Quantitative Estimates of Risk for Noncancer Endpoints

While quantitative estimates of risk have been a standard practice in cancer risk assessment for many years, no similar practice is evident in noncancer risk assessment. We use two recent examples involving methylmercury and arsenic to illustrate the negative impact of this discrepancy on risk communication and cost-benefit analysis. We argue for a more balanced treatment of cancer and noncancer risks and suggest an approach for reaching this goal.     

Use of Markov Chain Monte Carlo Analysis with a Physiologically-Based Pharmacokinetic Model of Methylmercury to Estimate Exposures in U.S. Women of Childbearing Age

A Bayesian approach, implemented using Markov Chain Monte Carlo (MCMC) analysis, was applied with a physiologically‐based pharmacokinetic (PBPK) model of methylmercury (MeHg) to evaluate the variability of MeHg exposure in women of childbearing age in the U.S. population. The analysis made use of the newly available National Health and Nutrition Survey (NHANES) blood and hair mercury concentration data for women of age 16–49 years (sample size, 1,582). Bayesian analysis was performed to estimate the population variability in MeHg exposure (daily ingestion rate) implied by the variation in blood and hair concentrations of mercury in the NHANES database. The measured variability in the NHANES blood and hair data represents the result of a process that includes interindividual variation in exposure to MeHg and interindividual variation in the pharmacokinetics (distribution, clearance) of MeHg. The PBPK model includes a number of pharmacokinetic parameters (e.g., tissue volumes, partition coefficients, rate constants for metabolism and elimination) that can vary from individual to individual within the subpopulation of interest. Using MCMC analysis, it was possible to combine prior distributions of the PBPK model parameters with the NHANES blood and hair data, as well as with kinetic data from controlled human exposures to MeHg, to derive posterior distributions that refine the estimates of both the population exposure distribution and the pharmacokinetic parameters. In general, based on the populations surveyed by NHANES, the results of the MCMC analysis indicate that a small fraction, less than 1%, of the U.S. population of women of childbearing age may have mercury exposures greater than the EPA RfD for MeHg of 0.1 μg/kgg/day, and that there are few, if any, exposures greater than the ATSDR MRL of 0.3 μgg/kgg/day. The analysis also indicates that typical exposures may be greater than previously estimated from food consumption surveys, but that the variability in exposure within the population of U.S. women of childbearing age may be less than previously assumed.     

A Risk-Benefit Analysis of French High Fish Consumption: A QALY Approach

The health risk and the nutritional benefit of a food are usually assessed separately. Toxicologists recommend limiting the consumption of certain fish because of methylmercury; while nutritionists recommend eating more oily fish because of omega 3. A common evaluation is imperative to provide coherent recommendations. In order to evaluate the risks along with the benefits related to fish consumption, a common metric based on the quality-adjusted life year (QALY) method has been used. The impact of a theoretical change from a medium n-3 PUFAs intake to a high intake is studied, in terms of the cardiovascular system (CHD mortality, stroke mortality and morbidity) and on fetal neuronal development (IQ loss or gain). This application can be considered as a sensitive analysis of the model used and looks at the impact of changing the dose-response relationships between cardiovascular diseases and n-3 PUFAs intakes. Results show that increasing fish consumption may have a beneficial impact on health. However, the confidence interval of the overall estimation has a negative lower bound, which means that this increase in fish consumption may have a negative impact due to MeHg contamination. Some limits of the QALY approach are identified. The first concerns determination of the dose-response relationships. The second concerns the economic origins of the approach and of individual preferences. Finally, since only one beneficial aspect and one risk element were studied, consideration should be given to how other beneficial and risk components may be integrated in the model.     

Use of Quality-Adjusted Life Year Weights with Dose-Response Models for Public Health Decisions: A Case Study of the Risks and Benefits of Fish Consumption

Risks associated with toxicants in food are often controlled by exposure reduction. When exposure recommendations are developed for foods with both harmful and beneficial qualities, however, they must balance the associated risks and benefits to maximize public health. Although quantitative methods are commonly used to evaluate health risks, such methods have not been generally applied to evaluating the health benefits associated with environmental exposures. A quantitative method for risk-benefit analysis is presented that allows for consideration of diverse health endpoints that differ in their impact (i.e., duration and severity) using dose-response modeling weighted by quality-adjusted life years saved. To demonstrate the usefulness of this method, the risks and benefits of fish consumption are evaluated using a single health risk and health benefit endpoint. Benefits are defined as the decrease in myocardial infarction mortality resulting from fish consumption, and risks are defined as the increase in neurodevelopmental delay (i.e., talking) resulting from prenatal methylmercury exposure. Fish consumption rates are based on information from Washington State. Using the proposed framework, the net health impact of eating fish is estimated in either a whole population or a population consisting of women of childbearing age and their children. It is demonstrated that across a range of fish methylmercury concentrations (0-1 ppm) and intake levels (0-25 g/day), individuals would have to weight the neurodevelopmental effects 6 times more (in the whole population) or 250 times less (among women of child-bearing age and their children) than the myocardial infarction benefits in order to be ambivalent about whether or not to consume fish. These methods can be generalized to evaluate the merits of other public health and risk management programs that involve trade-offs between risks and benefits.     

Physiologically Based Pharmacokinetic Modeling of the Lactational Transfer of Methylmercury

The developmental neurotoxicity of methylmercury (MeHg) in humans has been described following catastrophic events in Minamata Bay, Japan and in Iraq, and following the exposure to lower doses elsewhere in the world. The most common route of MeHg exposure in humans is through the intake of contaminated food, especially fish. Although the precautions against the ingestion of potentially contaminated food during pregnancy are well recognized, precautions against the ingestion of MeHg during lactation are not so uniformly recognized. However, the continued development of the central nervous system during the early postnatal period serves to prolong the period during which this critical system is susceptible to the toxic insult of MeHg. Because no direct method is available to quantitatively assess the lactational transfer of MeHg to humans, a computer-aided simulation method was developed. An available gestational physiologically based pharmacokinetic model was refined and expanded to include parameters and algorithms specific for the elimination of MeHg in breast milk. The predictions of the completed model were compared with experimental data obtained from rodents, and the model parameters were allometrically scaled to humans. Finally, the model was validated by comparing its predictions against the available clinical data for MeHg distribution and elimination in mothers and their nursing infants. This model incorporated current and previous maternal exposures to MeHg to accurately predict the kinetics of MeHg excretion in breast milk and the daily intake by the nursing infant. This model may be used to quantify MeHg intake by the nursing infant, under different rates of maternal MeHg ingestion.     

Effects of Uncertainties on Exposure Estimates to Methylmercury: A Monte Carlo Analysis of Exposure Biomarkers versus Dietary Recall Estimation

This article presents a general model for estimating population heterogeneity and "lack of knowledge" uncertainty in methylmercury (MeHg) exposure assessments using two-dimensional Monte Carlo analysis. Using data from fish-consuming populations in Bangladesh, Brazil, Sweden, and the United Kingdom, predictive model estimates of dietary MeHg exposures were compared against those derived from biomarkers (i.e., [Hg]hair and [Hg]blood). By disaggregating parameter uncertainty into components (i.e., population heterogeneity, measurement error, recall error, and sampling error) estimates were obtained of the contribution of each component to the overall uncertainty. Steady-state diet:hair and diet:blood MeHg exposure ratios were estimated for each population and were used to develop distributions useful for conducting biomarker-based probabilistic assessments of MeHg exposure. The 5th and 95th percentile modeled MeHg exposure estimates around mean population exposure from each of the four study populations are presented to demonstrate lack of knowledge uncertainty about a best estimate for a true mean. Results from a U.K. study population showed that a predictive dietary model resulted in a 74% lower lack of knowledge uncertainty around a central mean estimate relative to a hair biomarker model, and also in a 31% lower lack of knowledge uncertainty around central mean estimate relative to a blood biomarker model. Similar results were obtained for the Brazil and Bangladesh populations. Such analyses, used here to evaluate alternative models of dietary MeHg exposure, can be used to refine exposure instruments, improve information used in site management and remediation decision making, and identify sources of uncertainty in risk estimates.     

Factors in Exposure Assessment: Ethnic and Socioeconomic Differences in Fishing and Consumption of Fish Caught along the Savannah River

South Carolina has issued fish consumption advisories for the Savannah River based on mercury and radionuclide levels. We examine differences in fishing rates and fish consumption of 258 people interviewed while fishing along the Savannah River, as a function of age, education, ethnicity, employment history, and income, and test the assumption that the average consumption of fish is less than the recreational value of 19 kg/year assumed by risk assessors. Ethnicity and education contributed significantly to explaining variations in number of fish meals per month, serving size, and total quantity of fish consumed per year. Blacks fished more often, ate more fish meals of slightly larger serving sizes, and consumed more fish per year than did Whites. Although education and income were correlated, education contributed most significantly to behavior; people who did not graduate from high school ate fish more often, ate more fish per year, and ate more whole fish than people who graduated from high school. Computing consumption of fish for each person individually indicates that (1) people who eat fish more often also eat larger portions, (2) a substantial number of people consume more than the amount of fish used to compute risk to recreational fishermen, (3) some people consume more than the subsistence level default assumption (50 kg/year) and (4) Blacks consume more fish per year than Whites, putting them at greater risk from contaminants in fish. Overall, ethnicity, age, and education contributed to variations in fishing behavior and consumption.     

Fish for Dinner? Balancing Risks,Benefits, and Values in Formulating Food Consumption Advice

Many and complex factors underlie seemingly simple decisions about what to eat. This is particularly so for foods such as fish, which present consumers with both risks and benefits. Advice about what type of and how much fish to consume is abundant, but that advice is often confusing or contradictory, reflecting the differing mandates and orientations of those advising. We survey a range of issues that can and should be incorporated into dietary advice, and offer tools for health agencies tasked with providing it. We argue that risks and benefits should not be limited to direct physical health. Rather, socioeconomic and community factors, unintended or indirect effects, and nonhuman‐health outcomes such as animal welfare and planetary health should also be considered and weighed. We provide examples of existing fish consumption guidance to highlight the conflicting messages that emerge when different sources of advice with singular aims of avoiding risk, gaining nutritional benefit, or sustaining fish populations are juxtaposed. We then offer tools borrowed from health and other fields to guide health agencies toward developing more comprehensive advice and targeting that advice for specific populations.     

Methylmercury Risks and EPA + DHA Benefits Associated with Seafood Consumption in Europe

The intake of methyl‐Hg and EPA + DHA through consumption of seafood in Europe as well as the associated probability of exceeding the provisional tolerable weekly intake (PTWI) and the recommended daily intake (RDI), respectively, were estimated by combining methyl‐Hg and EPA + DHA contents in the five most consumed seafood species with hypothesized consumption distributions for eight European countries, chosen on the basis of size and representative significance. Two estimators were used: plug‐in (PI) and tail estimation (TE). The latter was based on the application of the extreme value theory to the intakes distribution curves. Whereas contents data were collected from own database and published scientific papers, consumption data were obtained from statistical sources of the various countries. Seafood consumption levels varied considerably between countries, from 140 in the United Kingdom to 628.5 g/(person.week) in Iceland. The main consumed species were also different between countries. The probability of exceeding the methyl‐Hg PTWI ranged from 0.04% in the United Kingdom to 9.61% in Iceland. Concerning the probability of exceeding the RDI of EPA + DHA, Iceland was third, after Portugal (66.05%) and Spain (61.05%) and the United Kingdom was the last (0.32%). While TE was most accurate for small probabilities, PI yielded best estimates for larger probabilities.     

Estimation of Risk Assessment of Some Heavy Metals Intake Through Black Scabbardfish (Aphanopus carbo) Consumption in Portugal

The intake of Cd, methyl‐Hg, and Pb through consumption of black scabbardfish (BSF) (Aphanopus carbo) in Portugal as well as the associated probability of exceeding the respective provisional tolerable weekly intakes (PTWIs) was estimated. For this purpose, the contamination levels of heavy metals in this fish species were combined with constructed consumption scenarios or with a hypothesized consumption distribution. Whereas Cd and Pb posed no serious risk, the consumption of at least one portion of BSF per month as well as the hypothetical study in the Portuguese population produced nonnegligible probabilities of surpassing the PTWI for Me‐Hg. Risk assessment for Portuguese consumers revealed a higher risk regarding Me‐Hg, 1.19% and 1.81% with the plug‐in (PI) and the tail estimation (TE) estimators, respectively. On the other hand, the risk for Cd and Pb was less than 1 in 100,000. TE was more realistic and accurate for Cd and Pb. Concerning Me‐Hg, TE and PI estimators produced similar results. Furthermore, the limitations of a deterministic approach were shown.