Community-level exposomics: a population-centered approach to address public health concerns.

Environmental factors affecting health and vulnerability far outweigh genetics in accounting for disparities in health status and longevity in US communities. The concept of the exposome, the totality of exposure from conception onwards, provides a paradigm for researchers to investigate the complex role of the environment on the health of individuals. We propose a complementary framework, community-level exposomics, for population-level exposome assessment. The goal is to bring the exposome paradigm to research and practice on the health of populations, defined by various axes including geographic, social, and occupational. This framework includes the integration of community-level measures of the built, natural and social environments, environmental pollution-derived from conventional and community science approaches, internal markers of exposure that can be measured at the population-level and early responses associated with health status that can be tracked using population-based monitoring. Primary challenges to the implementation of the proposed framework include needed advancements in population-level measurement, lack of existing models with the capability to produce interpretable and actionable evidence and the ethical considerations of labeling geographically-bound populations by exposomic profiles. To address these challenges, we propose a set of recommendations that begin with greater engagement with and empowerment of affected communities and targeted investment in community-based solutions. Applications to urban settings and disaster epidemiology are discussed as examples for implementation.

Integrating Environment and Aging Research: Opportunities for Synergy and Acceleration.

Despite significant overlaps in mission, the fields of environmental health sciences and aging biology are just beginning to intersect. It is increasingly clear that genetics alone does not predict an individual's neurological aging and sensitivity to disease. Accordingly, aging neuroscience is a growing area of mutual interest within environmental health sciences. The impetus for this review came from a workshop hosted by the National Academies of Sciences, Engineering, and Medicine in June of 2020, which focused on integrating the science of aging and environmental health research. It is critical to bridge disciplines with multidisciplinary collaborations across toxicology, comparative biology, epidemiology to understand the impacts of environmental toxicant exposures and age-related outcomes. This scoping review aims to highlight overlaps and gaps in existing knowledge and identify essential research initiatives. It begins with an overview of aging biology and biomarkers, followed by examples of synergy with environmental health sciences. New areas for synergistic research and policy development are also discussed. Technological advances including next-generation sequencing and other-omics tools now offer new opportunities, including exposomic research, to integrate aging biomarkers into environmental health assessments and bridge disciplinary gaps. This is necessary to advance a more complete mechanistic understanding of how life-time exposures to toxicants and other physical and social stressors alter biological aging. New cumulative risk frameworks in environmental health sciences acknowledge that exposures and other external stressors can accumulate across the life course and the advancement of new biomarkers of exposure and response grounded in aging biology can support increased understanding of population vulnerability. Identifying the role of environmental stressors, broadly defined, on aging biology and neuroscience can similarly advance opportunities for intervention and translational research. Several areas of growing research interest include expanding exposomics and use of multi-omics, the microbiome as a mediator of environmental stressors, toxicant mixtures and neurobiology, and the role of structural and historical marginalization and racism in shaping persistent disparities in population aging and outcomes. Integrated foundational and translational aging biology research in environmental health sciences is needed to improve policy, reduce disparities, and enhance the quality of life for older individuals.

Adopting a "Compound" Exposome Approach in Environmental Aging Biomarker Research: A Call to Action for Advancing Racial Health Equity.

BACKGROUND: In June 2020, the National Academies of Sciences, Engineering, and Medicine hosted a virtual workshop focused on integrating the science of aging and environmental health research. The concurrent COVID-19 pandemic and national attention on racism exposed shortcomings in the environmental research field's conceptualization and methodological use of race, which have subsequently hindered the ability of research to address racial health disparities. By the workshop's conclusion, the authors deduced that the utility of environmental aging biomarkers-aging biomarkers shown to be specifically influenced by environmental exposures-would be greatly diminished if these biomarkers are developed absent of considerations of broader societal factors-like structural racism-that impinge on racial health equity. OBJECTIVES: The authors reached a post-workshop consensus recommendation: To advance racial health equity, a "compound" exposome approach should be widely adopted in environmental aging biomarker research. We present this recommendation here. DISCUSSION: The authors believe that without explicit considerations of racial health equity, people in most need of the benefits afforded by a better understanding of the relationships between exposures and aging will be the least likely to receive them because biomarkers may not encompass cumulative impacts from their unique social and environmental stressors. Employing an exposome approach that allows for more comprehensive exposure-disease pathway characterization across broad domains, including the social exposome and neighborhood factors, is the first step. Exposome-centered study designs must then be supported with efforts aimed at increasing the recruitment and retention of racially diverse study populations and researchers and further "compounded" with strategies directed at improving the use and interpretation of race throughout the publication and dissemination process. This compound exposome approach maximizes the ability of our science to identify environmental aging biomarkers that explicate racial disparities in health and best positions the environmental research community to contribute to the elimination of racial health disparities. https://doi.org/10.1289/EHP8392.

Toluene inhalation exposure for 13 weeks causes persistent changes in electroretinograms of Long-Evans rats.

Studies of humans chronically exposed to volatile organic solvents have reported impaired visual functions, including low contrast sensitivity and reduced color discrimination. These reports, however, lacked confirmation from controlled laboratory experiments. To address this question experimentally, we examined visual function by recording visual evoked potentials (VEP) and/or electroretinograms (ERG) from four sets of rats exposed repeatedly to toluene. In addition, eyes of the rats were examined with an ophthalmoscope and some of the retinal tissues were evaluated for rod and M-cone photoreceptor immunohistochemistry. The first study examined rats following exposure to 0, 10, 100 or 1000ppm toluene by inhalation (6hr/d, 5d/wk) for 13 weeks. One week after the termination of exposure, the rats were implanted with chronically indwelling electrodes and the following week pattern-elicited VEPs were recorded. VEP amplitudes were not significantly changed by toluene exposure. Four to five weeks after completion of exposure, rats were dark-adapted overnight, anesthetized, and several sets of electroretinograms (ERG) were recorded. In dark-adapted ERGs recorded over a 5-log (cd-s/m(2)) range of flash luminance, b-wave amplitudes were significantly reduced at high stimulus luminance values in rats previously exposed to 1000ppm toluene. A second set of rats, exposed concurrently with the first set, was tested approximately one year after the termination of 13 weeks of exposure to toluene. Again, dark-adapted ERG b-wave amplitudes were reduced at high stimulus luminance values in rats previously exposed to 1000ppm toluene. A third set of rats was exposed to the same concentrations of toluene for only 4 weeks, and a fourth set of rats exposed to 0 or 1000ppm toluene for 4 weeks were tested approximately 1year after the completion of exposure. No statistically significant reductions of ERG b-wave amplitude were observed in either set of rats exposed for 4 weeks. No significant changes were observed in ERG a-wave amplitude or latency, b-wave latency, UV- or green-flicker ERGs, or in photopic flash ERGs. There were no changes in the density of rod or M-cone photoreceptors. The ERG b-wave reflects the firing patterns of on-bipolar cells. The reductions of b-wave amplitude after 13 weeks of exposure and persisting for 1year suggest that alterations may have occurred in the inner nuclear layer of the retina, where the bipolar cells reside, or the outer or inner plexiform layers where the bipolar cells make synaptic connections. These data provide experimental evidence that repeated exposure to toluene may lead to subtle persistent changes in visual function. The fact that toluene affected ERGs, but not VEPs, suggests that elements in the rat retina may be more sensitive to organic solvent exposure than the rat visual cortex.

GPS-based microenvironment tracker (MicroTrac) model to estimate time-location of individuals for air pollution exposure assessments: model evaluation in central North Carolina.

A critical aspect of air pollution exposure assessment is the estimation of the time spent by individuals in various microenvironments (ME). Accounting for the time spent in different ME with different pollutant concentrations can reduce exposure misclassifications, while failure to do so can add uncertainty and bias to risk estimates. In this study, a classification model, called MicroTrac, was developed to estimate time of day and duration spent in eight ME (indoors and outdoors at home, work, school; inside vehicles; other locations) from global positioning system (GPS) data and geocoded building boundaries. Based on a panel study, MicroTrac estimates were compared with 24-h diary data from nine participants, with corresponding GPS data and building boundaries of home, school, and work. MicroTrac correctly classified the ME for 99.5% of the daily time spent by the participants. The capability of MicroTrac could help to reduce the time-location uncertainty in air pollution exposure models and exposure metrics for individuals in health studies.

Analysis of NHANES measured blood PCBs in the general US population and application of SHEDS model to identify key exposure factors.

Studies have shown that the US population continues to be exposed to polychlorinated biphenyls (PCBs), despite their ban more than three decades ago, but the reasons are not fully understood. The objectives of this paper are to characterize patterns of PCBs in blood by age, gender, and ethnicity, and identify major exposure factors. EPA's Stochastic Human Exposure and Dose Simulation (SHEDS)-dietary exposure model was applied, combining fish tissue PCB levels from a NYC Asian Market survey with National Health and Nutrition Examination Survey (NHANES) dietary consumption data, and then linked with blood biomarkers for the same NHANES study subjects. Results reveal that the mean concentration of total PCBs in blood was higher with increasing age; however, for the same age, gender, and ethnicity, the blood PCB concentrations measured in the later NHANES survey were significantly lower than those in the earlier one. The decrease within an age group between the two survey periods lessened with increasing age. Blood PCBs among different ethnicities ranked differently between the older and the younger age groups within each survey. Non-Hispanic Blacks had significantly higher blood PCBs for the >30 year age group. For the 12 to ≤30 year age group, the "Asian, Pacific Islander, Native American or multiracial" group had the highest values, with patterns fairly consistent with fish consumption and modeled PCB exposure patterns. We conclude that for younger people, patterns correspond to reduced environmental contamination over time, and are strongly associated with fish consumption and dietary exposures. Higher PCB concentrations in blood of the older population may partially reflect past exposures to higher environmental PCB concentrations, particularly before the ban.

Methyl mercury exposure from fish consumption in vulnerable racial/ethnic populations: probabilistic SHEDS-Dietary model analyses using 1999-2006 NHANES and 1990-2002 TDS data.

NHANES subjects self-identified as "Asian, Pacific Islander, Native American, or multiracial" (A/P/N/M) have higher levels of blood organic mercury than other racial/ethnic groups; however, the reasons for this have been unclear. This research uses exposure modeling to determine the reasons for elevated blood methylmercury (MeHg) levels, and also extends previous analyses of observed NHANES blood levels. The probabilistic SHEDS-Dietary model was applied, using MeHg fish residue data from FDA's Total Diet Study (1990-2002) combined with NHANES/WWEIA (1999-2006) fish consumption data, to generate exposure estimates by race/ethnicity, age group, and fish type. Statistical analyses of blood methylmercury levels in the (6 times larger) 1999-2006 NHANES data were compared against previous published results for 1999-2002 data. The A/P/N/M group has higher fish intake, modeled MeHg exposures, and blood levels than the general population and other racial/ethnic groups. Tuna, other saltwater fish, and other freshwater fish are key food types driving dietary MeHg exposure. The 1-<3 years-old A/P/N/M group has the highest mean dietary MeHg intake per body weight (0.06 µg/kg/day; ~2.3 times higher than the rest of the population). Fish intake and modeled exposure predictions correlate well with NHANES blood biomarker levels. This study, using the SHEDS-Dietary model with national data, reinforces and expands upon previous observations that dietary exposure via fish consumption is an important route for methylmercury intake by the general population, and especially for racial/ethnic groups with higher fish consumption. These probabilistic dietary modeling approaches could be applied for local populations (e.g., tribes) and other chemicals and foods, if data are available.

The Environmental Protection Agency's Community-Focused Exposure and Risk Screening Tool (C-FERST) and its potential use for environmental justice efforts.

OBJECTIVES: Our primary objective was to provide higher quality, more accessible science to address challenges of characterizing local-scale exposures and risks for enhanced community-based assessments and environmental decision-making. METHODS: After identifying community needs, priority environmental issues, and current tools, we designed and populated the Community-Focused Exposure and Risk Screening Tool (C-FERST) in collaboration with stakeholders, following a set of defined principles, and considered it in the context of environmental justice. RESULTS: C-FERST is a geographic information system and resource access Web tool under development for supporting multimedia community assessments. Community-level exposure and risk research is being conducted to address specific local issues through case studies. CONCLUSIONS: C-FERST can be applied to support environmental justice efforts. It incorporates research to develop community-level data and modeled estimates for priority environmental issues, and other relevant information identified by communities. Initial case studies are under way to refine and test the tool to expand its applicability and transferability. Opportunities exist for scientists to address the many research needs in characterizing local cumulative exposures and risks and for community partners to apply and refine C-FERST.

Long-term perchloroethylene exposure: a meta-analysis of neurobehavioral deficits in occupationally and residentially exposed groups.

The literature concerning the neurobehavioral and neurophysiological effects of long-term exposure to perchloroethylene (PERC) in humans was meta-analyzed to provide a quantitative review and synthesis in the form of dose-effect curves. The useable database from this literature comprised studies reporting effects of long-term exposure to PERC, effects that included slowed reaction times, cognitive deficits, impaired color vision, and reduced visual contrast sensitivity. For the meta-analyses, dose was defined as the product of the concentration inhaled PERC and the duration of exposure, expressed in unites of ppm-h/1000 (for numerical convenience). Dose-related results were highly variable across studies. Reports involving low exposure concentrations characteristic of nonoccupational exposures consistently produced effects of a magnitude that were comparable to those reported for higher concentration occupational studies. If this finding is reliable and general, studies of occupationally exposed persons may underestimate the magnitude of effects of PERC and other chemicals in the total population. Given the limited scope of the available data for PERC and its methodological and reporting problems (small sample sizes, testers were not blind to the subjects' exposure conditions, and the timing and location of testing were insufficiently documented), it seems important to test this conclusion with a well-documented study of two groups (occupational and nonoccupational exposure) in which subjects are evaluated in randomized order, using the same procedures and with the testers kept blind to the status of the subjects.

Integrating epidemiology and toxicology in neurotoxicity risk assessment.

Neurotoxicity risk assessments depend on the best available scientific information, including data from animal toxicity studies, human experimental studies and human epidemiology studies. There are several factors to consider when evaluating the comparability of data from studies. Regarding the epidemiology literature, issues include choice of study design, use of appropriate controls, methods of exposure assessment, subjective or objective evaluation of neurological status, and assessment and statistical control of potential confounding factors, including co-exposure to other agents. Animal experiments must be evaluated regarding factors such as dose level and duration, procedures used to assess neurological or behavioural status, and appropriateness of inference from the animal model to human neurotoxicity. Major factors that may explain apparent differences between animal and human studies include: animal neurological status may be evaluated with different procedures than those used in humans; animal studies may involve shorter exposure durations and higher dose levels; and most animal studies evaluate a single substance whereas humans typically are exposed to multiple agents. The comparability of measured outcomes in animals and humans may be improved by considering functional domains rather than individual test measures. The application of predictive models, weight of evidence considerations and meta-analysis can help evaluate the consistency of outcomes across studies. An appropriate blend of scientific information from toxicology and epidemiology studies is necessary to evaluate potential human risks of exposure to neurotoxic substances.

Electroretinographic features of the retinopathy, globe enlarged (rge) chick phenotype.

PURPOSE: The purpose of the study was to characterize the electroretinographic features of the autosomal recessive retinopathy, globe enlarged (rge) phenotype, in chickens (Gallus gallus). METHODS: Dark-adapted, light-adapted intensity series and light-adapted 30 Hz flicker responses were recorded from rge and age matched normal control chicks from one to 270 days of age. Retinal sections from rge and control retinas were examined in 7 and 270-day-old chicks. RESULTS: Electroretinogram (ERG) thresholds of rge birds were raised, the intensity response plots were shifted toward brighter intensities, and retinal sensitivity was reduced. The leading slope of the dark- and light-adapted a-waves was more shallow than normal, suggesting altered photoreceptor responses. The inner retinal components to the ERG were also abnormal; there was a marked lack of oscillatory potentials and an abnormally smooth and broad shape to the b-wave. Additionally, the b-wave was supernormal in response to brighter stimuli in the earlier stages of the disease. There was a progressive deterioration in ERG amplitudes with age that mirrored a slowly progressive thinning of the photoreceptor layer. CONCLUSIONS: The rge chicken has unusual ERG changes from an early age with altered waveforms and initially they develop a supernormal b-wave. This is followed by a progressive reduction of ERG amplitudes with age. The changes suggest that both photoreceptor and inner retinal responses are abnormal. Additional studies are needed to further elucidate the origin of the abnormal ERG components in the rge chick.

Induction of asthma and the environment: what we know and need to know.

The prevalence of asthma has increased dramatically over the last 25 years in the United States and in other nations as a result of ill-defined changes in living conditions in modern society. On 18 and 19 October 2004 the U.S. Environmental Protection Agency and the National Institute of Environmental Health Sciences sponsored the workshop "Environmental Influences on the Induction and Incidence of Asthma" to review current scientific evidence with respect to factors that may contribute to the induction of asthma. Participants addressed two broad questions: a) What does the science suggest that regulatory and public health agencies could do now to reduce the incidence of asthma? and b) What research is needed to improve our understanding of the factors that contribute to the induction of asthma and our ability to manage this problem? In this article (one of four articles resulting from the workshop), we briefly characterize asthma and its public health and economic impacts, and intervention strategies that have been successfully used to prevent induction of asthma in the workplace. We conclude with the findings of seven working groups that focus on ambient air, indoor pollutants (biologics), occupational exposures, early life stages, older adults, intrinsic susceptibility, and lifestyle. These groups found strong scientific support for public health efforts to limit in utero and postnatal exposure to cigarette smoke. However, with respect to other potential types of interventions, participants noted many scientific questions, which are summarized in this article. Research to address these questions could have a significant public health and economic impact that would be well worth the investment.

Repeated spike exposure to the insecticide chlorpyrifos interferes with the recovery of visual sensitivity in rats.

Reports from Japan and India and data submissions to the US EPA indicate that exposure to cholinesterase (ChE)-inhibiting organophosphorous insecticides (OP) can produce ocular toxicity, in particular long-lasting changes in retinal physiology and anatomy. We have examined the effects of a 1 year dietary exposure to the OP chlorpyrifos (CPF) on retinal structure and function. Adult male Long-Evans rats were fed CPF in their diet at the rate of 0, 1 (low), or 5 (high) mg/kg body weight/day. In addition, half of each feeding group received an oral (spike) dose of CPF in corn oil (45 mg/kg) or corn oil (VEH) alone every 2 months, resulting in six exposure groups: Control-VEH, Control-CPF, Low-VEH, Low-CPF, High-VEH, and High-CPF. Dark-adapted electroretinograms (ERG) were measured 3-5 months (n= 15-18/group) after the completion of dosing. There were no significant differences between dose or spike groups in a-wave, b-wave, or oscillatory potential amplitudes or implicit times. In addition, the time course of dark adaptation were measured in a subset of these rats (6-8/group) eight months after the completion of dosing by determining the flash intensity needed to elicit a 40 microV b-wave at selected intervals after bleaching 90% of the photopigment. Rats receiving the episodic oral spike of CPF showed a slowed recovery of dark-adapted sensitivity compared to rats receiving the corn oil VEH across chronic dosing conditions. No effects were seen on retinal morphology. This result suggests that episodic high dose exposures to CPF may result in altered retinal function. This effect, akin to effects seen in aging humans and humans exposed to other ChE-inhibiting compounds, may reflect alterations in the photoreceptors and retinal pigment epithelium (RPE) complex necessary for regenerating photopigment.

Epilepsy and medication effects on the pattern visual evoked potential.

Visual disruption in patients diagnosed with epilepsy may be attributable to either the disease itself or to the anti-epileptic drugs prescribed to control the seizures. Effects on visual function may be due to perturbations of the GABAergic neurotransmitter system, since deficits in GABAergic cortical interneurons have been hypothesized to underlie some forms of epilepsy, some anti-epileptic medications increase cortical GABA levels, and GABAergic neural circuitry plays an important role in mediating the responses of cells in the visual cortex and retina. This paper characterizes the effects of epilepsy and epilepsy medications on the visual evoked response to patterned stimuli. Steady-state visual evoked potentials (VEP) evoked by onset-offset modulation of high-contrast sine-wave stimuli were measured in 24 control and 54 epileptic patients. Comparisons of VEP spectral amplitude as a function of spatial frequency were made between controls, complex partial, and generalized epilepsy groups. The effects of the GABA-active medication valproate were compared to those of carbamezepine. The amplitude of the fundamental (F1) component of the VEP was found to be sensitive to epilepsy type. Test subjects with generalized epilepsy had F1 spatial frequency-amplitude functions with peaks shifted to lower spatial frequencies relative to controls and test subjects with complex partial epilepsy. This shift may be due to reduced intracortical inhibition in the subjects with generalized epilepsy. The second harmonic component (F2) response was sensitive to medication effects. Complex partial epilepsy patients on VPA therapies showed reduced F2 response amplitude across spatial frequencies, consistent with previous findings that showed the F2 response is sensitive to GABA-ergic effects on transient components of the VEP.

Aging and the environment: a research framework.

The rapid growth in the number of older Americans has many implications for public health, including the need to better understand the risks posed to older adults by environmental exposures. Biologic capacity declines with normal aging; this may be exacerbated in individuals with pre-existing health conditions. This decline can result in compromised pharmacokinetic and pharmacodynamic responses to environmental exposures encountered in daily activities. In recognition of this issue, the U.S. Environmental Protection Agency (EPA) is developing a research agenda on the environment and older adults. The U.S. EPA proposes to apply an environmental public health paradigm to better understand the relationships between external pollution sources --> human exposures --> internal dose --> early biologic effect --> adverse health effects for older adults. The initial challenge will be using information about aging-related changes in exposure, pharmacokinetic, and pharmacodynamic factors to identify susceptible subgroups within the diverse population of older adults. These changes may interact with specific diseases of aging or medications used to treat these conditions. Constructs such as "frailty" may help to capture some of the diversity in the older adult population. Data are needed regarding a) behavior/activity patterns and exposure to the pollutants in the microenvironments of older adults; b) changes in absorption, distribution, metabolism, and excretion with aging; c) alterations in reserve capacity that alter the body's ability to compensate for the effects of environmental exposures; and d) strategies for effective communication of risk and risk reduction methods to older individuals and communities. This article summarizes the U.S. EPA's development of a framework to address and prioritize the exposure, health effects, and risk communications concerns for the U.S. EPA's evolving research program on older adults as a susceptible subpopulation.