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Assessing Health Risks from Multiple Environmental Stressors: Moving from G × E to I × E
Abstract
Research on disease causation often attempts to isolate the effects of individual factors, including individual genes or environmental factors. This reductionist approach has generated many discoveries, but misses important interactive and cumulative effects that may help explain the broad range of variability in disease occurrence observed across studies and individuals. A disease rarely results from a single factor, and instead results from a broader combination of factors, characterized here as intrinsic (I) and extrinsic (E) factors. Intrinsic vulnerability or resilience emanates from a variety of both fixed and shifting biological factors including genetic traits, while extrinsic factors comprise all biologically-relevant external stressors encountered across the lifespan. The I × E concept incorporates the multi-factorial and dynamic nature of health and disease and provides a unified, conceptual basis for integrating results from multiple areas of research, including genomics, G × E, developmental origins of health and disease, and the exposome. We describe the utility of the I × E concept to better understand and characterize the cumulative impact of multiple extrinsic and intrinsic factors on individual and population health. New research methods increasingly facilitate the measurement of multifactorial and interactive effects in epidemiological and toxicological studies. Tiered or indicator-based approaches can guide the selection of potentially relevant I and E factors for study and quantification, and exposomics methods may eventually produce results that can be used to generate a response function over the life course. Quantitative data on I × E interactive effects should generate a better understanding of the variability in human response to environmental factors. The proposed I × E concept highlights the role for broader study design in order to identify extrinsic and intrinsic factors amenable to interventions at the individual and population levels in order to enhance resilience, reduce vulnerability and improve health.
... 48 Variability in life exposures can pinpoint complex etiology of complex diseases To date gene-by-environmental (GxE) interaction models have generally focused on interacting individual genetic with singular environmental exposures-yielding what has appeared to be small to modest interactions. 49 There has been a movement in genomics research to study all intrinsicby-extrinsic factor interactions (IxE) instead of individual GxE interactions. Often environmental factors arise in conjunction with other factors. ...
... Recent immigrants should be a high priority for studies of exposomics, such as the varied IxE interactions described above. 49 The changing nature of extrinsic factors with the migration process present both opportunities for natural experiments and studies of mismatches between in utero, early, and later-life environments. For example, we have described what could be called IxE interaction in a recent study of polygenic score interactions on obesity in the HCHS/SOL study. ...
Immigrants are an important part of many high-income nations, in that they contribute to the sociocultural tapestry, economic well-being, and demographic diversity of their receiving countries and communities. Yet, genomic studies to date have generally focused on non-immigrant, European-ancestry populations. Although this approach has proven fruitful in discovering and validating genomic loci, within the context of racially/ethnically diverse countries like the United States-wherein half of immigrants hail from Latin America and another quarter from Asia-this approach is insufficient. There is a persistent diversity gap in genomic research in terms of both current samples and genome-wide association studies, meaning that the field's understanding of genetic architecture and gene-environmental interactions is being hampered. In this commentary, I provide motivating examples of recent research developments related to the following: (1) how the increased ancestral diversity, such as seen among Latin American immigrants, improves power to discover and document genomic loci, (2) informs how environmental factors, such as immigration-related exposures, interact with genotypes to influence phenotypes, and (3) how inclusion can be promoted through community-engaged research programs and policies. I conclude that greater inclusion of immigrants in genomic research can move the field forward toward novel discoveries and interventions to address racial/ethnic health disparities.
... Understanding those who are in the highest exposed group and/or who are most affected can help target interventions and policies that protect those most at-risk and subsequently the whole population. While many intrinsic and extrinsic factors, including age/life stage of development, genetics, underlying physiological function, and socioeconomic status (SES), can either separately or together enhance individual susceptibility and affect population variability in response to chemical exposures [1][2][3][4], current doseresponse assessment methods often do not adequately account for these factors [5,6]. For example, current methods often do not account for in utero susceptibility to chemical exposures, despite ample scientific literature demonstrating increased susceptibility among developing fetuses and the potential for fetal origins of disease [7][8][9][10][11]. ...
... Updated methods should make use of the best available science, but these methods should never be employed to weaken risk estimate or exposure limits. Similar recommendations have been made in the past for combining multiple data streams into a holistic framework that allows for the examination of intrinsic and extrinsic factors in combination [3,4,140] and that provides risk assessors with a tool chest of options for addressing variability in chemical risk assessment that is more protective of susceptible subgroups [93,100]. ...
A key element of risk assessment is accounting for the full range of variability in response to environmental exposures. Default dose-response methods typically assume a 10-fold difference in response to chemical exposures between average (healthy) and susceptible humans, despite evidence of wider variability. Experts and authoritative bodies support using advanced techniques to better account for human variability due to factors such as in utero or early life exposure and exposure to multiple environmental, social, and economic stressors.
This review describes: 1) sources of human variability and susceptibility in dose-response assessment, 2) existing US frameworks for addressing response variability in risk assessment; 3) key scientific inadequacies necessitating updated methods; 4) improved approaches and opportunities for better use of science; and 5) specific and quantitative recommendations to address evidence and policy needs.
Current default adjustment factors do not sufficiently capture human variability in dose-response and thus are inadequate to protect the entire population. Susceptible groups are not appropriately protected under current regulatory guidelines. Emerging tools and data sources that better account for human variability and susceptibility include probabilistic methods, genetically diverse in vivo and in vitro models, and the use of human data to capture underlying risk and/or assess combined effects from chemical and non-chemical stressors.
We recommend using updated methods and data to improve consideration of human variability and susceptibility in risk assessment, including the use of increased default human variability factors and separate adjustment factors for capturing age/life stage of development and exposure to multiple chemical and non-chemical stressors. Updated methods would result in greater transparency and protection for susceptible groups, including children, infants, people who are pregnant or nursing, people with disabilities, and those burdened by additional environmental exposures and/or social factors such as poverty and racism.
... Biomonitoring programs, such as the National Health and Nutrition Examination Survey (NHANES) in the United States and the Consortium to Perform Human Biomonitoring on a European Scale (COPHES), have increased awareness on the extent of exposure to diverse chemicals (Bocato et al. 2019). It follows that a single exposure approach to environmental health research is inadequate, and traditional research strategies (e.g., genome-wide association and Gene × Environment studies) have limited ability to assess complex exposures and their interactions with intrinsic factors to influence biology and health outcomes (McHale et al. 2018). Correspondingly, experts across multiple disciplines have acknowledged the need for research and regulatory frameworks that move beyond single chemicals and address the effects of combined exposures (encompassing both combinations of chemicals and chemical and nonchemical stressors) and complex mixtures [i.e., mixtures of unknown or variable composition, complex reaction products, or biological materials (UVCBs)] on disease (Carlin et al. 2013;Drakvik et al. 2020). ...
... For example, proliferative lesions (e.g., hyperplasia, polyp) mark an important step in the continuum from healthy tissue to metastatic tumor in some cancer types (Cardiff et al. 2006). Although the transgenic model approach described here is focused on simultaneous chemical exposures, the study design could easily be adapted to assess more complex mixture scenarios, such as sequential exposures, exposure during critical developmental windows, and addition of nonchemical stressors (e.g., physiological stress, chronic infection, obesity) (McHale et al. 2018). For example, obesity increases the risk of arsenicassociated lung and bladder cancer in humans by several-fold compared with risks for nonobese individuals (Steinmaus et al. 2015). ...
Background: People are exposed to numerous chemicals throughout their lifetimes. Many of these chemicals display one or more of the key characteristics of carcinogens or interact with processes described in the hallmarks of cancer. Therefore, evaluating the effects of chemical mixtures on cancer development is an important pursuit. Challenges involved in designing research studies to evaluate the joint action of chemicals on cancer risk include the time taken to perform the experiments because of the long latency and choosing an appropriate experimental design.
Objectives: The objectives of this work are to present the case for developing a research program on mixtures of environmental chemicals and cancer risk and describe recommended approaches.
Methods: A working group comprising the co-authors focused attention on the design of mixtures studies to inform cancer risk assessment as part of a larger effort to refine the key characteristics of carcinogens and explore their application. Working group members reviewed the key characteristics of carcinogens, hallmarks of cancer, and mixtures research for other disease endpoints. The group discussed options for developing tractable projects to evaluate the joint effects of environmental chemicals on cancer development.
Results and Discussion: Three approaches for developing a research program to evaluate the effects of mixtures on cancer development were proposed: a chemical screening approach, a transgenic model-based approach, and a disease-centered approach. Advantages and disadvantages of each were discussed.
... Known as the Developmental Origins of Health and Disease (DOHaD), this field has expanded from nutritional stressors to those imposed by toxicant exposures (13,25,26). While programming events occurring during development are likely essential for adapting to the external milieu, this process of "adaptation" may be corrupted when developmental programs and the external milieu are mismatched, creating a disease-promoting interaction between intrinsic and extrinsic risk factors (27). Indeed, exposure to several MDCs across developmental windows in early life (e.g., in utero and early postnatal [reviewed in ref. ...
... Finally, avoidance of diets that amplify the deleterious effects of MDCs in favor of those that antagonize their effects is essential, while standard clinical advice to exercise and lose weight are equally necessary components for addressing the threat of environmental toxicants to metabolic health. As we gain a greater appreciation for how the diverse array of intrinsic and extrinsic risk factors that promote metabolic disease development interact with each other (27,169), new interventions are likely to emerge. ...
Metabolic disease rates have increased dramatically over the last four decades. Classic understanding of metabolic physiology has attributed these global trends to decreased physical activity and caloric excess; however, these traditional risk factors insufficiently explain the magnitude and rapidity of metabolic health deterioration. Recently, the novel contribution of environmental metabolism-disrupting chemicals (MDCs) to various metabolic diseases (including obesity, diabetes, and non-alcoholic fatty liver disease) is becoming recognized. As this burgeoning body of evidence has matured, various organic and inorganic pollutants of human and natural origin have emerged as metabolic disease risk factors based on population-level and experimental data. Recognition of these heretofore underappreciated metabolic stressors now mandates that efforts to mitigate the devastating consequences of metabolic disease include dedicated efforts to address environmental drivers of disease risk; however, there have not been adequate recommendations to reduce exposures or to mitigate the effects of exposures on disease outcomes. To address this knowledge gap and advance the clinical translation of MDC science, herein discussed are behaviors that increase exposures to MDCs, interventional studies to reduce those exposures, and small-scale clinical trials to reduce the body burden of MDCs. Also, we discuss evidence from cell-based and animal studies that provide insights into MDC mechanisms of action, the influence of modifiable dietary factors on MDC toxicity, and factors that modulate MDC transplacental carriage as well as their impact on metabolic homeostasis. A particular emphasis of this discussion is on critical developmental windows during which short-term MDC exposure can elicit long-term disruptions in metabolic health with potential inter- and transgenerational effects. While data gaps remain and further studies are needed, the current state of evidence regarding interventions to address MDC exposures illuminates approaches to address environmental drivers of metabolic disease risk. It is now incumbent on clinicians and public health agencies to incorporate this knowledge into comprehensive strategies to address the metabolic disease pandemic.
... Use case 3: multiple chemicals-1 disease: surveying how different exposures converge on the same molecular mechanisms Various environmental factors have been associated with male infertility (Rodprasert et al., 2023;Szab o et al., 2023), consistent with the idea that diseases can be the result of multifactorial components, both genetic and environmental, often from an assortment of stressors over a lifetime. Understanding the interplay between multiple low-dose chemical exposures and an array of genetic factors is necessary to formulate testable, realistic models for environmental health (McHale et al., 2018;Virolainen et al., 2023). To survey how different types of chemical exposures could converge to potentially influence male infertility, we utilized CTD Tetramers to independently generate 342 tetramers (62 chemicals and 12 genes) and 757 tetramers (78 chemicals and 14 genes), respectively, connecting the phenotypes of "spermatogenesis" and "apoptotic process" (and descendants) to the disease outcome of male infertility (Figure 7). ...
The molecular mechanisms connecting environmental exposures to adverse endpoints are often unknown, reflecting knowledge gaps. At the Comparative Toxicogenomics Database (CTD), we developed a bioinformatics approach that integrates manually curated, literature-based interactions from CTD to generate a "CGPD-tetramer": a four-unit block of information organized as a step-wise molecular mechanism linking an initiating Chemical, an interacting Gene, a Phenotype, and a Disease outcome. Here, we describe a novel, user-friendly tool called CTD Tetramers that generates these evidence-based CGPD-tetramers for any curated chemical, gene, phenotype, or disease of interest. Tetramers offer potential solutions for the unknown underlying mechanisms and intermediary phenotypes connecting a chemical exposure to a disease. Additionally, multiple tetramers can be assembled to construct detailed modes-of-action for chemical-induced disease pathways. As well, tetramers can help inform environmental influences on adverse outcome pathways (AOPs). We demonstrate the tool's utility with relevant use cases for a variety of environmental chemicals (e.g., perfluoroalkyl substances, bisphenol A), phenotypes (e.g., apoptosis, spermatogenesis, inflammatory response), and diseases (e.g., asthma, obesity, male infertility). Finally, we map AOP adverse outcome terms to corresponding CTD terms, allowing users to query for tetramers that can help augment AOP pathways with additional stressors, genes, and phenotypes, as well as formulate potential AOP disease networks (e.g., liver cirrhosis and prostate cancer). This novel tool, as part of the complete suite of tools offered at CTD, provides users with computational data sets and their supporting evidence to potentially fill exposure knowledge gaps and develop testable hypotheses about environmental health.
... However, inheritance studies clearly demonstrate that genetics alone can explain only a portion of brain or behavioral dysfunction (the heritability of depression, for example, is ∼ 37%; Sullivan et al. 2000), leaving the rest to nongenetic influences. If the environment includes all nongenetic components, it is necessary to consider toxicant exposures, activity, diet, physical surroundings, and social forces (McHale et al. 2018). The exposome provides an example of a holistic characterization of the environment and provides a scientific framework to uncover the wide breadth of nongenetic contributors to mental health as well as the biological consequences of exposures (Burkett and Miller 2021;Vermeulen et al. 2020). ...
Background:
To date, health-effects research on environmental stressors has rarely focused on behavioral and mental health outcomes. That lack of research is beginning to change. Science and policy experts in the environmental and behavioral health sciences are coming together to explore converging evidence on the relationship-harmful or beneficial-between environmental factors and mental health.
Objectives:
To organize evidence and catalyze new findings, the National Academy of Sciences, Engineering, and Medicine (NASEM) hosted a workshop 2-3 February 2021 on the interplay of environmental exposures and mental health outcomes.
Methods:
This commentary provides a nonsystematic, expert-guided conceptual review and interdisciplinary perspective on the convergence of environmental and mental health, drawing from hypotheses, findings, and research gaps presented and discussed at the workshop. Featured is an overview of what is known about the intersection of the environment and mental health, focusing on the effects of neurotoxic pollutants, threats related to climate change, and the importance of health promoting environments, such as urban green spaces.
Discussion:
We describe what can be gained by bridging environmental and psychological research disciplines and present a synthesis of what is needed to advance interdisciplinary investigations. We also consider the implications of the current evidence for a) foundational knowledge of the etiology of mental health and illness, b) toxicant policy and regulation, c) definitions of climate adaptation and community resilience, d) interventions targeting marginalized communities, and e) the future of research training and funding. We include a call to action for environmental and mental health researchers, focusing on the environmental contributions to mental health to unlock primary prevention strategies at the population level and open equitable paths for preventing mental disorders and achieving optimal mental health for all. https://doi.org/10.1289/EHP9889.
... Following a number of conceptual and methodological advances during the last decades, toxicology has considerably evolved. A large number of studies have highlighted the relevance of low-dose effects, nonmonotonous dose response curves (Vandenberg et al., 2012), vulnerable developmental stages for the assessment of the link between exposure and effects (Barouki et al., 2012;Grandjean et al., 2015), and the importance of the interplay between intrinsic (genetic, epigenetics, etc.) and extrinsic factors (nutritional, toxic, social, etc.) (McHale et al., 2018). There has been enhanced focus on long-term effects and programming leading to strong connections between toxicology and epigenetics Chung and Herceg, 2020). ...
The development of the exposome concept has been one of the hallmarks of environmental and health research for the last decade. The exposome encompasses the life course environmental exposures including lifestyle factors, from the prenatal period onwards. It has inspired many research programs and is expected to influence environmental and health research, practices, and policies. Yet, the links bridging toxicology and the exposome concept have not been well developed. In this review, we describe how the exposome framework can interface with and influence the field of toxicology, as well as how the field of toxicology can help advance the exposome field by providing the needed mechanistic understanding of the exposome impacts on health. Indeed, exposome-informed toxicology is expected to emphasize several orientations including 1) developing approaches integrating multiple stressors, in particular chemical mixtures, as well as the interaction of chemicals with other stressors, 2) using mechanistic frameworks such as the adverse outcome pathways to link the different stressors with toxicity outcomes, 3) characterizing the mechanistic basis of long-term effects by distinguishing different patterns of exposures and further exploring the environment-DNA interface through genetic and epigenetic studies, and 4) improving the links between environmental and human health, in particular through a stronger connection between alterations in our ecosystems and human toxicology. The exposome concept provides the linkage between the complex environment and contemporary mechanistic toxicology. What toxicology can bring to exposome characterization is a needed framework for mechanistic understanding and regulatory outcomes in risk assessment.
... As such, the 'metabolism disrupting chemical (MDC) hypothesis' was proposed, which postulates that environmental chemicals can promote metabolic changes that lead to metabolic disorders, and may play an important role in the global epidemic of metabolic diseases (Heindel et al., 2017). However, current epidemiological research predominantly focuses on targeted chemicals and metals, resulting in the lack of detailed characterization of the E in the G × E (genome-environment) paradigm, compared with the resolution of genome-wide association studies (Rappaport et al., 2014;McHale et al., 2018). It is therefore imperative to further explore the health impacts of environmental exposure under the exposome concept. ...
Humans are exposed to an ever-increasing number of environmental toxicants, some of which have gradually been elucidated to be important risk factors for metabolic diseases, such as diabetes and obesity. These metabolism-sensitive diseases typically occur when key metabolic and signaling pathways were disrupted, which can be influenced by the exposure to contaminants such as endocrine disrupting chemicals (EDCs), along with genetic and lifestyle factors. This promotes the concept and research on environmental metabolism disrupting chemicals (MDCs). In addition, identifying endogenous biochemical markers of effect linked to disease states is becoming an important tool to screen the biological targets following environmental contaminant exposure, as well as to provide an overview of toxicity risk assessment. As such, the current review aims to contribute to the further understanding of exposome and human health and disease by characterizing environmental exposure and effect metabolic biomarkers. We summarized MDC-associated metabolic biomarkers in laboratory animal and human cohort studies using high throughput targeted and nontargeted metabolomics techniques. Contaminants including heavy metals and organohalogen compounds, especially EDCs, have been repetitively associated with metabolic disorders, whereas emerging contaminants such as perfluoroalkyl substances and microplastics have also been found to disrupt metabolism. In addition, we found major limitations in the effective identification of metabolic biomarkers especially in human studies, toxicological research on the mixed effect of environmental exposure has also been insufficient compared to the research on single chemicals. Thus, it is timely to call for research efforts dedicated to the study of combined effect and metabolic alterations for the better assessment of exposomic toxicology and health risks. Moreover, advanced computational and prediction tools, further validation of metabolic biomarkers, as well as systematic and integrative investigations are also needed in order to reliably identify novel biomarkers and elucidate toxicity mechanisms, and to further utilize exposome and metabolome profiling in public health and safety management.
... Additional consideration is warranted for individuals taking more than one such medication simultaneously for management of multiple conditions, which may result in increased exposure to these carcinogenic contaminants across different medications. Additionally, individuals may be more or less susceptible to development of cancer as disease results from a combination of fixed and variable intrinsic factors (e.g., sex, epigenome, nutritional status) and potentially modifiable extrinsic factors (e.g., occupational exposures, racism and other psychosocial stressors, physical activity, diet) that comprise all biologically relevant external stressors [31]. The fact that some of these affected medications are first-line treatments for conditions that disproportionately impact populations with health disparities who may be more susceptible, should be of public health concern. ...
Many nitrosamines are potent carcinogens, with more than 30 listed under California’s Proposition 65. Recently, nitrosamine contamination of commonly used drugs for treatment of hypertension, heartburn, and type 2 diabetes has prompted numerous Food and Drug Administration (FDA) recalls in the US. These contaminants include the carcinogens NDMA (N-nitrosodimethylamine) and NDEA (N-nitrosodiethylamine) and the animal tumorigen NMBA (N-nitroso-N-methyl-4-aminobutyric acid). NMBA and NDEA are metabolically and/or structurally related to NDMA, an N-nitrosomethyl-n-alkylamine (NMA), and 12 other carcinogenic NMAs. These nitrosamines exhibit common genotoxic and tumorigenic activities, with shared target tumor sites amongst chemicals and within a given laboratory animal species. We use the drug valsartan as a case study to estimate the additional cancer risks associated with NDMA and NDEA contamination, based on nitrosamine levels reported by the US FDA, cancer potencies developed by California’s Proposition 65 program and the US Environmental Protection Agency (EPA), and specific exposure scenarios. These estimates suggest that nitrosamine contamination in drugs that are used long-term can increase cancer risks and pose a serious concern to public health.
... Pioneers in the field addressing how to assess multiple stressors developed techniques for disentangling joint effects into attribution of the partial contributions by each stressor (Cox, 1984(Cox, , 1985. Over time, US EPA has developed guidelines on cumulative risk assessment (US EPA, 2003, 2008, and scholars have developed updated analytic frameworks for cumulative risk assessment of exposure to multiple stressors (e.g., Fox, Brewer, & Martin, 2017;Gallagher et al., 2015;Kappes et al., 2012;McHale et al., 2018;Morreto et al., 2017;Sexton & Hattis, 2007) and associated strategies for risk management (Knudsen, 2017). ...
Risk assessment, perception, and management tend to focus on one risk at a time. But we live in a multirisk world. This essay in honor of the 40th anniversary of the Society for Risk Analysis (SRA) and the journal Risk Analysis suggests that we can-and have already begun to-strengthen risk analysis and policy outcomes by moving from a focus on the single to the multiple-multiple stressors, multiple impacts, and multiple decisions. This evolution can improve our abilities to assess actual risks, to confront and weigh risk-risk trade-offs and innovate risk-superior moves, and to build learning into adaptive regulation that adjusts over time. Recognizing the multirisk reality can help us understand complex systems, foresee unintended consequences, design better policy solutions, and learn to improve.
... 7 It is even harder to quantify vulnerability across populations due to factors such as age, coexposures, comorbidities, nutrition, genetics, and other stressors. 8 The result is that risk assessments are often debated for years, 6 paralyzing regulatory action on toxic chemicals. More fundamentally, a risk-based framework includes the assumption that reducing the risk below a specified threshold, rather than eliminating the risk by removing the hazard, is the final goal. ...
In 2008, California enacted laws to restructure chemical policy and promote green chemistry. Ten years after the passage of California’s green chemistry laws, we assessed their performance through structured interviews with a sample of experts from government, academia, business, and the nonprofit sector. We combined the interviews with a scoping literature review to propose a new ten-point framework for evaluating the effectiveness of a chemical regulatory policy, and we assessed the performance of the California law against this framework. The California program performed well on transparency of the regulatory process; protecting vulnerable populations; placing the primary burden on the manufacturer; breadth of regulatory authority; and advancing the public right-to-know. Areas of weakness include unclear authority to require data on chemical use in products; an inefficient pace of implementation; and limited incentives for innovation. Promoting safer chemicals in products will require additional incentives to protect public health and the environment.
... Connections between environmental toxin exposure and several human diseases have stimulated increased investigation into the toxicity of environmental contaminants using different model organisms 32,33 . Despite the evolutionary distance between yeast and humans, the underlying molecular players of numerous important pathways including programmed cell death, cell cycle progression and gene expression are conserved between the two species, allowing for the study of neurotoxins using highly-developed omics approaches in yeast 34 . ...
Manganese (Mn) is an essential element, but in humans, chronic and/or acute exposure to this metal can lead to neurotoxicity and neurodegenerative disorders including Parkinsonism and Parkinson’s Disease by unclear mechanisms. To better understand the effects that exposure to Mn2+ exert on eukaryotic cell biology, we exposed a non-essential deletion library of the yeast Saccharomyces cerevisiae to a sub-inhibitory concentration of Mn2+ followed by targeted functional analyses of the positive hits. This screen produced a set of 43 sensitive deletion mutants that were enriched for genes associated with protein biosynthesis. Our follow-up investigations demonstrated that Mn reduced total rRNA levels in a dose-dependent manner and decreased expression of a β-galactosidase reporter gene. This was subsequently supported by analysis of ribosome profiles that suggested Mn-induced toxicity was associated with a reduction in formation of active ribosomes on the mRNAs. Altogether, these findings contribute to the current understanding of the mechanism of Mn-triggered cytotoxicity. Lastly, using the Comparative Toxicogenomic Database, we revealed that Mn shared certain similarities in toxicological mechanisms with neurodegenerative disorders including amyotrophic lateral sclerosis, Alzheimer’s, Parkinson’s and Huntington’s diseases.
... We prioritized highest cumulative exposure based on evidence of glyphosate's persistence in the environment [47][48][49] and because chronic disease, including cancer, is usually the result of cumulative exposures [50]. We selected the longest lag or latency because decades may be needed for the health effects of many environmental toxicants to manifest as detectable cancers. ...
Glyphosate is the most widely used broad-spectrum systemic herbicide in the world. Recent evaluations of the carcinogenic potential of glyphosate-based herbicides (GBHs) by various regional, national, and international agencies have engendered controversy. We investigated whether there was an association between high cumulative exposures to GBHs and increased risk of non-Hodgkin lymphoma (NHL) in humans. We conducted a new meta-analysis that includes the most recent update of the Agricultural Health Study (AHS) cohort published in 2018 along with five case-control studies. Using the highest exposure groups when available in each study, we report the overall meta-relative risk (meta-RR) of NHL in GBH-exposed individuals was increased by 41% (meta-RR = 1.41, 95% confidence interval, CI: 1.13-1.75). For comparison, we also performed a secondary meta-analysis using high-exposure groups with the earlier AHS (2005), and we calculated a meta-RR for NHL of 1.45 (95% CI: 1.11-1.91), which was higher than the meta-RRs reported previously. Multiple sensitivity tests conducted to assess the validity of our findings did not reveal meaningful differences from our primary estimated meta-RR. To contextualize our findings of an increased NHL risk in individuals with high GBH exposure, we reviewed publicly available animal and mechanistic studies related to lymphoma. We documented further support from studies of malignant lymphoma incidence in mice treated with pure glyphosate, as well as potential links between glyphosate / GBH exposure and immunosuppression, endocrine disruption, and genetic alterations that are commonly associated with NHL or lymphomagenesis. Overall, in accordance with findings from experimental animal and mechanistic studies, our current meta-analysis of human epidemiological studies suggests a compelling link between exposures to GBHs and increased risk for NHL.
... enduring vulnerability (McHale et al., 2018). Sources of vulnerability can also amplify each other. ...
California’s Fourth Climate Change Assessment (Fourth Assessment) advances actionable science that serves the
growing needs of state and local-level decision-makers from a variety of sectors. This cutting-edge research initiative
is comprised of a wide-ranging body of technical reports, including rigorous, comprehensive climate change
scenarios at a scale suitable for illuminating regional vulnerabilities and localized adaptation strategies in California;
datasets and tools that improve integration of observed and projected knowledge about climate change into decision-
making; and recommendations and information to directly inform vulnerability assessments and adaptation
strategies for California’s energy sector, water resources and management, oceans and coasts, forests, wildfires,
agriculture, biodiversity and habitat, and public health. In addition, these technical reports have been distilled into
summary reports and a brochure, allowing the public and decision-makers to easily access relevant findings from the
Fourth Assessment.
... Positive perception of environmental quality of the mentioned aspects strengthens the contribution of microclimate variables to outdoor thermal comfort or subjective assessment on thermal environment, i.e. high sensitivity to microclimate determinant was shown. This could be explained by the influence of environmental stressors (air pollution, noise, unsatisfying urban landscape, inconvenient commute) when a person has negative perception of the environmental quality (McHale et al. 2017;Li et al. 2018). Psychological effects associated with such negative perceptions of other environmental aspects would suppress the roles of co-existing microclimate attributors, whether on a positive scale (contributed by high wind speed) or negative (contributed by high temperature and radiation level). ...
Although outdoor thermal comfort has gained increasing research attention, meteorological conditions and thermal sensation in different urban settings in high-density cities have not been systematically studied from the perspective of urban planning and design. Considering the potential relationship between environmental quality and thermal sensation in outdoor spaces— an emerging topic in perceived comfort, this study offers a new approach for planning and design for climate resilience in cities. This paper presents the results of an outdoor thermal comfort survey conducted on hot summer days in Hong Kong. Diverse patterns of PET-comfort ratings relationships were found in different urban settings. The study revealed that air temperature, subjective assessments of solar radiation and wind environment were strong determinants of thermal sensation and evaluation. In our analysis, wind condition showed a significant indirect effect on comfort through subjective perception. Statistical modelling showed that subjective perceptions on microclimate condition and comfort are moderated by various aspects of environmental quality. The findings of this study help inform future design for climate resilience in outdoor urban spaces in hot-humid subtropical cities.
... The concept of cumulative impacts, the focus of this review, refers to potential adverse human health effects resulting from combined exposures to multiple environmental and social stressors [6][7][8]. 'Cumulative risk' aims to quantify to the extent possible 'combined risks from aggregate exposures to multiple [environmental] agents or stressors' [1]. Statistical methods used to characterize and model the combined and potential interactive effects of multiple environmental hazard and social stressor exposures are referred to as cumulative risk and impact modeling. ...
Purpose of review:
The goal of this review is to identify cumulative modeling methods used to evaluate combined effects of exposures to environmental chemicals and social stressors. The specific review question is: What are the existing quantitative methods used to examine the cumulative impacts of exposures to environmental chemical and social stressors on health?
Recent findings:
There has been an increase in literature that evaluates combined effects of exposures to environmental chemicals and social stressors on health using regression models; very few studies applied other data mining and machine learning techniques to this problem. The majority of studies we identified used regression models to evaluate combined effects of multiple environmental and social stressors. With proper study design and appropriate modeling assumptions, additional data mining methods may be useful to examine combined effects of environmental and social stressors.
With the growing awareness of stressors, cumulative risk assessment (CRA) has been proposed as a potential method to evaluate possible additive and synergistic effects of multiple stressors on human health, thus informing environmental regulation and protecting public health. However, CRA is still in its exploratory stage due to the lack of generally accepted quantitative approaches. It is an ideal time to summarize the existing progress to guide future research. To this end, a systematic review of the literature on CRA issues dealing with combinations of environmental and psychosocial stressors was conducted in this study. Using typology and bibliometric analysis, the body of knowledge, hot topics, and research gaps in this field were characterized. It was found that research topics and objectives mainly focus on qualitative analysis and community settings, more concentration should be paid to the development of quantitative approaches and the inclusion of occupational settings. Further, the roles of air pollution and vulnerability factors in CRA have attracted the most attention. This study ends with views on future prospects to promote the theoretical and practical development in this field, specifically, CRA is a multifaceted topic which requires substantial collaborations with various stakeholders and enormous knowledge from multidisciplinary fields. This study displays an overall state as well as the research directions worth investigating in this field, which provides a historical reference for future study.
Environmental health is a discipline that examines human health effects from harmful agents or health stressors in the environment, including in indoor or outdoor air, water, food, soil, dust, or manufactured products, as well as cumulative effects from multiple stressors, and broader issues such as climate change and health. This field is multi-disciplinary and includes elements of experimental and predictive toxicology; epidemiology; environmental and occupational medicine; food safety and sanitation; engineering, exposure science and industrial hygiene; public health; environmental policy and law; and psychology, sociology and communication.
Although outdoor thermal comfort has gained increasing research attention, meteorological conditions and thermal sensation in different urban settings in high-density cities have not been systematically studied from the perspective of urban planning and design. Considering the potential relationship between environmental quality and thermal sensation in outdoor spaces—an emerging topic in perceived comfort, this study offers a new approach for planning and design for climate resilience in cities. This chapter presents the results of an outdoor thermal comfort survey conducted on hot summer days in Hong Kong. Diverse patterns of PET-comfort ratings relationships were found in different urban settings. The study revealed that air temperature, subjective assessments of solar radiation, and wind environment were strong determinants of thermal sensation and evaluation. In our analysis, wind condition showed a significant indirect effect on comfort through subjective perception. Statistical modelling showed that subjective perceptions on microclimate condition and comfort are moderated by various aspects of environmental quality. The findings help inform future design for climate resilience in outdoor urban spaces in hot–humid subtropical cities.
The “nontargeted effects” of ionizing radiation, including bystander effects and genomic instability, predominate after low dose exposures and dominate response outcomes. These effects are unique in that no classic mutagenic event occurs in the cell showing the effect. In the case of bystander effects, cells which were not in the field affected by the radiation show high levels of mutations, chromosome aberrations, ROS, and membrane signaling changes (i.e., horizontal transmission of mutations and information which may be damaging). This can be contrasted with the case of genomic instability, where generations of cells derived from an irradiated progenitor appear normal, but then lethal and nonlethal mutations appear in distant progeny (i.e., vertical transmission). These phenomena are characterized by high yields of mutations and distant occurrences of events both in space and time. This precludes a mutator phenotype or other conventional explanation and appears to indicate a generalized form of ROS-mediated, stress-induced mutagenesis, which is well documented in bacteria. The nature of the signal traveling between irradiated and unirradiated cells and organisms is currently unknown, but recent evidence suggests that there may be a physical component such as a vibration wave involved. UV photon-mediated transmission has also been documented and the latter mechanisms can induce the release of exosomes, which by themselves can induce bystander effects when added to recipient cells. This review will discuss the phenomenology of nontargeted effects both in vitro and in vivo; it includes recent data suggesting that excitation decay-induced photons in the UVA range lead to exosome release, resulting in mitochondrial malfunction and elevated ROS in recipient cells. Photons, calcium, and neurochemicals are important factors in signal production, while the exosome cargo and cytokine mediated pathways, especially TGFb, are implicated in response to the signal. Important clues from the field of chemical ecology are reviewed to highlight the fact that signaling is very widespread in biota, and that many mechanisms and signals are extensively researched in the field. By highlighting some key challenges and controversies concerning the mechanisms and, more importantly, the reason these effects exist, we will discuss current ideas about the wider implications of nontargeted effects in evolution and environmental biology.
According to the WHO, Arab countries have the highest relative increase in Breast Cancer (BC) rates worldwide. Current shifts in dietary patterns in these countries are postulated as important modifiable risk factors of the disease. The objectives of this review were to examine the gaps and opportunities in the extent, range and nature of nutrition-related BC research in Arab countries. Studies (n = 286) were identified through searching 14 electronic databases. Among the gaps identified were limited international collaborations, preponderance of laboratory-based research at the expense of population-based research, focus on single supplement/nutrient/food research, limited use of dietary assessment tools, and studying nutrition in isolation of other environmental factors. Despite these gaps, several opportunities appeared. The distribution of papers among Arab countries suggested that collaboration between high and middle income countries could create a positive synergy between research expertise and wealth. In addition, the steady increase in the number of articles published during the last two decades reflected a promising momentum in nutrition and BC research in the Arab world. These gaps and opportunities constituted context-specific evidence to orient nutrition and BC research in Arab countries which could ultimately lead to development of effective interventions for prevention of BC in these countries.
Numerous papers have highlighted the need for Cumulative Risk Assessments (CRAs) that evaluate the impacts of multiple chemical and non-chemical stressors on human health [1, 2]. Non-chemical stressors represent a diverse suite of factors (e.g., social and economic adversity) that are only beginning to be explored in risk assessment [3]. Approaches incorporating both chemical and non-chemical stressors are critical for better understanding relative contributions of real-world stressors and developing effective intervention strategies. However, moving from traditional single chemical evaluations to cumulative risk assessments presents multiple challenges.
Humans are exposed to a milieu of environmental stressors of a chemical, physical, and social nature that may change over time. Interaction of these stressors with various intrinsic factors such as genetics, sex, life stage, and health status determines susceptibility to related diseases. Cumulative risk assessment seeks to determine the combined risks to health from exposures to multiple agents or stressors. This can be achieved by expanding beyond a G × E approach—where “G” represents genetic susceptibility and “E” (environment) represents a limited range of exposures—to an I × E approach—where “I” (intrinsic) represents the many inter-related biological factors that contribute to disease susceptibility and “E” (extrinsic) represents all nongenetic factors including the exposome. Exposomics is poised to advance this concept and make significant advances in environmental health science and our understanding of the causes of chronic diseases. The internal exposome can be assessed using targeted and untargeted exposomics tools to measure individual chemicals, groups of chemicals, or the totality of chemicals acting on a particular receptor or biological pathway in a functional assay. Comprehensive data on the internal, external, and public health components of the exposome together could inform risk assessment and ultimately guide risk management. These approaches could be applied in vulnerable populations such as migrants or those burdened with multiple types of stressor simultaneously as identified through map- or indicator-based approaches. Development and refinement of additional exposomics tools that can be applied in prospective human epidemiology studies should be a focus of future studies.
Background:
Evaluation of interindividual variability is a challenging step in risk assessment. For most environmental pollutants, including perchloroethylene (PERC), experimental data are lacking, resulting in default assumptions being used to account for variability in toxicokinetics and toxicodynamics.
Objective:
We quantitatively examined the relationship between PERC toxicokinetics and toxicodynamics at the population level to test whether individuals with increased oxidative metabolism are be more sensitive to hepatotoxicity following PERC exposure.
Methods:
Male mice from 45 strains of the Collaborative Cross (CC) were orally administered a single dose of PERC (1,000 mg/kg) or vehicle (Alkamuls-EL620) and euthanized at various time points (n = 1/strain/time). Concentration–time profiles were generated for PERC and its primary oxidative metabolite trichloroacetate (TCA) in multiple tissues. Toxicodynamic phenotyping was also performed.
Results:
Significant variability among strains was observed in toxicokinetics of PERC and TCA in every tissue examined. Based on area under the curve (AUC), the range of liver TCA levels spanned nearly an order of magnitude (~8-fold). Expression of liver cytochrome P4502E1 did not correlate with TCA levels. Toxicodynamic phenotyping revealed an effect of PERC on bodyweight loss, induction of peroxisome proliferator activated receptor-alpha (PPARα)-regulated genes, and dysregulation of hepatic lipid homeostasis. Clustering was observed among a) liver levels of PERC, TCA, and triglycerides; b) TCA levels in liver and kidney; and c) TCA levels in serum, brain, fat, and lung.
Conclusions:
Using the CC mouse population model, we have demonstrated a complex and highly variable relationship between PERC and TCA toxicokinetics and toxicodynamics at the population level. https://doi.org/10.1289/EHP788.
Concurrent exposure to a wide variety of xenobiotics and their combined toxic effects can play a pivotal role in health and disease, yet are largely unexplored. Investigating the totality of these exposures, i.e. the exposome, and their specific biological effects constitutes a new paradigm for environmental health but still lacks high-throughput, user-friendly technology. We demonstrate the utility of mass spectrometry-based global exposure metabolomics combined with tailored database queries and cognitive computing for comprehensive exposure assessment and the straightforward elucidation of biological effects. The METLIN Exposome database has been redesigned to help identify environmental toxicants, food contaminants and supplements, drugs, and antibiotics as well as their biotransformation products, through its expansion with over 700,000 chemical structures to now include more than 950,000 unique small molecules. More importantly, we demonstrate how the XCMS/METLIN platform now allows for the readout of the biological effect of a toxicant through metabolomic-derived pathway analysis and further, cognitive computing provides a means of assessing the role of a potential toxicant. The presented workflow addresses many of the methodological challenges current exposome research is facing and will serve to gain a deeper understanding of the impact of environmental exposures and combinatory toxic effects on human health.
Background:
The prevalence of obesity is increasing in all countries, becoming a substantial public health concern worldwide. Increasing evidence has associated obesity with persistent pollutants such as the pesticide DDT and its metabolite p,p′-DDE.
Objectives:
Our objective was to systematically review the literature on the association between exposure to the pesticide DDT and its metabolites and obesity to develop hazard identification conclusions.
Methods:
We applied a systematic review-based strategy to identify and integrate evidence from epidemiological, in vivo, and in vitro studies. The evidence from prospective epidemiological studies was quantitatively synthesized by meta-analysis. We rated the body of evidence and integrated the streams of evidence to systematically develop hazard identification conclusions.
Results:
We identified seven epidemiological studies reporting prospective associations between exposure to p,p′-DDE and adiposity assessed by body mass index (BMI) z-score. The results from the meta-analysis revealed positive associations between exposure to p,p′-DDE and BMI z-score (β=0.13 BMI z-score (95% CI: 0.01, 0.25) per log increase of p,p′-DDE). Two studies constituted the primary in vivo evidence. Both studies reported positive associations between exposure to p,p′-DDT and increased adiposity in rodents. We identified 19 in vivo studies and 7 in vitro studies that supported the biological plausibility of the obesogenic effects of p,p′-DDT and p,p′-DDE.
Conclusions:
We classified p,p′-DDT and p,p′-DDE as “presumed” to be obesogenic for humans, based on a moderate level of primary human evidence, a moderate level of primary in vivo evidence, and a moderate level of supporting evidence from in vivo and in vitro studies.
Background: Gene-diet interactions have been reported to contribute to the development of type 2 diabetes (T2D). However, to our knowledge, few examples have been consistently replicated to date.
Objective: We aimed to identify existing evidence for gene-macronutrient interactions and T2D and to examine the reported interactions in a large-scale study.
Design: We systematically reviewed studies reporting gene-macronutrient interactions and T2D. We searched the MEDLINE, Human Genome Epidemiology Network, and WHO International Clinical Trials Registry Platform electronic databases to identify studies published up to October 2015. Eligibility criteria included assessment of macronutrient quantity (e.g., total carbohydrate) or indicators of quality (e.g., dietary fiber) by use of self-report or objective biomarkers of intake. Interactions identified in the review were subsequently examined in the EPIC (European Prospective Investigation into Cancer)-InterAct case-cohort study (n = 21,148, with 9403 T2D cases; 8 European countries). Prentice-weighted Cox regression was used to estimate country-specific HRs, 95% CIs, and P-interaction values, which were then pooled by random-effects meta-analysis. A primary model was fitted by using the same covariates as reported in the published studies, and a second model adjusted for additional covariates and estimated the effects of isocaloric macronutrient substitution.
Results: Thirteen observational studies met the eligibility criteria (n < 1700 cases). Eight unique interactions were reported to be significant between macronutrients [carbohydrate, fat, saturated fat, dietary fiber, and glycemic load derived from self-report of dietary intake and circulating n–3 (ω-3) polyunsaturated fatty acids] and genetic variants in or near transcription factor 7–like 2 (TCF7L2), gastric inhibitory polypeptide receptor (GIPR), caveolin 2 (CAV2), and peptidase D (PEPD) (P-interaction < 0.05). We found no evidence of interaction when we tried to replicate previously reported interactions. In addition, no interactions were detected in models with additional covariates.
Conclusions: Eight gene-macronutrient interactions were identified for the risk of T2D from the literature. These interactions were not replicated in the EPIC-InterAct study, which mirrored the analyses undertaken in the original reports. Our findings highlight the importance of independent replication of reported interactions.
Background:
From 1999 through 2014, obesity prevalence increased among adults and youth. Obese individuals may be uniquely susceptible to the pro-inflammatory effects of ozone because obese humans and animals have been shown to experience a greater decline in lung function than normal weight subjects. Obesity is independently associated with limitations in lung mechanics with increased ozone dose. However, few epidemiologic studies have examined the interaction between excess weight and ozone exposure among adults.
Methods:
Using PubMed keyword searches and reference lists, we reviewed epidemiologic evidence to identify potential response-modifying factors and to determine if obese or overweight adults are at increased risk of ozone-related health effects.
Results:
We initially identified 170 studies, of which seven studies met the criteria of examining the interaction of excess weight and ozone exposure on cardiopulmonary outcomes in adults, including four short-term ozone exposure studies in controlled laboratory settings and three community epidemiologic studies. In the studies identified, obesity was associated with decreased lung function and increased inflammatory mediators. Results were inconclusive about the effect modification when data were stratified by sex.
Conclusions:
Obese and overweight populations should be considered as candidate at-risk groups for epidemiologic studies of cardiopulmonary health related to air pollution exposures. Air pollution is a modifiable risk factor that may decrease lung function among obese individuals with implications for environmental and occupational health policy.
The increasing prevalence of neurodevelopmental disorders, especially autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD), calls for more research into the identification of etiologic and risk factors. The Developmental Origin of Health and Disease (DOHaD) hypothesizes that the environment during fetal and childhood development affects the risk for many chronic diseases in later stages of life, including neurodevelopmental disorders. Epigenetics, a term describing mechanisms that cause changes in the chromosome state without affecting DNA sequences, is suggested to be the underlying mechanism, according to the DOHaD hypothesis. Moreover, many neurodevelopmental disorders are also related to epigenetic abnormalities. Experimental and epidemiological studies suggest that exposure to prenatal environmental toxicants is associated with neurodevelopmental disorders. In addition, there is also evidence that environmental toxicants can result in epigenetic alterations, notably DNA methylation. In this review, we first focus on the relationship between neurodevelopmental disorders and environmental toxicants, in particular maternal smoking, plastic-derived chemicals (bisphenol A and phthalates), persistent organic pollutants, and heavy metals. We then review studies showing the epigenetic effects of those environmental factors in humans that may affect normal neurodevelopment.
An aim of systems biology is to understand complex interactions between genes, proteins and metabolites by integrating and modeling multiple data sources. We report an ‘integrated-omics’ approach within XCMS Online
that automatically superimposes raw metabolomic data onto metabolic pathways and integrates it with
transcriptomic and proteomic data (http://XCMSOnline.scripps.edu/).
Mapping do
Systems biology guided by XCMS Online metabolomics. Available from: https://www.researchgate.net/publication/316529559_Systems_biology_guided_by_XCMS_Online_metabolomics [accessed May 2, 2017].
The exposome comprises all environmental exposures that a person experiences from conception throughout the life course. Here we review the state of the science for assessing external exposures within the exposome. This article reviews (a) categories of exposures that can be assessed externally, (b) the current state of the science in external exposure assessment, (c) current tools available for external exposure assessment, and (d) priority research needs. We describe major scientific and technological advances that inform external assessment of the exposome, including geographic information systems; remote sensing; global positioning system and geolocation technologies; portable and personal sensing, including smartphone-based sensors and assessments; and self-reported questionnaire assessments, which increasingly rely on Internet-based platforms. We also discuss priority research needs related to methodological and technological improvement, data analysis and interpretation, data sharing, and other practical considerations, including improved assessment of exposure variability as well as exposure in multiple, critical life stages.
In our era of digital biomedicine, data take many forms, from "omics" to imaging, mobile health (mHealth), and electronic health records (EHRs). With the availability of more efficient digital collection methods, scientists in many domains now find themselves confronting ever larger sets of data and trying to make sense of it all (1-4). Indeed, data which used to be considered large now seems small as the amount of data now being collected in a single day by an investigator can surpass what might have been generated over his/her career even a decade ago (e.g., (5)). This deluge of biomedical information requires new thinking about how data are generated, managed, and ultimately leveraged to further scientific understanding and for improving healthcare. Responding to this challenge, the National Institutes of Health (NIH) has spearheaded the "Big Data to Knowledge" (BD2K) program (6). Data scientists are being engaged through BD2K to guide biomedical researchers through the thickets of data they are producing. NIH Director, Francis Collins, has noted, "Indeed, we are at a point in history where Big Data should not intimidate, but inspire us. We are in the midst of a revolution that is transforming the way we do biomedical research?we just have to devise creative ways to sift through this mountain of data and make sense of it" (7). The NIH is now taking its first major steps toward realizing biomedical science as an interdisciplinary "big data" science.
Purpose of Review
Mixtures, or combinations and interactions between multiple environmental exposures, are hypothesized to be causally linked with disease and health-related phenotypes. Established and emerging molecular measurement technologies to assay the exposome, the comprehensive battery of exposures encountered from birth to death, promise a new way of identifying mixtures in disease in the epidemiological setting. In this opinion, we describe the analytic complexity and challenges in identifying mixtures associated with phenotype and disease.
Recent Findings
Existing and emerging machine-learning methods and data analytic approaches (e.g., “environment-wide association studies” [EWASs]), as well as large cohorts may enhance possibilities to identify mixtures of correlated exposures associated with phenotypes; however, the analytic complexity of identifying mixtures is immense.
Summary
If the exposome concept is realized, new analytical methods and large sample sizes will be required to ascertain how mixtures are associated with disease. The author recommends documenting prevalent correlated exposures and replicated main effects prior to identifying mixtures.
The National Health and Nutrition Examination Survey (NHANES) is a population survey implemented by the Centers for Disease Control and Prevention (CDC) to monitor the health of the United States whose data is publicly available in hundreds of files. This Data Descriptor describes a single unified and universally accessible data file, merging across 255 separate files and stitching data across 4 surveys, encompassing 41,474 individuals and 1,191 variables. The variables consist of phenotype and environmental exposure information on each individual, specifically (1) demographic information, physical exam results (e.g., height, body mass index), laboratory results (e.g., cholesterol, glucose, and environmental exposures), and (4) questionnaire items. Second, the data descriptor describes a dictionary to enable analysts find variables by category and human-readable description. The datasets are available on DataDryad and a hands-on analytics tutorial is available on GitHub. Through a new big data platform, BD2K Patient Centered Information Commons (http://pic-sure.org), we provide a new way to browse the dataset via a web browser (https://nhanes.hms.harvard.edu) and provide application programming interface for programmatic access.
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
The risk of acquiring a chronic disease is influenced by a person's genetics (G) and exposures received during life (the 'exposome', E) plus their interactions (G×E). Yet, investigators use genome-wide association studies (GWAS) to characterize G while relying on self-reported information to classify E. If E and G×E dominate disease risks, this imbalance obscures important causal factors. To estimate proportions of disease risk attributable to G (plus shared exposures), published data from Western European monozygotic (MZ) twins were used to estimate population attributable fractions (PAFs) for 28 chronic diseases. Genetic PAFs ranged from 3.4% for leukemia to 48.6% for asthma with a median value of 18.5%. Cancers had the lowest PAFs (median = 8.26%) while neurological (median = 26.1%) and lung (median = 33.6%) diseases had the highest PAFs. These PAFs were then linked with Western European mortality statistics to estimate deaths attributable to G for heart disease and nine cancer types. Of 1.53 million Western European deaths in 2000, 0.25 million (16.4%) could be attributed to genetics plus shared exposures. Given the modest influences of G-related factors on the risks of chronic diseases in MZ twins, the disparity in coverage of G and E in etiological research is problematic. To discover causes of disease, GWAS should be complemented with exposome-wide association studies (EWAS) that profile chemicals in biospecimens from incident disease cases and matched controls.
Background:
The Next Generation (NexGen) of Risk Assessment effort is a multiyear collaboration among several organizations evaluating new, potentially more efficient molecular, computational and systems biology approaches to risk assessment. This paper summarizes our findings, suggests applications to risk assessment, and identifies strategic research directions.
Objective:
Our specific objectives were to test whether advanced biological data and methods could better inform our understanding of public health risks posed by environmental exposures.
Methods:
New data and methods were applied and evaluated for use in hazard identification and dose-response assessment. Biomarkers of exposure and effect, and risk characterization were also examined. Consideration was given to various decision contexts with increasing regulatory and public health impacts. Data types included transcriptomics, genomics, and proteomics; methods included molecular epidemiology and clinical studies, bioinformatic knowledge mining, pathway and network analyses, short-duration in vivo and in vitro bioassays, and quantitative structure activity relationship modeling.
Discussion:
NexGen has advanced our ability to apply new science by more rapidly identifying chemicals and exposures of potential concern, helping characterize mechanisms of action that influence conclusions about causality, exposure-response relationships, susceptibility and cumulative risk, and by elucidating new biomarkers of exposure and effects. Additionally, NexGen has fostered extensive discussion among risk scientists and managers and improved confidence in interpreting and applying new data streams.
Conclusions:
While considerable uncertainties remain, thoughtful application of new knowledge to risk assessment appears reasonable for augmenting major scope assessments, forming the basis for or augmenting limited scope assessments, and for prioritization and screening of very data limited chemicals.
Prostate cancer (PCa) is a multifactorial disease involving complex genetic and environmental factors interactions. Gene-gene and gene-environment interactions associated with PCa in Chinese men are less studied. We explored the association between 36 SNPs and PCa in 574 subjects from northern China. Body mass index (BMI), smoking, and alcohol consumption were determined through self-administered questionnaires in 134 PCa patients. Then gene-gene and gene-environment interactions among the PCa-associated SNPs were analyzed using the generalized multifactor dimensionality reduction (GMDR) and logistic regression methods. Allelic and genotypic association analyses showed that six variants were associated with PCa and the cumulative effect suggested men who carried any combination of 1, 2, or ≥3 risk genotypes had a gradually increased PCa risk (odds ratios (ORs) = 1.79-4.41). GMDR analysis identified the best gene-gene interaction model with scores of 10 for both the cross-validation consistency and sign tests. For gene-environment interactions, rs6983561 CC and rs16901966 GG in individuals with a BMI ≥ 28 had ORs of 7.66 (p = 0.032) and 5.33 (p = 0.046), respectively. rs7679673 CC + CA and rs12653946 TT in individuals that smoked had ORs of 2.77 (p = 0.007) and 3.11 (p = 0.024), respectively. rs7679673 CC in individuals that consumed alcohol had an OR of 4.37 (p = 0.041). These results suggest that polymorphisms, either individually or by interacting with other genes or environmental factors, contribute to an increased risk of PCa.
Background:
Exposure to secondhand smoke (SHS) may increase risk for obesity, but few studies have investigated the joint effects of exposure to SHS and diet.
Objectives:
We examined the interaction of exposure to SHS and diet on the prevalence of obesity among 6-19 year olds who participated in the 2007-2010 National Health and Nutrition Examination Survey.
Methods:
We characterized exposure using a novel biomarker (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol [NNAL]), an established biomarker (cotinine), and self-report. Multinomial logistic regression models examined the association of SHS exposure on the prevalence of overweight and obesity as separate outcomes (compared with normal/underweight). Interaction by diet was assessed by introducing interaction terms (with SHS) of the individual nutrients (dietary fiber, eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA], vitamin C, and vitamin E) into separate models.
Results:
Approximately half of the children had NNAL and cotinine levels above the limit of detection, indicating exposure to SHS. Interaction results suggest that the prevalence of obesity among children with both high exposure to SHS and low levels of certain nutrients (dietary fiber, DHA, or EPA) is greater than would be expected due to the effects of the individual exposures alone. Little or no evidence suggesting more or less than additive or multiplicative interaction was observed for vitamin C or vitamin E. The association between SHS and obesity did not appear to be modified by dietary vitamin C or vitamin E.
Conclusions:
Childhood obesity prevention strategies aimed at reducing SHS exposures and improving diets may exceed the expected benefits based on targeting either risk factor alone.
The exposome is a complement to the genome that includes non-genetic causes of disease. Multiple definitions are available, with salient points being global inclusion of exposures and behaviors, and cumulative integration of associated biologic responses. As such, the concept is both refreshingly simple and dauntingly complex. This article reviews high-resolution metabolomics (HRM) as an affordable approach to routinely analyze samples for a broad spectrum of environmental chemicals and biologic responses. HRM has been successfully used in multiple exposome research paradigms and is suitable to implement in a prototype universal exposure surveillance system. Development of such a structure for systematic monitoring of environmental exposures is an important step toward sequencing the exposome because it builds upon successes of exposure science, naturally connects external exposure to body burden and partitions the exposome into workable components. Practical results would be repositories of quantitative data on chemicals according to geography and biology. This would support new opportunities for environmental health analysis and predictive modeling. Complementary approaches to hasten development of exposome theory and associated biologic response networks could include experimental studies with model systems, analysis of archival samples from longitudinal studies with outcome data and study of relatively short-lived animals, such as household pets (dogs and cats) and non-human primates (common marmoset). International investment and cooperation to sequence the human exposome will advance scientific knowledge and also provide an important foundation to control adverse environmental exposures to sustain healthy living spaces and improve prediction and management of disease.
Background:
A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the more than 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens.
Objectives and methods:
IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens.
Discussion:
These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The ten characteristics are the abilities of an agent to: (1) act as an electrophile either directly or after metabolic activation; (2) be genotoxic; (3) alter DNA repair or cause genomic instability; (4) induce epigenetic alterations; (5) induce oxidative stress; (6) induce chronic inflammation; (7) be immunosuppressive; (8) modulate receptor-mediated effects; (9) cause immortalization; and (10) alter cell proliferation, cell death, or nutrient supply.
Conclusion:
We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant endpoints and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA's IRIS Program and the U.S. National Toxicology Program.
Understanding the human condition is a Big Data problem. This statement is nicely illustrated by the articles that follow from seven of the Centers for Data Excellence that have been funded by the National Institutes of Health (NIH) Big Data to Knowledge (BD2K) initiative. BD2K is a trans-NIH program, funded by all Institutes and Centers at NIH as well as the NIH Common Fund; it is overseen by the NIH Office of Data Science within the NIH Office of the Director.
The beginnings of BD2K have been described previously,1 and the purpose here is to provide an overall context, from …
Exposures during the early life (periconceptional, prenatal and early postnatal) period are increasingly recognized as playing an important role in the aetiology of chronic non-communicable diseases (NCD), including coronary heart disease, stroke, hypertension, Type 2 diabetes and osteoporosis. The 'Developmental Origins of Health and Disease' (DOHaD) hypothesis states that these disorders originate through unbalanced nutrition early in life and risk is highest when there is a 'mismatch' between the early- and later-life environments. Thus, the DOHaD hypothesis would predict highest risk in countries where an excess of infants are born with low birth weight and where there is a rapid transition to nutritional adequacy or excess in adulthood. Here, I will review data from work conducted in rural Gambia, West Africa. Using demographic data dating back to the 1940s, the follow-up of randomized controlled trials of nutritional supplementation in pregnancy and the 'experiment of nature' that seasonality in this region provides, we have investigated the DOHaD hypothesis in a population with high rates of maternal and infant under-nutrition, a high burden from infectious disease, and an emerging risk of NCDs.
Background:
Studies suggested that variants in the ABCB1 gene encoding P-glycoprotein, a xenobiotic transporter, may increase susceptibility to pesticide exposures linked to Parkinson's Disease (PD) risk.
Objectives:
To investigate the joint impact of two ABCB1 polymorphisms and pesticide exposures on PD risk.
Methods:
In a population-based case control study, we genotyped ABCB1 gene variants at rs1045642 (c.3435C/T) and rs2032582 (c.2677G/T/A) and assessed occupational exposures to organochlorine (OC) and organophosphorus (OP) pesticides based on self-reported occupational use and record-based ambient workplace exposures for 282 PD cases and 514 controls of European ancestry. We identified active ingredients in self-reported occupational use pesticides from a California database and estimated ambient workplace exposures between 1974 and 1999 employing a geographic information system together with records for state pesticide and land use. With unconditional logistic regression, we estimated marginal and joint contributions for occupational pesticide exposures and ABCB1 variants in PD.
Results:
For occupationally exposed carriers of homozygous ABCB1 variant genotypes, we estimated odds ratios of 1.89 [95% confidence interval (CI): (0.87, 4.07)] to 3.71 [95% CI: (1.96, 7.02)], with the highest odds ratios estimated for occupationally exposed carriers of homozygous ABCB1 variant genotypes at both SNPs; but we found no multiplicative scale interactions.
Conclusions:
This study lends support to a previous report that commonly used pesticides, specifically OCs and OPs, and variant ABCB1 genotypes at two polymorphic sites jointly increase risk of PD.
Many communities are located near multiple sources of pollution, including current and former industrial sites, major roadways, and agricultural operations. Populations in such locations are predominantly low-income, with a large percentage of minorities and non-English speakers. These communities face challenges that can affect the health of their residents, including limited access to health care, a shortage of grocery stores, poor housing quality, and a lack of parks and open spaces. Environmental exposures may interact with social stressors, thereby worsening health outcomes. Age, genetic characteristics, and preexisting health conditions increase the risk of adverse health effects from exposure to pollutants. There are existing approaches for characterizing cumulative exposures, cumulative risks, and cumulative health impacts. Although such approaches have merit, they also have significant constraints. New developments in exposure monitoring, mapping, toxicology, and epidemiology, especially when inf...
Evidence for a relationship between trihalomethane (THM) or haloacetic acid (HAA) exposure and adverse fetal growth is inconsistent. Disinfection by-products exist as complex mixtures in water supplies, but THMs and HAAs have typically been examined separately.
To investigate joint exposure at individual level to THMs and HAAs in relation to birth weight in the multi-ethnic Born in Bradford birth cohort.
Pregnant women reported their water consumption and activities via questionnaire. These data were combined with area-level THM and HAA concentrations to estimate integrated uptake of THMs into blood and HAA ingestion, accounting for boiling/filtering. We examined the relationship between THM and HAA exposures and birth weight of up to 7,438 singleton term babies using multiple linear regression, stratified by ethnicity.
Among Pakistani-origin infants, mean birth weight was significantly lower in association with the highest versus lowest tertiles of integrated THM uptake (e.g. -53.7g; 95% CI: -89.9, -17.5 for ≥1.82 vs. <1.05 µg/day of total THM) and there were significant trends (P<0.01) across increasing tertiles, but there were no associations among White British infants. Neither ingestion of HAAs alone or jointly with THMs was associated with birth weight. Estimated THM uptake via showering, bathing, and swimming was significantly associated with lower birth weight in Pakistani-origin infants, when adjusting for THM and HAA ingestion via water consumption.
To our knowledge, this is the largest DBP and fetal growth study to date with individual water use data, and the first to examine individual-level estimates of joint THM-HAA exposure. Our findings demonstrate associations between THM, but not HAA, exposure during pregnancy and reduced birth weight, but suggest this differs by ethnicity. This study suggests that THMs are not acting as a proxy for HAAs, or vice-versa.
The Mouse Phenome Database was originally conceived as a platform for the integration of phenotype data collected on a defined collection of 40 inbred mouse strains-the "phenome panel." This model provided an impetus for community data sharing, and integration was readily achieved through the reproducible genotypes of the phenome panel strains. Advances in the development of mouse populations lead to an expanded role of the Mouse Phenome Database to encompass new strain panels and inbred strain crosses. The recent introduction of the Collaborative Cross and Diversity Outbred mice, which share an extensive pool of genetic variation from eight founder inbred strains, presents new opportunities and challenges for community data resources. A wide variety of molecular and clinical phenotypes are being collected across genotypes, tissues, ages, environmental exposures, interventions, and treatments. The Mouse Phenome Database provides a framework for retrieval, integration, analysis, and display of these data, enabling them to be evaluated in the context of existing data from standard inbred strains. Primary data in the Mouse Phenome Database are supported by extensive metadata on protocols and procedures. These are centrally curated to ensure accuracy and reproducibility and to provide data in consistent formats. The Mouse Phenome Database represents an established and growing community data resource for mouse phenotype data and encourages submissions from new mouse resources, enabling investigators to integrate existing data into their studies of the phenotypic consequences of genetic variation.
The Developmental Origins of Health and Disease (DOHaD) paradigm is one of the most rapidly expanding areas of biomedical research. Environmental stressors that can impact on DOHaD encompass a variety of environmental and occupational hazards as well as deficiency and oversupply of nutrients and energy. They can disrupt early developmental processes and lead to increased susceptibility to disease/dysfunctions later in life. Presentations at the fourth Conference on Prenatal Programming and Toxicity in Boston, in October 2014, provided important insights and led to new recommendations for research and public health action. The conference highlighted vulnerable exposure windows that can occur as early as the preconception period and epigenetics as a major mechanism than can lead to disadvantageous "reprogramming" of the genome, thereby potentially resulting in transgenerational effects. Stem cells can also be targets of environmental stressors, thus paving another way for effects that may last a lifetime. Current testing paradigms do not allow proper characterization of risk factors and their interactions. Thus, relevant exposure levels and combinations for testing must be identified from human exposure situations and outcome assessments. Testing of potential underpinning mechanisms and biomarker development require laboratory animal models and in vitro approaches. Only few large-scale birth cohorts exist, and collaboration between birth cohorts on a global scale should be facilitated. DOHaD-based research has a crucial role in establishing factors leading to detrimental outcomes and developing early preventative/remediation strategies to combat these risks.
When chemical health hazards have been identified, probabilistic dose-response assessment ("hazard characterization") quantifies uncertainty and/or variability in toxicity as a function of human exposure. Existing probabilistic approaches differ for different types of endpoints or modes-of-action, lacking a unifying framework.
Developing a unified framework for probabilistic dose-response assessment.
We establish a framework based on four principles: (1) individual and population dose-response are distinct; (2) dose-response relationships for all (including quantal) endpoints can be recast as relating to an underlying continuous measure of response at the individual level; (3) for effects relevant to humans, "effect metrics" can be specified to define "toxicologically equivalent" sizes for this underlying individual response; and (4) dose-response assessment requires making adjustments and accounting for uncertainty and variability. We then derive a step-by-step probabilistic approach for dose-response assessment of animal toxicology data similar to how non-probabilistic reference doses are derived, illustrating the approach with example noncancer and cancer datasets.
Probabilistically-derived exposure limits are based on estimating a "target human dose" HDM(I), which requires risk management-informed choices for the magnitude (M) of individual effect being protected against, the remaining incidence (I) of individuals with effects ≥M in the population, and the percent confidence. In the example datasets, probabilistically-derived 90% confidence intervals span a 40-60-fold range for HDM(I)s where I=1% of the population experiences ≥M=1%-10% effect sizes.
While some implementation challenges remain, this unified probabilistic framework can provide substantially more complete and transparent characterization of chemical hazards and support better-informed risk management decisions.
The cysteine (Cys) proteome is a major component of the adaptive interface between the genome and the exposome. The thiol moiety of Cys undergoes a range of biologic modifications enabling biological switching of structure and reactivity. These biological modifications include sulfenylation and disulfide formation, formation of higher oxidation states, S-nitrosylation, persulfidation, metallation, and other modifications. Extensive knowledge about these systems and their compartmentalization now provides a foundation to develop advanced integrative models of Cys proteome regulation. In particular, detailed understanding of redox signaling pathways and sensing networks is becoming available to discriminate network structures. This research focuses attention on the need for atlases of Cys modifications to develop systems biology models. Such atlases will be especially useful for integrative studies linking the Cys proteome to imaging and other omics platforms, providing a basis for improved redox-based therapeutics. Thus, a framework is emerging to place the Cys proteome as a complement to the quantitative proteome in the omics continuum connecting the genome to the exposome.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
© The Author 2015. Published by Oxford University Press.
Trichloroethylene (TCE) is a widely used organic solvent. Although TCE is classified as carcinogenic to humans, substantial gaps remain in our understanding of interindividual variability in TCE metabolism and toxicity, especially in the liver. A hypothesis was tested that amounts of oxidative metabolites of TCE in mouse liver are associated with hepatic-specific toxicity. Oral dosing with TCE was conducted in subacute (600 mg/kg/d; 5 d; 7 inbred mouse strains) and subchronic (100 or 400 mg/kg/d; 1, 2, or 4 wk; 2 inbred mouse strains) designs. The quantitative relationship was evaluated between strain-, dose-, and time-dependent formation of TCE metabolites from cytochrome P-450-mediated oxidation (trichloroacetic acid [TCA], dichloroacetic acid [DCA], and trichloroethanol) and glutathione conjugation [S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)glutathione] in serum and liver, and various hepatic toxicity phenotypes. In subacute study, interstrain variability in TCE metabolite amounts was observed in serum and liver. No marked induction of Cyp2e1 protein levels in liver was detected. Serum and hepatic levels of TCA and DCA were correlated with increased transcription of peroxisome proliferator-marker genes Cyp4a10 and Acox1 but not with degree of induction in hepatocellular proliferation. In subchronic study, serum and liver levels of oxidative metabolites gradually decreased over time despite continuous dosing. Hepatic protein levels of CYP2E1, ADH, and ALDH2 were unaffected by treatment with TCE. While the magnitude of induction of peroxisome proliferator-marker genes also declined, hepatocellular proliferation increased. This study offers a unique opportunity to provide a scientific data-driven rationale for some of the major assumptions in human health assessment of TCE.
The exposome is defined as the totality of all human environmental exposures from conception to death. It is often regarded as the complement to the genome, with the interaction between the exposome and the genome ultimately determining one's phenotype. The 'toxic exposome' is the complete collection of chronically or acutely toxic compounds to which humans can be exposed. Considerable interest in defining the toxic exposome has been spurred on by the realization that most human injuries, deaths and diseases are directly or indirectly caused by toxic substances found in the air, water, food, home or workplace. The Toxin-Toxin-Target Database (T3DB - www.t3db.ca) is a resource that was specifically designed to capture information about the toxic exposome. Originally released in 2010, the first version of T3DB contained data on nearly 2900 common toxic substances along with detailed information on their chemical properties, descriptions, targets, toxic effects, toxicity thresholds, sequences (for both targets and toxins), mechanisms and references. To more closely align itself with the needs of epidemiologists, toxicologists and exposome scientists, the latest release of T3DB has been substantially upgraded to include many more compounds (>3600), targets (>2000) and gene expression datasets (>15 000 genes). It now includes extensive data on 'normal' toxic compound concentrations in human biofluids as well as detailed chemical taxonomies, informative chemical ontologies and a large number of referential NMR, MS/MS and GC-MS spectra. This manuscript describes the most recent update to the T3DB, which was previously featured in the 2010 NAR Database Issue.
Cloud-based bioinformatic platforms address the fundamental demands of creating a flexible scientific environment, facilitating data processing and general accessibility independent of a countries' affluence. These platforms have a multitude of advantages as demonstrated by omics technologies, helping to support both government and scientific mandates of a more open environment.
Almost two decades after the identification of SNCA as the first causative gene in Parkinson's disease (PD) and the subsequent understanding that genetic factors play a substantial role in PD development, our knowledge of the genetic architecture underlying this disease has vastly improved. Approximately 5–10% of patients suffer from a monogenic form of PD where autosomal dominant mutations in SNCA, LRRK2, and VPS35 and autosomal recessive mutations in PINK1, DJ-1, and Parkin cause the disease with high penetrance. Furthermore, recent whole-exome sequencing have described autosomal recessive DNAJC6 mutations in predominately atypical, but also cases with typical PD. In addition, several other genes have been linked to atypical Parkinsonian phenotypes. However, the vast majority of PD is genetically complex, i.e. it is caused by the combined action of common genetic variants in concert with environmental factors. By the application of genome-wide association studies, 26 PD risk loci have been established to date. Similar to other genetically complex diseases, these show only moderate effects on PD risk. Increasing this etiologic complexity, many of the involved genetic and environmental risk factors likely interact in an intricate fashion. This article aims to provide a comprehensive overview of the current knowledge in PD genetics.
“Sola dosis facit venenum.” These words of Paracelsus, “the dose makes the poison”, can lead to a cavalier attitude concerning potential toxicities of the vast array of low abundance environmental chemicals to which humans are exposed. Exposome research teaches that 80-85% of human disease is linked to environmental exposures. The human exposome is estimated to include >400,000 environmental chemicals, most of which are uncharacterized with regard to human health. In fact, mass spectrometry measures >200,000 m/z features (ions) in microliter volumes derived from human samples; most are unidentified. This crystalizes a grand challenge for chemical research in toxicology: to develop reliable and affordable analytical methods to understand health impacts of the extensive human chemical experience. To this end, there appears to be no choice but to abandon the limitations of measuring one chemical at a time. The present article reviews progress in computational metabolomics to provide probability-based annotation linking ions to known chemicals and serve as a foundation for unambiguous designation of unidentified ions for toxicologic study. We review methods to characterize ions in terms of accurate mass m/z, chromatographic retention time, correlation of adduct, isotopic and fragment forms, association with metabolic pathways and measurement of collision-induced dissociation products, collision cross section and chirality. Such information can support a largely unambiguous system for documenting unidentified ions in environmental surveillance and human biomonitoring. Assembly of this data would provide a resource to characterize and understand health risks of the array of low-abundance chemicals to which humans are exposed.
The ILSI Health and Environmental Sciences Institute (HESI) has developed a framework to support a transition in the way in which information for chemical risk assessment is obtained and used (RISK21). The approach is based on detailed problem formulation, where exposure drives the data acquisition process in order to enable informed decision-making on human health safety as soon as sufficient evidence is available. Information is evaluated in a transparent and consistent way with the aim of optimizing available resources. In the context of risk assessment, cumulative risk assessment (CRA) poses additional problems and questions that can be addressed using the RISK21 approach. The focus in CRA to date has generally been on chemicals that have common mechanisms of action. Recently, concern has also been expressed about chemicals acting on multiple pathways that lead to a common health outcome, and non-chemical other conditions (non-chemical stressors) that can lead to or modify a common outcome. Acknowledging that CRAs, as described above, are more conceptually, methodologically and computationally complex than traditional single-stressor risk assessments, RISK21 further developed the framework for implementation of workable processes and procedures for conducting assessments of combined effects from exposure to multiple chemicals and non-chemical stressors. As part of the problem formulation process, this evidence-based framework allows the identification of the circumstances in which it is appropriate to conduct a CRA for a group of compounds. A tiered approach is then proposed, where additional chemical stressors and/or non-chemical modulating factors (ModFs) are considered sequentially. Criteria are provided to facilitate the decision on whether or not to include ModFs in the formal quantitative assessment, with the intention to help focus the use of available resources to have the greatest potential to protect public health.
The worldwide obesity epidemic has been mainly attributed to lifestyle changes. However, who becomes obese in an obesity-prone environment is largely determined by genetic factors. In the last 20 years, important progress has been made in the elucidation of the genetic architecture of obesity. In parallel with successful gene identifications, the number of gene-environment interaction (GEI) studies has grown rapidly. This paper reviews the growing body of evidence supporting gene-environment interactions in the field of obesity. Heritability, monogenic and polygenic obesity studies provide converging evidence that obesity-predisposing genes interact with a variety of environmental, lifestyle and treatment exposures. However, some skepticism remains regarding the validity of these studies based on several issues, which include statistical modelling, confounding, low replication rate, underpowered analyses, biological assumptions and measurement precision. What follows in this review includes (1) an introduction to the study of GEI, (2) the evidence of GEI in the field of obesity, (3) an outline of the biological mechanisms that may explain these interaction effects, (4) methodological challenges associated with GEI studies and potential solutions, and (5) future directions of GEI research. Thus far, this growing body of evidence has provided a deeper understanding of GEI influencing obesity and may have tremendous applications in the emerging field of personalized medicine and individualized lifestyle recommendations.
Asbestos in combination with tobacco smoke exposure reportedly leads to more severe physiological consequences than asbestos alone; limited data also show an increased disease risk due to environmental tobacco smoke (ETS) exposure. Environmental influences during gestation and early lung development can result in physiological changes that alter risk for disease development throughout an individual’s lifetime. Therefore, maternal lifestyle may impact the ability of offspring to subsequently respond to environmental insults and alter overall disease susceptibility. In this study, we examined the effects of exposure to ETS in utero and during early postnatal development on asbestos-related inflammation and disease in adulthood. ETS exposure in utero appeared to shift inflammation towards a Th2 phenotype, via suppression of Th1 inflammatory cytokine production. This effect was further pronounced in mice exposed to ETS in utero and during early postnatal development. In utero ETS exposure led to increased collagen deposition, a marker of fibrotic disease, when the offspring was later exposed to asbestos, which was further increased with additional ETS exposure during early postnatal development. These data suggest that ETS exposure in utero alters the immune responses and leads to greater disease development after asbestos exposure, which is further exacerbated when exposure to ETS continues during early postnatal development.
Background:
Risk of cancer is determined by a complex interplay of genetic and environmental factors. Although the study of gene-environment interactions (G×E) has been an active area of research, little is reported about the known findings in the literature.
Methods:
To examine the state of the science in G×E research in cancer, we performed a systematic review of published literature using gene-environment or pharmacogenomic flags from two curated databases of genetic association studies, the Human Genome Epidemiology (HuGE) literature finder and Cancer Genome-Wide Association and Meta Analyses Database (CancerGAMAdb), from January 1, 2001, to January 31, 2011. A supplemental search using HuGE was conducted for articles published from February 1, 2011, to April 11, 2013. A 25% sample of the supplemental publications was reviewed.
Results:
A total of 3,019 articles were identified in the original search. From these articles, 243 articles were determined to be relevant based on inclusion criteria (more than 3,500 interactions). From the supplemental search (1,400 articles identified), 29 additional relevant articles (1,370 interactions) were included. The majority of publications in both searches examined G×E in colon, rectal, or colorectal; breast; or lung cancer. Specific interactions examined most frequently included environmental factors categorized as energy balance (e.g., body mass index, diet), exogenous (e.g., oral contraceptives) and endogenous hormones (e.g., menopausal status), chemical environment (e.g., grilled meats), and lifestyle (e.g., smoking, alcohol intake). In both searches, the majority of interactions examined were using loci from candidate genes studies and none of the studies were genome-wide interaction studies (GEWIS). The most commonly reported measure was the interaction P-value, of which a sizable number of P-values were considered statistically significant (i.e., <0.05). In addition, the magnitude of interactions reported was modest.
Conclusion:
Observations of published literature suggest that opportunity exists for increased sample size in G×E research, including GWAS-identified loci in G×E studies, exploring more GWAS approaches in G×E such as GEWIS, and improving the reporting of G×E findings.
The combination of genetic background together with food excess and lack of exercise has become the cornerstone of metabolic disorders associated to lifestyle. The scenario is furthermore reinforced by their interaction with other environmental factors (stress, sleeping patterns, education, culture, rural versus urban locations, and xenobiotics, among others) inducing epigenetic changes in the exposed individuals. The immediate consequence is the development of further alterations like obesity and metabolic syndrome, and other adverse health conditions (type-2 diabetes, cardiovascular diseases, cancer, reproductive, immune and neurological disorders). Thus, having in mind the impact of the metabolic syndrome on the worldwide public health, the present review affords the relative roles and the interrelationships of nature (genetic predisposition to metabolic syndrome) and nurture (lifestyle and environmental effects causing epigenetic changes), on the establishment of the metabolic disorders in women; disorders that may evolve to metabolic syndrome prior or during pregnancy and may be transmitted to their descendants.
Valproic acid (VPA) is an anti-epileptic drug used in patients with convulsive seizures and psychic disorders. Despite its therapeutic use, VPA administration is associated with several side effects of which hepatosteatosis (lipid deposition in liver >10% of organ weight) is of concern. Recently, the consumption of western-type diet rich in fat and simple sugar has increased, the pathological consequences of which has been linked to the escalating incidence of metabolic disorders. The hypothesis of the study is that the metabolic stress induced by high-calorie diet may potentiate VPA-induced hepatosteatosis. Two groups of Swiss Mus musculus male mice weighing 25-35 g were fed either normal chow or high fat and high fructose diet (HFFD) and maintained for 30 days. On the 16th day of the experiment, VPA (100 mg/kg bw) administration was initiated in one set of animals from each group and the other set was left without VPA treatment. Assays were done in the hemolysate, plasma and liver tissue of mice after the experimental period. Deregulated lipid metabolism, loss of insulin sensitivity, enhanced CYP2E1 activity and oxidative damage, and diminution of cellular antioxidants were observed in animals that received HFFD and VPA. HFFD-fed mice are sensitized to VPA toxicity than the normal chow-fed counterparts. The results of this study show that preformed metabolic derangements due to high-energy diet may infuriate VPA-induced hepatosteatosis and insulin resistance.
Under the exposome paradigm all nongenetic factors contributing to disease are considered to be 'environmental' including chemicals, drugs, infectious agents, and psychosocial stress. We can consider these collectively as environmental stressors. Exposomics is the comprehensive analysis of exposure to all environmental stressors and should yield a more thorough understanding of chronic disease development. We can operationalize exposomics by studying all the small molecules in the body and their influence on biological pathways that lead to impaired health. Here, we describe methods by which this may be achieved and discuss the application of exposomics to cumulative risk assessment in vulnerable populations. Since the goal of cumulative risk assessment is to analyze, characterize, and quantify the combined risks to health from exposures to multiple agents or stressors, it seems that exposomics is perfectly poised to advance this important area of environmental health science. We should therefore support development of tools for exposomic analysis and begin to engage impacted communities in participatory exposome research. A first step may be to apply exposomics to vulnerable populations already studied by more conventional cumulative risk approaches. We further propose that recent migrants, low socioeconomic groups with high environmental chemical exposures, and pregnant women should be high priority populations for study by exposomics. Moreover, exposomics allows us to study interactions between chronic stress and environmental chemicals that disrupt stress response pathways (i.e., 'stressogens'). Exploring the impact of early life exposures and maternal stress may be an interesting and accessible topic for investigation by exposomics using biobanked samples. Environ. Mol. Mutagen., 2015. © 2015 Wiley Periodicals, Inc.
Elevated body mass index (BMI) is a risk factor for cardiovascular disease, diabetes, cancer, and other diseases. Inflammation or oxidative stress induced by high BMI may explain some of these effects. Millions of people drink arsenic-contaminated water worldwide, and ingested arsenic has also been associated with inflammation, oxidative stress, and cancer.
To assess the unique situation of people living in northern Chile exposed to high arsenic concentrations in drinking water and investigate interactions between arsenic and BMI, and associations with lung and bladder cancer risks.
Information on self-reported body mass index (BMI) at various life stages, smoking, diet, and lifetime arsenic exposure was collected from 532 cancer cases and 634 population-based controls.
In subjects with BMIs <90th percentile in early adulthood (27.7 and 28.6kg/m(2) in males and females, respectively), odds ratios (OR) for lung and bladder cancer combined for arsenic concentrations of <100, 100-800 and >800µg/L were 1.00, 1.64 (95% CI, 1.19-2.27), and 3.12 (2.30-4.22). In subjects with BMIs ≥90th percentile in early adulthood, the corresponding ORs were higher: 1.00, 1.84 (0.75-4.52), and 9.37 (2.88-30.53), respectively (synergy index=4.05, 95% CI, 1.27-12.88). Arsenic-related cancer ORs >20 were seen in those with elevated BMIs in both early adulthood and in later life. Adjustments for smoking, diet, and other factors had little impact.
These findings provide novel preliminary evidence supporting the notion that environmentally-related cancer risks may be markedly increased in people with elevated BMIs, especially in those with an elevated BMI in early-life.
Copyright © 2015 Elsevier Inc. All rights reserved.
Little information exists regarding the effect of interaction of obesity and long-term air pollution exposure on children's blood pressure and hypertension in areas with high levels of air pollution. The aim of this study is to assess effect modification by obesity on the association between exposure and blood pressure in Chinese children.
We studied 9,354 Chinese children, ages 5-17 years old, from 24 elementary schools and 24 middle schools in the Seven Northeastern Cities during 2012-2013. Four-year average concentrations of particles with an aerodynamic diameter ≤10 µm (PM10), sulfur dioxide, nitrogen dioxides, and ozone (O3) were measured at the monitoring stations in the 24 districts. We used generalized additive models and two-level logistic regression models to examine the health effects.
Consistent interactions were found between exposure and obesity on blood pressure and hypertension. The association between exposure and hypertension was consistently larger for overweight/obese children than for children with normal-weight, with odds ratios for hypertension ranging from 1.16 per 46.3μg/m for O3 (95% confidence interval [CI] = 1.12, 1.20) to 2.91 per 30.6μg/m for PM10 (95% CI = 2.32, 3.64), and estimated increases in mean systolic and diastolic blood pressure ranging from 0.57 mmHg (95% CI = 0.36, 0.78) and 0.63 mmHg (95% CI = 0.46, 0.81) per 46.3 μg/m for O3 to 4.04 mmHg (95% CI = 3.00, 5.09) and 2.02 mmHg (95% CI = 1.14, 2.89) per 23.4 μg/m for sulfur dioxide.
Obesity amplifies the association of long-term air pollution exposure with blood pressure and hypertension in Chinese children.
Objective:
This article presents a new formulation of the relationship between stress and the processes leading to disease. It emphasizes the hidden cost of chronic stress to the body over long time periods, which act as a predisposing factor for the effects of acute, stressful life events. It also presents a model showing how individual differences in the susceptibility to stress are tied to individual behavioral responses to environmental challenges that are coupled to physiologic and pathophysiologic responses.Data Sources:
Published original articles from human and animal studies and selected reviews. Literature was surveyed using MEDLINE.Data Extraction:
Independent extraction and cross-referencing by us.Data Synthesis:
Stress is frequently seen as a significant contributor to disease, and clinical evidence is mounting for specific effects of stress on immune and cardiovascular systems. Yet, until recently, aspects of stress that precipitate disease have been obscure. The concept of homeostasis has failed to help us understand the hidden toll of chronic stress on the body. Rather than maintaining constancy, the physiologic systems within the body fluctuate to meet demands from external forces, a state termed allostasis. In this article, we extend the concept of allostasis over the dimension of time and we define allostatic load as the cost of chronic exposure to fluctuating or heightened neural or neuroendocrine response resulting from repeated or chronic environmental challenge that an individual reacts to as being particularly stressful.Conclusions:
This new formulation emphasizes the cascading relationships, beginning early in life, between environmental factors and genetic predispositions that lead to large individual differences in susceptibility to stress and, in some cases, to disease. There are now empirical studies based on this formulation, as well as new insights into mechanisms involving specific changes in neural, neuroendocrine, and immune systems. The practical implications of this formulation for clinical practice and further research are discussed.(Arch Intern Med. 1993;153:2093-2101)
Objectives: We carried out a detailed exposure assessment of benzene and toluene in two shoe factories in Tianjin, China. Our goal was to identify workers with a broad range of benzene exposures, for an epidemiologic study relating exposure to early biologic effects. Methods: A comprehensive exposure survey program was initiated. Over a period of 16 months, 2783 personal solvent exposure samples were collected in two workplaces from 250 workers. Mixed-effects models were used to identify factors affecting exposure. Principal component analyses (PCA) and subsequent regression analyses on the scores of the identified principal components were used to relate potential co-exposures to various exposure sources present in the workplace. Results: The mean benzene exposure level was 21.86 p.p.m. (10th-90th percentiles 5.23-50.63 p.p.m.) in the smaller shoe factory (factory A) and 3.46 p.p.m. (10th-90th percentiles 0.20-7.00 p.p.m.) in the larger shoe factory (factory B). Within-factory exposure levels differed among job titles and were higher for subjects directly involved in handling glues. In contrast, mean toluene levels were relatively similar in the two factories (factory A, 9.52 p.p.m.; factory B, 15.88 p.p.m.). A seasonal trend was identified for both benzene and toluene in factory B. This could be explained in part by changes in air movement and ventilation patterns occurring during the year. A seasonal trend was not present in the smaller shoe factory, where general ventilation was absent. Supplemental analysis showed that exposure levels to other hydrocarbons were low (≤5 p.p.m.), less than 5% of their respective ACGIH threshold limit values, and generally comparable in the two factories. PCA showed that co-exposures in factory B could largely be explained by glue sources that were used in distinct areas in the workplace. Conclusions: We demonstrated the occurrence of a broad range of benzene exposure levels in two shoe manufacturing factories in Tianjin, China. Benzene and toluene exposures were determined in part by the degree of contact with glues, the benzene and toluene content of each glue, air movement and ventilation patterns. The availability of long-term monthly personal monitoring data provides an excellent opportunity to estimate individual exposures at different times during the 1 yr period of observation.
Polycyclic aromatic hydrocarbons are common carcinogenic and neurotoxic urban air pollutants. Toxic exposures, including air pollution, are disproportionately high in communities of color and frequently co-occur with chronic economic deprivation.
We examined whether the association between child IQ and prenatal exposure to polycyclic aromatic hydrocarbons differed between groups of children whose mothers reported high vs. low material hardship during their pregnancy and through child age 5. We tested statistical interactions between hardships and polycyclic aromatic hydrocarbons, as measured by DNA adducts in cord blood, to determine whether material hardship exacerbated the association between adducts and IQ scores.
Prospective cohort. Participants were recruited from 1998 to 2006 and followed from gestation through age 7 years.
Urban community (New York City) PARTICIPANTS: A community-based sample of 276 minority urban youth EXPOSURE MEASURE: Polycyclic aromatic hydrocarbon-DNA adducts in cord blood as an individual biomarker of prenatal polycyclic aromatic hydrocarbon exposure. Maternal material hardship self-reported prenatally and at multiple timepoints through early childhood.
Child IQ at 7 years assessed using the Wechsler Intelligence Scale for Children.
Significant inverse effects of high cord PAH-DNA adducts on full scale IQ, perceptual reasoning and working memory scores were observed in the groups whose mothers reported a high level of material hardship during pregnancy or recurring high hardship into the child's early years, and not in those without reported high hardship. Significant interactions were observed between high cord adducts and prenatal hardship on working memory scores (β=-8.07, 95% CI (-14.48, -1.66) and between high cord adducts and recurrent material hardship (β=-9.82, 95% CI (-16.22, -3.42).
The findings add to other evidence that socioeconomic disadvantage can increase the adverse effects of toxic physical "stressors" like air pollutants. Observed associations between high cord adducts and reduced IQ were significant only among the group of children whose mothers reported high material hardship. These results indicate the need for a multifaceted approach to prevention.
Copyright © 2015. Published by Elsevier Inc.
A growing body of literature suggests that more unequal societies have more polluted and degraded environments, perhaps helping explain why more unequal societies are often less healthy. We summarize the mechanisms by which inequality can lead to environmental degradation and their relevance for public health. We review the evidence of a relationship between environmental quality and social inequality along the axes of income, wealth, political power, and race and ethnicity. Our review suggests that the evidence is strongest for air- and water-quality measures that have more immediate health implications; evidence is less strong for more dispersed pollutants that have longer-term health impacts. More attention should be paid in research and in practice to links among inequality, the environment, and health, including more within-country studies that may elucidate causal pathways and points of intervention. We synthesize common metrics of inequality and methodological considerations in an effort to bring cohesion to such efforts.
The environment plays a major role in influencing diseases and health. The phenomenon of environmental exposure is complex and humans are not exposed to one or a handful factors but potentially hundreds factors throughout their lives. The exposome, the totality of exposures encountered from birth, is hypothesized to consist of multiple inter-dependencies, or correlations, between individual exposures. These correlations may reflect how individuals are exposed. Currently, we lack methods to comprehensively identify robust and replicated correlations between environmental exposures of the exposome. Further, we have not mapped how exposures associated with disease identified by environment-wide association studies (EWAS) are correlated with other exposures. To this end, we implement methods to describe a first "exposome globe", a comprehensive display of replicated correlations between individual exposures of the exposome. First, we describe overall characteristics of the dense correlations between exposures, showing that we are able to replicate 2,656 correlations between individual exposures of 81,937 total considered (3%). We document the correlation within and between broad a priori defined categories of exposures (e.g., pollutants and nutrient exposures). We also demonstrate utility of the exposome globe to contextualize exposures found through two EWASs in type 2 diabetes and all-cause mortality, such as exposure clusters putatively related to smoking behaviors and persistent pollutant exposure. The exposome globe construct is a useful tool for the display and communication of the complex relationships between exposure factors and between exposure factors related to disease status.
Our goal was to investigate whether obesity increases susceptibility to the adverse effects of indoor particulate matter on respiratory morbidity among individuals with chronic obstructive pulmonary disease (COPD). Participants with COPD were studied at baseline, 3 and 6 months. Obesity was defined as a body mass index ⩾30 kg·m(-2). At each time point, indoor air was sampled for 5-7 days and particulate matter (PM) with an aerodynamic size ⩽2.5 μm (PM2.5) and 2.5-10 μm (PM2.5-10) was measured. Respiratory symptoms, health status, rescue medication use, exacerbations, blood biomarkers and exhaled nitric oxide were assessed simultaneously. Of the 84 participants enrolled, 56% were obese and all were former smokers with moderate-to-severe COPD. Obese participants tended to have less severe disease as assessed by Global Initiative for Chronic Obstructive Pulmonary Disease stage and fewer pack-years of smoking. There was evidence that obesity modified the effects of indoor PM on COPD respiratory outcomes. Increases in PM2.5 and PM2.5-10 were associated with greater increases in nocturnal symptoms, dyspnoea and rescue medication use among obese versus non-obese participants. The impact of indoor PM on exacerbations, respiratory status and wheeze also tended to be greater among obese versus non-obese participants, as were differences in airway and systemic inflammatory responses to indoor PM. We found evidence that obesity was associated with exaggerated responses to indoor fine and coarse PM exposure among individuals with COPD.
Copyright ©ERS 2014.