Mary A. Fox

Global methylmercury exposure from seafood consumption and risk of developmental neurotoxicity: a systematic review

OBJECTIVE To examine biomarkers of methylmercury (MeHg) intake in women and infants from seafood-consuming populations globally and characterize the comparative risk of fetal developmental neurotoxicity. METHODS A search was conducted of the published literature reporting total mercury (Hg) in hair and blood in women and infants. These biomarkers are validated proxy measures of MeHg, a neurotoxin found primarily in seafood. Average and high-end biomarkers were extracted, stratified by seafood consumption context, and pooled by category. Medians for average and high-end pooled distributions were compared with the reference level established by a joint expert committee of the Food and Agriculture Organization (FAO) and the World Health Organization (WHO). FINDINGS Selection criteria were met by 164 studies of women and infants from 43 countries. Pooled average biomarkers suggest an intake of MeHg several times over the FAO/WHO reference in fish-consuming riparians living near small-scale gold mining and well over the reference in consumers of marine mammals in Arctic regions. In coastal regions of south-eastern Asia, the western Pacific and the Mediterranean, average biomarkers approach the reference. Although the two former groups have a higher risk of neurotoxicity than the latter, coastal regions are home to the largest number at risk. High-end biomarkers across all categories indicate MeHg intake is in excess of the reference value. CONCLUSION There is a need for policies to reduce Hg exposure among women and infants and for surveillance in high-risk populations, the majority of which live in low-and middle-income countries.

State-of-the-Science Workshop Report: Issues and Approaches in Low-Dose― Response Extrapolation for Environmental Health Risk Assessment

Low-dose extrapolation model selection for evaluating the health effects of environmental pollutants is a key component of the risk assessment process. At a workshop held in Baltimore, Maryland, on 23–24 April 2007, sponsored by U.S. Environmental Protection Agency and Johns Hopkins Risk Sciences and Public Policy Institute, a multidisciplinary group of experts reviewed the state of the science regarding low-dose extrapolation modeling and its application in environmental health risk assessments. Participants identified discussion topics based on a literature review, which included examples for which human responses to ambient exposures have been extensively characterized for cancer and/or noncancer outcomes. Topics included the need for formalized approaches and criteria to assess the evidence for mode of action (MOA), the use of human versus animal data, the use of MOA information in biologically based models, and the implications of interindividual variability, background disease processes, and background exposures in threshold versus nonthreshold model choice. Participants recommended approaches that differ from current practice for extrapolating high-dose animal data to low-dose human exposures, including categorical approaches for integrating information on MOA, statistical approaches such as model averaging, and inference-based models that explicitly consider uncertainty and interindividual variability.

Differential Exposure to Hazardous Air Pollution in the United States: A Multilevel Analysis of Urbanization and Neighborhood Socioeconomic Deprivation

Population exposure to multiple chemicals in air presents significant challenges for environmental public health. Air quality regulations distinguish criteria air pollutants (CAPs) (e.g., ozone, PM2.5) from hazardous air pollutants (HAPs)—187 chemicals which include carcinogens and others that are associated with respiratory, cardiovascular, neurological and numerous other non-cancer health effects. Evidence of the public’s cumulative exposure and the health effects of HAPs are quite limited. A multilevel model is used to assess differential exposure to HAP respiratory, neurological, and cancer hazards (2005) related to the Townsend Index of Socioeconomic Deprivation (TSI), after adjustment for regional population size and economic activity, and local population density. We found significant positive associations between tract TSI and respiratory and cancer HAP exposure hazards, and smaller effects for neurological HAPs. Tracts in the top quintile of TSI have between 38%–60% higher HAP exposure than the bottom quintile; increasing population size from the bottom quintile to the top quintile modifies HAP exposure hazard related to TSI, increasing cancer HAP exposure hazard by 6% to 20% and increasing respiratory HAP exposure hazard by 12% to 27%. This study demonstrates the value of social epidemiological methods for analyzing differential exposure and advancing cumulative risk assessment.

Potential for Chemical Mixture Exposures and Health Risks in New Orleans Post–Hurricane Katrina

ABSTRACT Toxic chemical exposure following Hurricane Katrina was a major concern given the industrial base of the New Orleans area. We evaluated the potential for chemical mixture exposures in the USEPAs hurricane response sampling in Orleans Parish and identified health effects of concern for mixtures observed. Environmental sampling (excluding hazardous waste sites and spills) yielded 165 floodwater sampling locations, 206 soil sampling locations, and 451 sediment sampling locations. Frequently reported chemicals included manufacturing intermediates, metallic elements, and polycyclic aromatic hydrocarbons. Health effects associated with chemicals frequently reported included: blood effects, cancer, cardiovascular, gastrointestinal, kidney, liver and neurological effects. Effect-specific mixtures of two or more chemicals were found at many sampling locations. For example, two carcinogens frequently reported in soil were found together at 64 (31%) soil sample locations; seven nephrotoxicants were found together at 112 (25%) sediment sample locations; three neurotoxic chemicals were found together in 230 (51%) sediment sample locations. Hurricane response sampling showed effect-specific chemical mixtures at many locations indicating opportunity for mixture exposures. Chemicals found together are not unique to New Orleans or to post-hurricane conditions. The results highlight the limitations of single substance risk assessments and have important implications for disaster preparedness and response and surveillance.

Leveraging Epidemiology to Improve Risk Assessment

The field of environmental public health is at an important crossroad. Our current biomonitoring efforts document widespread exposure to a host of chemicals for which toxicity information is lacking. At the same time, advances in the fields of genomics, proteomics, metabolomics, genetics and epigenetics are yielding volumes of data at a rapid pace. Our ability to detect chemicals in biological and environmental media has far outpaced our ability to interpret their health relevance, and as a result, the environmental risk paradigm, in its current state, is antiquated and ill-equipped to make the best use of these new data. In light of new scientific developments and the pressing need to characterize the public health burdens of chemicals, it is imperative to reinvigorate the use of environmental epidemiology in chemical risk assessment. Two case studies of chemical assessments from the Environmental Protection Agency Integrated Risk Information System database are presented to illustrate opportunities where epidemiologic data could have been used in place of experimental animal data in dose-response assessment, or where different approaches, techniques, or studies could have been employed to better utilize existing epidemiologic evidence. Based on the case studies and what can be learned from recent scientific advances and improved approaches to utilizing human data for dose-response estimation, recommendations are provided for the disciplines of epidemiology and risk assessment for enhancing the role of epidemiologic data in hazard identification and dose-response assessment.

The Impact of Local Environmental Health Capacity on Foodborne Illness Morbidity in Maryland

OBJECTIVES We evaluated the relationship between local food protection capacity and service provision in Marylands 24 local food protection programs (FPPs) and incidence of foodborne illness at the county level. METHODS We conducted regression analyses to determine the relationship between foodborne illness and local FPP characteristics. We used the Centers for Disease Control and Preventions FoodNet and Maryland Department of Health and Mental Hygiene outbreak data set, along with data on Marylands local FPP capacity (workforce size and experience levels, budget) and service provision (food service facility inspections, public notification programs). RESULTS Counties with higher capacity, such as larger workforce, higher budget, and greater employee experience, had fewer foodborne illnesses. Counties with better performance and county-level regulations, such as high food service facility inspection rates and requiring certified food manager programs, respectively, had lower rates of illness. CONCLUSIONS Counties with strong local food protection capacity and services can protect the public from foodborne illness. Research on public health services can enhance our understanding of the food protection infrastructure, and the effectiveness of food protection programs in preventing foodborne illness.

Integrating Susceptibility into Environmental Policy: An Analysis of the National Ambient Air Quality Standard for Lead

Susceptibility to chemical toxins has not been adequately addressed in risk assessment methodologies. As a result, environmental policies may fail to meet their fundamental goal of protecting the public from harm. This study examines how characterization of risk may change when susceptibility is explicitly considered in policy development; in particular we examine the process used by the U.S. Environmental Protection Agency (EPA) to set a National Ambient Air Quality Standard (NAAQS) for lead. To determine a NAAQS, EPA estimated air lead-related decreases in child neurocognitive function through a combination of multiple data elements including concentration-response (CR) functions. In this article, we present alternative scenarios for determining a lead NAAQS using CR functions developed in populations more susceptible to lead toxicity due to socioeconomic disadvantage. The use of CR functions developed in susceptible groups resulted in cognitive decrements greater than original EPA estimates. EPA’s analysis suggested that a standard level of 0.15 µg/m3 would fulfill decision criteria, but by incorporating susceptibility we found that options for the standard could reasonably be extended to lower levels. The use of data developed in susceptible populations would result in the selection of a more protective NAAQS under the same decision framework applied by EPA. Results are used to frame discussion regarding why cumulative risk assessment methodologies are needed to help inform policy development.

Association of markers of chronic viral hepatitis and blood mercury levels in US reproductive-age women from NHANES 2001–2008: a cross-sectional study

BackgroundMethylmercury (MeHg) is a neurotoxin primarily found in seafood; exposures in reproductive-age women are of concern due to vulnerability of the developing fetus. MeHg is mainly eliminated via an enterohepatic cycle involving the liver and gallbladder. Dysfunction in these organs has been associated with slower MeHg elimination in laboratory animals. We hypothesized that women testing positive for chronic hepatitis B (HBV) or C (HCV), both associated with risk of longer-term liver and gallbladder impairment, would have higher total blood mercury (TBHg) concentrations than those negative for the viruses, reflecting slower MeHg elimination.MethodsGeometric mean (GM) TBHg levels from a representative sample of over 5,000 seafood-consuming, reproductive-age women from eight years (2001–2008) of the US NHANES survey were compared by viral hepatitis status (as determined by serological assay) using multiple linear regression. Adjustment was made for estimated MeHg intake from seafood consumption, social and demographic variables and other predictors.ResultsWomen with chronic HBV had 1.52 (95% CI 1.13, 2.05, p < 0.01) times the GM TBHg of women who had not come into contact with the virus. The positive association was strongest in those with most severe disease. A modest negative association was found with HCV markers.ConclusionsWhile study design prevents inferences on causality, the finding that MeHg biomarkers differ by hepatitis status in this population suggests viral hepatitis may alter the pace of MeHg elimination. Offspring of HBV-infected seafood-consuming women may be at higher risk of MeHg-induced developmental delays than offspring of those uninfected. Possible reasons for the unanticipated negative association with HCV are explored.

An Overview of Literature Topics Related to Current Concepts, Methods, Tools, and Applications for Cumulative Risk Assessment (2007–2016)

Cumulative risk assessments (CRAs) address combined risks from exposures to multiple chemical and nonchemical stressors and may focus on vulnerable communities or populations. Significant contributions have been made to the development of concepts, methods, and applications for CRA over the past decade. Work in both human health and ecological cumulative risk has advanced in two different contexts. The first context is the effects of chemical mixtures that share common modes of action, or that cause common adverse outcomes. In this context two primary models are used for predicting mixture effects, dose addition or response addition. The second context is evaluating the combined effects of chemical and nonchemical (e.g., radiation, biological, nutritional, economic, psychological, habitat alteration, land-use change, global climate change, and natural disasters) stressors. CRA can be adapted to address risk in many contexts, and this adaptability is reflected in the range in disciplinary perspectives in the published literature. This article presents the results of a literature search and discusses a range of selected work with the intention to give a broad overview of relevant topics and provide a starting point for researchers interested in CRA applications.

Linear Low-Dose Extrapolation for Non-Cancer Responses: Burke et al. Respond.

In his letter, Rhomberg raises several issues concerning recommendations in our report of the workshop “Issues and Approaches to Low Dose–Response Extrapolation for Environmental Health Risk Assessment” (White et al. 2009). One recommendation of the workshop was to set aside the generally held presumption that dose–response functions should follow a threshold model when extrapolating from higher dose studies of non-carcinogenic responses to lower dose levels typical for environmental exposures to chemicals. Workshop participants generally concluded that the selection of population-level low-dose extrapolation models should be informed by population factors such as inter individual variability in susceptibility and coexposures, as well as by categorization of mechanisms of toxicity. As indicated in the meeting report (White et al. 2009), most workshop participants preferred a linear, no-threshold approach to low-dose extrapolation modeling, combined with modeled estimates of the low range of observed data, for noncancer, as well as cancer, outcomes in the absence of convincing evidence to indicate that an alternative model is more appropriate. We recognize that this recommendation represents a departure from current generally accepted practice. On a nonsubstantive point, Rhomberg’s comment that we did not include additional information regarding “fuller discussions” at the workshop on this and other issues reflects the constraints imposed by EHP’s article length limits and changes made to accommodate reviewer comments encouraging emphasis on workshop findings and recommendations rather than on workshop discussions. We disagree with Rhomberg’s assertion that the finding of a linear, no-threshold exposure–response relationship in many epidemiologic studies of the effect of environmental pollutants, such as particulate matter and ozone air pollution, can be attributed entirely to a small range of exposures and measurement error. Although these factors need to be considered in evaluating epidemiologic study results, modeling techniques such as non parametric smoothing methods have demonstrated the capacity to identify potential threshold relationships even in the context of relatively extreme measurement error (Cakmak et al. 1999; Schwartz and Zanobetti 2000). As we noted in our meeting report (White et al. 2009), for the limited number of chemicals and agents for which robust low-dose response data exists (e.g., epidemiologic studies of large populations with exposures to particulate matter and ozone air pollution extending from relatively high to low ambient levels), thresholds have not been observed for non cancer or cancer outcomes [U.S. Environmental Protection Agency (EPA) 2006a, 2006b]. Additionally, for some of the exposures considered, the mechanisms of action thought to underlie the observed effects have been characterized by some as threshold mechanisms (e.g., the disruption of the homeostatic conditions for reactive oxygen species). In such cases, interindividual variability, background disease processes, and coexposures may explain the observed linearity. Although we acknowledge that there are differences in the intrinsic biological processes involved in generating cancer and non cancer outcomes, we disagree with Rhomberg’s assertion that heterogeneity in intrinsic population susceptibility and additivity to background disease processes result in simply “broadening” the dose–response relationship (which we presume means making the dose–response curve shallower). The underlying concept that additivity to background disease processes and variability in population susceptibility results in a linearization of the dose–response function for populations exposed to environmentally relevant levels was originally discussed in the context of cancer outcomes [Crump et al. 1976; Lutz 1990; National Research Council (NRC) 2005], and the suggestion that this same concept applies to noncancer outcomes is not novel (Clewell and Crump 2005; Crawford and Wilson 1996). Similarly, the importance of considering interindividual variability in assessing uncertainty associated with chemical risk assessments of noncancer effects has been recognized (Hattis and Silver 1994). The significance of these factors in the selection of dose–response models for use in environmental health risk assessment was also highlighted in a recent NRC report (NRC 2008). Regarding the assumption of additivity to background disease on low-dose extrapolation, in our meeting report (White et al. 2009) we noted the importance of assessing, to the extent possible, whether the mode or mechanism of action of the key events involved are consistent. However, current knowledge of these detailed biologic processes is still quite limited for most chemicals and pollutants, and as noted by Hoel (1997) [L]ow-dose linearity is speculative and it is a reasonable assumption for public health purposes in those instances where there is no scientific evidence to the contrary. We recognize that uncertainty increases as the dose–response extrapolation extends farther below observed data. The findings regarding exposure–response relationships from large-scale epidemiologic studies of environmental pollutants suggest that when considering population-level dose–response factors, interindividual variability, additivity to background disease processes, coexposures, and mechanisms of action, warrant careful consideration. As a consequence, we continue to recommend that the approach proposed in our meeting report (White et al. 2009) is appropriate and necessary.