFA/Environmental Protection Agency (EPA) one-compartment pharmacokinetic model to calculate weekly intake (WI PKM) shows that only 2% of subjects exceed the PTWI. The mean of the individual ratios WI FFQ/WI PKM is 4.3 and the higher the WI FFQ and the blood MeHg level, the lower is the ratio, close to 1-2. CONCLUSIONS: These analyses support the assumption that the calculated dose of methylmercury is overestimated with the FFQ-based method used in this study. Since FFQ are commonly used in risk assessments, the overestimate of dose is public health protective and this finding is somewhat reassuring from a public health point of view, especially since the JECFA or EPA have applied uncertainty factors of 3.2 or 3, respectively, to take into account the inter-individual pharmacokinetic variability.

Confounder selection in environmental epidemiology: assessment of health effects of prenatal mercury exposure.

PURPOSE: The purpose of the study is to compare different approaches to the identification of confounders needed for analyzing observational data. Whereas standard analysis usually is conducted as if the confounders were known a priori, selection uncertainty also must be taken into account. METHODS: Confounders were selected by using backward elimination (BE), change in estimate (CIE) method, Akaike information criterion, Bayesian information criterion (BIC), and an empirical approach using a priori information. A modified ridge regression estimator, which shrinks effects of confounders toward zero, also was considered. For each criterion, uncertainty in the estimated exposure effect was assessed by using bootstrap simulations for which confounders were selected in each sample. These methods were illustrated by using data for mercury neurotoxicity in Faroe Islands children. Point estimates and standard errors of mercury effects on confounder-sensitive neurobehavioral outcomes were calculated for each selection procedure. RESULTS: The full model and the empirical a priori model showed approximately the same precision, and these methods were (slightly) inferior to only modified ridge regression. Lower precisions were obtained by using BE with a low cutoff level, BIC, and CIE. CONCLUSIONS: Standard analysis ignores model selection uncertainty and is likely to yield overoptimistic inferences. Thus, the traditional BE procedure with p = 5% should be avoided. If data-dependent procedures are required for confounder identification, we recommend that inferences be based on bootstrap statistics to describe the selection process.

Mental retardation and prenatal methylmercury toxicity.

BACKGROUND: Methylmercury (MeHg) is a developmental neurotoxicant; exposure results principally from consumption of seafood contaminated by mercury (Hg). In this analysis, the burden of mental retardation (MR) associated with methylmercury exposure in the 2000 U.S. birth cohort is estimated, and the portion of this burden attributable to mercury (Hg) emissions from coal-fired power plants is identified. METHODS: The aggregate loss in cognition associated with MeHg exposure in the 2000 U.S. birth cohort was estimated using two previously published dose-response models that relate increases in cord blood Hg concentrations with decrements in IQ. MeHg exposure was assumed not to be correlated with native cognitive ability. Previously published estimates were used to estimate economic costs of MR caused by MeHg. RESULTS: Downward shifts in IQ resulting from prenatal exposure to MeHg of anthropogenic origin are associated with 1,566 excess cases of MR annually (range: 376-14,293). This represents 3.2% of MR cases in the US (range: 0.8%-29.2%). The MR costs associated with decreases in IQ in these children amount to $2.0 billion/year (range: $0.5-17.9 billion). Hg from American power plants accounts for 231 of the excess MR cases/year (range: 28-2,109), or 0.5% (range: 0.06%-4.3%) of all MR. These cases cost $289 million (range: $35 million-2.6 billion). CONCLUSIONS: Toxic injury to the fetal brain caused by Hg emitted from coal-fired power plants exacts a significant human and economic toll on American children.

A revised probabilistic estimate of the maternal methyl mercury intake dose corresponding to a measured cord blood mercury concentration.

In 2001, the U.S. Environmental Protection Agency (EPA) adopted a revised reference dose (RfD) for methyl mercury (MeHg) of 0.1 microg/kg/day. The RfD is based on neurologic developmental effects measured in children associated with exposure in utero to MeHg from the maternal diet. The RfD derivation proceeded from a point of departure based on measured concentration of mercury in fetal cord blood (micrograms per liter). The RfD, however, is a maternal dose (micrograms per kilogram per day). Reconstruction of the maternal dose corresponding to this cord blood concentration, including the variability around this estimate, is a critical step in the RfD derivation. The dose reconstruction employed by the U.S. EPA using the one-compartment pharmacokinetic model contains two areas of significant uncertainty: It does not directly account for the influence of the ratio of cord blood: maternal blood Hg concentration, and it does not resolve uncertainty regarding the most appropriate central tendency estimates for pregnancy and third-trimester-specific model parameters. A probabilistic reassessment of this dose reconstruction was undertaken to address these areas of uncertainty and generally to reconsider the specification of model input parameters. On the basis of a thorough review of the literature and recalculation of the one-compartment model including sensitivity analyses, I estimated that the 95th and 99th percentiles (i.e., the lower 5th and 1st percentiles) of the maternal intake dose corresponding to a fetal cord blood Hg concentration of 58 microg/L are 0.3 and 0.2 microg/kg/day, respectively. For the 99th percentile, this is half the value previously estimated by the U.S. EPA.

An exposure assessment for methylmercury from seafood for consumers in the United States.

An exposure model was developed to relate seafood consumption to levels of methylmercury (reported as mercury) in blood and hair in the U.S. population, and two subpopulations defined as children aged 2-5 and women aged 18-45. Seafood consumption was initially modeled using short-term (three-day) U.S.-consumption surveys that recorded the amount of fish eaten per meal. Since longer exposure periods include more eaters with a lower daily mean intake, the consumption distribution was adjusted by broadening the distribution to include more eaters and reducing the distribution mean to keep total population intake constant. The estimate for the total number of eaters was based on long-term purchase diaries. Levels of mercury in canned tuna, swordfish, and shark were based on FDA survey data. The distribution of mercury levels in other species was based on reported mean levels, with the frequency of consumption of each species based on market share. The shape distribution for the given mean was based on the range of variation encountered among shark, tuna, and swordfish. These distributions were integrated with a simulation that estimated average daily intake over a 360-day period, with 10,000 simulated individuals and 1,000 uncertainty iterations. The results of this simulation were then used as an input to a second simulation that modeled levels of mercury in blood and hair. The relationship between dietary intake and blood mercury in a population was modeled from data obtained from a 90-day study with controlled seafood intake. The relationship between blood and hair mercury in a population was modeled from data obtained from several sources. The biomarker simulation employed 2,000 simulated individuals and 1,000 uncertainty iterations. These results were then compared to the recent National Health and Nutrition Examination Survey (NHANES) that tabulated blood and hair mercury levels in a cross-section of the U.S. population. The output of the model and NHANES results were similar for both children and adult women, with predicted mercury biomarker concentrations within a factor of two or less of NHANES biomarker results. However, the model tended to underpredict blood levels for women and overpredict blood and hair levels for children.

Estimation of the interindividual variability in the one-compartment pharmacokinetic model for methylmercury: implications for the derivation of a reference dose.

A critical step in the U.S. EPA's derivation of an Reference Dose (RfD) for methylmercury is conversion of the maternal hair Hg concentration of 11 ppm to average daily intake using the one-compartment pharmacokinetic model. A default uncertainty factor (UF) adjustment of 3 for interindividual variability was then applied to this conversion. A probabilistic (Monte Carlo) analysis is presented estimating the interindividual variability inherent in this dose conversion for women 18-40 years old based on data in the scientific literature. The dose of 1.1 micrograms/kg/day, calculated by the U.S. EPA to correspond to 11 ppm Hg in hair, is estimated in this analysis to be larger than 94-99% of corresponding doses. The application of a UF of 3 to this U.S. EPA value gives a dose which is estimated to be larger than 28-73% of corresponding doses. This analysis suggests that if the dose conversion in the RfD is intended to be inclusive of 95-99% of women 18-40, the daily intake should be set at 0.1-0.3 microgram/kg/day. The RfD of 0.03-0.1 microgram/kg/day, derived from this dose by the U.S. EPA's application of an additional UF of 3 for additional toxicologic concerns, is somewhat smaller than the current RfD of 0.1 microgram/kg/day.

Balancing human exposure, risk and reality: questions raised by the Canadian aboriginal methylmercury program.

Environmental contaminants such as methylmercury which bio-accumulate in aquatic ecosystems present an exposure risk to Aboriginal peoples living traditional lifestyles. The results of a 20 year testing program of methylmercury exposure levels of 38,571 Canadian Aboriginal people in 514 native communities across Canada are presented. 608 individuals had blood or blood equivalent levels over 100 micrograms/l. The highest individual level was 660 micrograms/l. The highest mean levels were found in the Inuit in N.W.T. In that same group, over 30% of women aged 15-45 years who were tested had levels over 10 micrograms/g methylmercury in hair with a mean of 16 micrograms/g, well into the 10-20 micrograms/g "risk" range defined by WHO for fetal exposure. A discussion of the management of risk from exposure to methylmercury in the Canadian Aboriginal population is presented, concentrating especially on the need to balance the theoretical basis of the risk assessment, for different population groups and for different exposure patterns, against the potential real impact on health caused by restrictive advice on consumption of traditional foods, especially fish.