Sustainable Control of Water-Related Infectious Diseases: A Review and Proposal for Interdisciplinary Health-Based Systems Research

Objective

Even when initially successful, many interventions aimed at reducing the toll of water-related infectious disease have not been sustainable over longer periods of time. Here we review historical practices in water-related infectious disease research and propose an interdisciplinary public health oriented systems approach to research and intervention design.

Data sources

On the basis of the literature and the authors’ experiences, we summarize contributions from key disciplines and identify common problems and trends. Practices in developing countries, where the disease burden is the most severe, are emphasized.

Data extraction

We define waterborne and water-associated vectorborne diseases and identify disciplinary themes and conceptual needs by drawing from ecologic, anthropologic, engineering, political/economic, and public health fields. A case study examines one of the classes of water-related infectious disease.

Data synthesis

The limited success in designing sustainable interventions is attributable to factors that include the complexity and interactions among the social, ecologic, engineering, political/economic, and public health domains; incomplete data; a lack of relevant indicators; and most important, an inadequate understanding of the proximal and distal factors that cause water-related infectious disease. Fundamental change is needed for research on water-related infectious diseases, and we advocate a systems approach framework using an ongoing evidence-based health outcomes focus with an extended time horizon. The examples and case study in the review show many opportunities for interdisciplinary collaborations, data fusion techniques, and other advances.

Conclusions

The proposed framework will facilitate research by addressing the complexity and divergent scales of problems and by engaging scientists in the disciplines needed to tackle these difficult problems. Such research can enhance the prevention and control of water-related infectious diseases in a manner that is sustainable and focused on public health outcomes.     

A Review of Advocate–Scientist Collaboration in Federally Funded Environmental Breast Cancer Research Centers

Background

The Long Island Breast Cancer Study Project was the first federally funded study of environmental causes of breast cancer. Although advocates were expected to participate in this study, the details of their participation were not adequately clarified in project guidelines, which resulted in confusion over their role in the project. The Breast Cancer and Environment Research Centers (BCERCs) are funded by the National Institute of Environmental Health Sciences and the National Cancer Institute; these centers continue to conduct research into environmental links to breast cancer and to clarify advocate–scientist guidelines for collaboration.

Objectives

Practitioners in community-based participatory research (CBPR) are grappling with how to improve CBPR projects for all groups involved in breast cancer and environmental studies. The ever-growing body of literature on CBPR elaborates on a number of factors that make CBPR particularly challenging, specifically regarding partnerships between advocate and scientific communities. This study draws on CBPR principles to evaluate advocate–scientist collaboration in the BCERCs.

Methods

We conducted surveys at BCERC annual meetings in 2005 and 2007 and 11 in-depth open-ended interviews with key stakeholders such as primary investigators within the centers to assess the perceptions of the advocates and scientists regarding collaboration between advocates and scientists who were engaged in CBPR studies.

Results

We found that although participatory guidelines were a focus of BCERCs, underlying differences between advocates and scientists with regard to paradigms of scientific inquiry, priorities, and desired outcomes need to be addressed for more effective collaboration to take place.

Conclusion

Our findings contribute to the broader CBPR literature by highlighting the role of underlying assumptions that may hinder the collaborative process and suggest the need for continued assessment research into participatory research projects on breast cancer and the environment.     

Climate Variability,Social and Environmental Factors,and Ross River Virus Transmission: Research Development and Future Research Needs

Background

Arbovirus diseases have emerged as a global public health concern. However, the impact of climatic, social, and environmental variability on the transmission of arbovirus diseases remains to be determined.

Objective

Our goal for this study was to provide an overview of research development and future research directions about the interrelationship between climate variability, social and environmental factors, and the transmission of Ross River virus (RRV), the most common and widespread arbovirus disease in Australia.

Methods

We conducted a systematic literature search on climatic, social, and environmental factors and RRV disease. Potentially relevant studies were identified from a series of electronic searches.

Results

The body of evidence revealed that the transmission cycles of RRV disease appear to be sensitive to climate and tidal variability. Rainfall, temperature, and high tides were among major determinants of the transmission of RRV disease at the macro level. However, the nature and magnitude of the interrelationship between climate variability, mosquito density, and the transmission of RRV disease varied with geographic area and socioenvironmental condition. Projected anthropogenic global climatic change may result in an increase in RRV infections, and the key determinants of RRV transmission we have identified here may be useful in the development of an early warning system.

Conclusions

The analysis indicates that there is a complex relationship between climate variability, social and environmental factors, and RRV transmission. Different strategies may be needed for the control and prevention of RRV disease at different levels. These research findings could be used as an additional tool to support decision making in disease control/surveillance and risk management.     

Environmental Health Indicators of Climate Change for the United States: Findings from the State Environmental Health Indicator Collaborative

Objective

To develop public health adaptation strategies and to project the impacts of climate change on human health, indicators of vulnerability and preparedness along with accurate surveillance data on climate-sensitive health outcomes are needed. We researched and developed environmental health indicators for inputs into human health vulnerability assessments for climate change and to propose public health preventative actions.

Data sources

We conducted a review of the scientific literature to identify outcomes and actions that were related to climate change. Data sources included governmental and nongovernmental agencies and the published literature.

Data extraction

Sources were identified and assessed for completeness, usability, and accuracy. Priority was then given to identifying longitudinal data sets that were applicable at the state and community level.

Data synthesis

We present a list of surveillance indicators for practitioners and policy makers that include climate-sensitive health outcomes and environmental and vulnerability indicators, as well as mitigation, adaptation, and policy indicators of climate change.

Conclusions

A review of environmental health indicators for climate change shows that data exist for many of these measures, but more evaluation of their sensitivity and usefulness is needed. Further attention is necessary to increase data quality and availability and to develop new surveillance databases, especially for climate-sensitive morbidity.     

Global climate change and children's health: threats and strategies for prevention

Background

Global climate change will have multiple effects on human health. Vulnerable populations—children, the elderly, and the poor—will be disproportionately affected.

Objective

We reviewed projected impacts of climate change on children’s health, the pathways involved in these effects, and prevention strategies.

Data sources

We assessed primary studies, review articles, and organizational reports.

Data synthesis

Climate change is increasing the global burden of disease and in the year 2000 was responsible for > 150,000 deaths worldwide. Of this disease burden, 88% fell upon children. Documented health effects include changing ranges of vector-borne diseases such as malaria and dengue; increased diarrheal and respiratory disease; increased morbidity and mortality from extreme weather; changed exposures to toxic chemicals; worsened poverty; food and physical insecurity; and threats to human habitation. Heat-related health effects for which research is emerging include diminished school performance, increased rates of pregnancy complications, and renal effects. Stark variation in these outcomes is evident by geographic region and socioeconomic status, and these impacts will exacerbate health disparities. Prevention strategies to reduce health impacts of climate change include reduction of greenhouse gas emissions and adaptation through multiple public health interventions.

Conclusions

Further quantification of the effects of climate change on children’s health is needed globally and also at regional and local levels through enhanced monitoring of children’s environmental health and by tracking selected indicators. Climate change preparedness strategies need to be incorporated into public health programs.     

Qualitative Environmental Health Research: An Analysis of the Literature, 1991–2008

Background

Recent articles have advocated for the use of qualitative methods in environmental health research. Qualitative research uses nonnumeric data to understand people’s opinions, motives, understanding, and beliefs about events or phenomena.

Objective

In this analysis of the literature, I report the use of qualitative methods and data in the study of the relationship between environmental exposures and human health.

Data sources

A primary search on ISI Web of Knowledge/Web of Science for peer-reviewed journal articles dated from 1991 through 2008 included the following three terms: qualitative, environ*, and health. Inclusion and exclusion criteria are described.

Data extraction

Searches resulted in 3,155 records. Data were extracted and findings of articles analyzed to determine where and by whom qualitative environmental health research is conducted and published, the types of methods and analyses used in qualitative studies of environmental health, and the types of information qualitative data contribute to environmental health.

Data synthesis

Ninety-one articles met inclusion criteria. These articles were published in 58 different journals, with a maximum of eight for a single journal. The results highlight a diversity of disciplines and techniques among researchers who used qualitative methods to study environmental health, with most studies relying on one-on-one interviews. Details of the analyses were absent from a large number of studies. Nearly all of the studies identified increased scientific understanding of lay perceptions of environmental health exposures.

Discussion and conclusions

Qualitative data are published in traditionally quantitative environmental health studies to a limited extent. However, this analysis demonstrates the potential of qualitative data to improve understanding of complex exposure pathways, including the influence of social factors on environmental health, and health outcomes.     

Adverse Effects of Methylmercury: Environmental Health Research Implications

Background

The scientific discoveries of health risks resulting from methylmercury exposure began in 1865 describing ataxia, dysarthria, constriction of visual fields, impaired hearing, and sensory disturbance as symptoms of fatal methylmercury poisoning.

Objective

Our aim was to examine how knowledge and consensus on methylmercury toxicity have developed in order to identify problems of wider concern in research.

Data sources and extraction

We tracked key publications that reflected new insights into human methylmercury toxicity. From this evidence, we identified possible caveats of potential significance for environmental health research in general.

Synthesis

At first, methylmercury research was impaired by inappropriate attention to narrow case definitions and uncertain chemical speciation. It also ignored the link between ecotoxicity and human toxicity. As a result, serious delays affected the recognition of methylmercury as a cause of serious human poisonings in Minamata, Japan. Developmental neurotoxicity was first reported in 1952, but despite accumulating evidence, the vulnerability of the developing nervous system was not taken into account in risk assessment internationally until approximately 50 years later. Imprecision in exposure assessment and other forms of uncertainty tended to cause an underestimation of methylmercury toxicity and repeatedly led to calls for more research rather than prevention.

Conclusions

Coupled with legal and political rigidity that demanded convincing documentation before considering prevention and compensation, types of uncertainty that are common in environmental research delayed the scientific consensus and were used as an excuse for deferring corrective action. Symptoms of methylmercury toxicity, such as tunnel vision, forgetfulness, and lack of coordination, also seemed to affect environmental health research and its interpretation.     

Toward the Assessment of Scientific and Public Health Impacts of the National Institute of Environmental Health Sciences Extramural Asthma Research Program Using Available Data

Background

In the past 15 years, asthma prevalence has increased and is disproportionately distributed among children, minorities, and low-income persons. The National Institute of Environmental Health Sciences (NIEHS) Division of Extramural Research and Training developed a framework to measure the scientific and health impacts of its extramural asthma research to improve the scientific basis for reducing the health effects of asthma.

Objectives

Here we apply the framework to characterize the NIEHS asthma portfolio’s impact in terms of publications, clinical applications of findings, community interventions, and technology developments.

Methods

A logic model was tailored to inputs, outputs, and outcomes of the NIEHS asthma portfolio. Data from existing National Institutes of Health (NIH) databases are used, along with publicly available bibliometric data and structured elicitation of expert judgment.

Results

NIEHS is the third largest source of asthma-related research grant funding within the NIH between 1975 and 2005, after the National Heart, Lung, and Blood Institute and the National Institute of Allergy and Infectious Diseases. Much of NIEHS-funded asthma research focuses on basic research, but results are often published in journals focused on clinical investigation, increasing the likelihood that the work is moved into practice along the “bench to bedside” continuum. NIEHS support has led to key breakthroughs in scientific research concerning susceptibility to asthma, environmental conditions that heighten asthma symptoms, and cellular mechanisms that may be involved in treating asthma.

Conclusions

If gaps and limitations in publicly available data receive adequate attention, further linkages can be demonstrated between research activities and public health improvements. This logic model approach to research impact assessment demonstrates that it is possible to conceptualize program components, mine existing databases, and begin to show longer-term impacts of program results. The next challenges will be to modify current data structures, improve the linkages among relevant databases, incorporate as much electronically available data as possible, and determine how to improve the quality and health impact of the science that we support.     

Critical issues in the development of health information systems in supporting environmental health: a case study of ciguatera

Background

Emerging environmental pressures resulting from climate change and globalization challenge the capacity of health information systems (HIS) in the Pacific to inform future policy and public health interventions. Ciguatera, a globally common marine food-borne illness, is used here to illustrate specific HIS challenges in the Pacific and how these might be overcome proactively to meet the changing surveillance needs resulting from environmental change.

Objectives

We review and highlight inefficiencies in the reactive nature of existing HIS in the Pacific to collect, collate, and communicate ciguatera fish poisoning data currently used to inform public health intervention. Further, we review the capacity of existing HIS to respond to new data needs associated with shifts in ciguatera disease burden likely to result from coral reef habitat disruption.

Discussion

Improved knowledge on the ecological drivers of ciguatera prevalence at local and regional levels is needed, combined with enhanced surveillance techniques and data management systems, to capture environmental drivers as well as health outcomes data.

Conclusions

The capacity of public HIS to detect and prevent future outbreaks is largely dependent on the future development of governance strategies that promote proactive surveillance and health action. Accordingly, we present an innovative framework from which to stimulate scientific debate on how this might be achieved by using existing larger scale data sets and multidisciplinary collaborations.     

Is There Evidence for Synergy Among Air Pollutants in Causing Health Effects?

Background

Environmental air pollutants are inhaled as complex mixtures, but the long dominant focus of monitoring and research on individual pollutants has provided modest insight into pollutant interactions that may be important to health. Trends toward managing multiple pollutants to maximize aggregate health gains place increasing value on knowing whether the effects of combinations of pollutants are greater than the sum of the effects of individual pollutants (synergy).

Objective

We reviewed selected published literature to determine whether synergistic effects of combinations of pollutants on health outcomes have actually been demonstrated.

Methods and results

We reviewed 36 laboratory studies of combinations of ozone with other pollutants that were reported in the recent U.S. Environmental Protection Agency Ozone Criteria Document. We examined original reports to determine whether the experimental design tested for synergy and whether synergy was demonstrated. Fourteen studies demonstrated synergism, although synergistic, additive, and antagonistic effects were sometimes observed among different outcomes or at different times after exposure.

Conclusions

Synergisms involving O₃ have been demonstrated by laboratory studies of humans and animals. We conclude that the plausibility of synergisms among environmental pollutants has been established, although comparisons are limited, and most involved exposure concentrations much higher than typical of environmental pollutants. Epidemiologic research has limited ability to address the issue explicitly.     

Meeting Report: Consensus Statement—Parkinson’s Disease and the Environment: Collaborative on Health and the Environment and Parkinson’s Action Network (CHE PAN) Conference 26–28 June 2007

Background

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. People with PD, their families, scientists, health care providers, and the general public are increasingly interested in identifying environmental contributors to PD risk.

Methods

In June 2007, a multidisciplinary group of experts gathered in Sunnyvale, California, USA, to assess what is known about the contribution of environmental factors to PD.

Results

We describe the conclusions around which they came to consensus with respect to environmental contributors to PD risk. We conclude with a brief summary of research needs.

Conclusions

PD is a complex disorder, and multiple different pathogenic pathways and mechanisms can ultimately lead to PD. Within the individual there are many determinants of PD risk, and within populations, the causes of PD are heterogeneous. Although rare recognized genetic mutations are sufficient to cause PD, these account for < 10% of PD in the U.S. population, and incomplete penetrance suggests that environmental factors may be involved. Indeed, interplay among environmental factors and genetic makeup likely influences the risk of developing PD. There is a need for further understanding of how risk factors interact, and studying PD is likely to increase understanding of other neurodegenerative disorders.     

Modern Environmental Health Hazards: A Public Health Issue of Increasing Significance in Africa

Objectives

Traditional hazards such as poor sanitation currently account for most of Africa’s environmentally related disease burden. However, with rapid development absent appropriate safeguards for environment and health, modern environmental health hazards (MEHHs) may emerge as critical contributors to the continent’s disease burden. We review recent evidence of human exposure to and health effects from MEHHs, and their occurrence in environmental media and consumer products. Our purpose is to highlight the growing significance of these hazards as African countries experience urbanization, industrial growth, and development.

Data sources

We reviewed published epidemiologic, exposure, and environmental studies of chemical agents such as heavy metals and pesticides.

Data synthesis

The body of evidence demonstrates ongoing environmental releases of MEHHs and human exposures sometimes at toxicologically relevant levels. Several sources of MEHHs in environmental media have been identified, including natural resource mining and processing and automobile exhaust. Biomonitoring studies provided direct evidence of human exposure to metals such as mercury and lead and pesticides such as p,p′-dichlorodiphenyltrichloroethane (DDT) and organophosphates. Land and water resource pollution and industrial air toxics are areas of significant data gaps, notwithstanding the presence of several emitting sources.

Conclusion

Unmitigated MEHH releases and human exposure have implications for Africa’s disease burden. For Africans encumbered by conditions such as malnutrition that impair resilience to toxicologic challenges, the burden may be higher. A shift in public health policy toward accommodating the emerging diversity in Africa’s environmental health issues is necessary to successfully alleviate the burden of avoidable ill health and premature death for all its communities now and in the future.     

Breaking Patterns of Environmentally Influenced Disease for Health Risk Reduction: Immune Perspectives

Background

Diseases rarely, if ever, occur in isolation. Instead, most represent part of a more complex web or “pattern” of conditions that are connected via underlying biological mechanisms and processes, emerge across a lifetime, and have been identified with the aid of large medical databases.

Objective

We have described how an understanding of patterns of disease may be used to develop new strategies for reducing the prevalence and risk of major immune-based illnesses and diseases influenced by environmental stimuli.

Findings

Examples of recently defined patterns of diseases that begin in childhood include not only metabolic syndrome, with its characteristics of inflammatory dysregulation, but also allergic, autoimmune, recurrent infection, and other inflammatory patterns of disease. The recent identification of major immune-based disease patterns beginning in childhood suggests that the immune system may play an even more important role in determining health status and health care needs across a lifetime than was previously understood.

Conclusions

Focusing on patterns of disease, as opposed to individual conditions, offers two important venues for environmental health risk reduction. First, prevention of developmental immunotoxicity and pediatric immune dysfunction can be used to act against multiple diseases. Second, pattern-based treatment of entryway diseases can be tailored with the aim of disrupting the entire disease pattern and reducing the risk of later-life illnesses connected to underlying immune dysfunction. Disease-pattern–based evaluation, prevention, and treatment will require a change from the current approach for both immune safety testing and pediatric disease management.     

Community-based participatory research: a vehicle to promote public engagement for environmental health in China

Background

In the past 25 years, China has experienced remarkable economic growth and rapid agricultural-to-industrial and rural-to-urban transitions. As a consequence, China now faces many daunting environmental challenges that are significantly affecting human health and quality of life, including indoor and outdoor air pollution, water pollution, deforestation, loss of agricultural land, and sustainability. Chinese government leaders have recently emphasized the need for better environmental protection practices along with interventions involving strong public participation.

Objectives

Community-based participatory research (CBPR) is a collaborative approach to research that involves community members, organizational representatives, and researchers as equal participants in all phases of the research process. Over the past 15 years, CBPR has gained recognition and acceptance and is now valued as a means to effect change and provide scientific knowledge relevant to human health and the environment. In this article we highlight the success of CBPR in the United States and suggest that it could be a useful model for addressing environmental health problems in the People’s Republic of China.

Discussion

CBPR can reduce the tension between science and society by promoting genuine communication, by enabling scientists and administrators to listen and respond to the public, by allowing communities to help shape the research agenda, and by increasing accountability of researchers and governments to the public.

Conclusions

CBPR can potentially help improve environmental health in China, but it is likely to take a different form than it has in the West because the government will be leading the way.     

From Good Intentions to Proven Interventions: Effectiveness of Actions to Reduce the Health Impacts of Air Pollution

Background

Associations between air pollution and a multitude of health effects are now well established. Given ubiquitous exposure to some level of air pollution, the attributable health burden can be high, particularly for susceptible populations.

Objectives

An international multidisciplinary workshop was convened to discuss evidence of the effectiveness of actions to reduce health impacts of air pollution at both the community and individual level. The overall aim was to summarize current knowledge regarding air pollution exposure and health impacts leading to public health recommendations.

Discussion

During the workshop, experts reviewed the biological mechanisms of action of air pollution in the initiation and progression of disease, as well as the state of the science regarding community and individual-level interventions. The workshop highlighted strategies to reduce individual baseline risk of conditions associated with increased susceptibility to the effects of air pollution and the need to better understand the role of exposure duration in disease progression, reversal, and adaptation.

Conclusion

We have identified two promising and largely unexplored strategies to address and mitigate air pollution–related health impacts: reducing individual baseline risk of cardiovascular disease and incorporating air pollution–related health impacts into land-use decisions.     

Low-Dose Arsenic Compromises the Immune Response to Influenza A Infection in Vivo

Background

Arsenic exposure is a significant worldwide environmental health concern. We recently reported that 5-week exposure to environmentally relevant levels (10 and 100 ppb) of As in drinking water significantly altered components of the innate immune response in mouse lung, which we hypothesize is an important contributor to the increased risk of lung disease in exposed human populations.

Objectives

We investigated the effects of As exposure on respiratory influenza A (H1N1) virus infection, a common and potentially fatal disease.

Methods

In this study, we exposed C57BL/6J mice to 100 ppb As in drinking water for 5 weeks, followed by intranasal inoculation with a sub lethal dose of influenza A/PuertoRico/8/34 (H1N1) virus. Multiple end points were assessed postinfection.

Results

Arsenic was associated with a number of significant changes in response to influenza, including an increase in morbidity and higher pulmonary influenza virus titers on day 7 post-infection. We also found many alterations in the immune response relative to As-unexposed controls, including a decrease in the number of dendritic cells in the mediastinal lymph nodes early in the course of infection.

Conclusions

Our data indicate that chronic As exposure significantly compromises the immune response to infection. Alterations in response to repeated lung infection may also contribute to other chronic illnesses, such as bronchiectasis, which is elevated by As exposure in epidemiology studies.     

Sharing Unexpected Biomarker Results with Study Participants

Background

The Breast Cancer and the Environment Research Centers (BCERCs) include collaborators from basic sciences, epidemiology, and the community, conducting studies to investigate whether environmental exposures are associated with the timing of puberty. A pilot study of a subset of the study participants assessed the feasibility of measuring selected biomarkers of exposure in blood and urine in girls 6–8 years of age. In the Greater Cincinnati study population, we found an elevated serum concentration of perfluorooctanoate (PFOA) among > 90% of young girls living in a small community.

Objectives

The research team deliberated whether and how to report the PFOA findings to our study families. We will address the issues considered in our decision, as well as the formats we used to present the findings.

Methods

The results were verified as we searched for potential sources of the elevated PFOA levels. As a research team, we grappled with issues regarding the reporting of unexpected results, derived from unknown sources and with unknown clinical significance. Ultimately, we did decide to present these findings to the study families through a well-developed communication plan.

Discussion

Research team members came from a variety of experiences and backgrounds, which led to different interpretations about the clinical, ethical, and public health issues surrounding these findings. The ethical debates centered around the precautionary principle, the right to know, and do no harm.

Conclusions

Given advances in environmental biomarker technologies and greater use of the transdisciplinary research model, a communication plan must be developed for those involved as study participants.     

Cancer risks near nuclear facilities: the importance of research design and explicit study hypotheses

Background

In April 2010, the U.S. Nuclear Regulatory Commission asked the National Academy of Sciences to update a 1990 study of cancer risks near nuclear facilities. Prior research on this topic has suffered from problems in hypothesis formulation and research design.

Objectives

We review epidemiologic principles used in studies of generic exposure–response associations and in studies of specific sources of exposure. We then describe logical problems with assumptions, formation of testable hypotheses, and interpretation of evidence in previous research on cancer risks near nuclear facilities.

Discussion

Advancement of knowledge about cancer risks near nuclear facilities depends on testing specific hypotheses grounded in physical and biological mechanisms of exposure and susceptibility while considering sample size and ability to adequately quantify exposure, ascertain cancer cases, and evaluate plausible confounders.

Conclusions

Next steps in advancing knowledge about cancer risks near nuclear facilities require studies of childhood cancer incidence, focus on in utero and early childhood exposures, use of specific geographic information, and consideration of pathways for transport and uptake of radionuclides. Studies of cancer mortality among adults, cancers with long latencies, large geographic zones, and populations that reside at large distances from nuclear facilities are better suited for public relations than for scientific purposes.     

Disruption of MicroRNA Expression in Human Airway Cells by Diesel Exhaust Particles Is Linked to Tumorigenesis-Associated Pathways

Background

Particulate matter (PM) is associated with adverse airway health effects; however, the underlying mechanism in disease initiation is still largely unknown. Recently, microRNAs (miRNAs; small noncoding RNAs) have been suggested to be important in maintaining the lung in a disease-free state through regulation of gene expression. Although many studies have shown aberrant miRNA expression patterns in diseased versus healthy tissue, little is known regarding whether environmental agents can induce such changes.

Objectives

We used diesel exhaust particles (DEP), the largest source of emitted airborne PM, to investigate pollutant-induced changes in miRNA expression in airway epithelial cells. We hypothesized that DEP exposure can lead to disruption of normal miRNA expression patterns, representing a plausible novel mechanism through which DEP can mediate disease initiation.

Methods

Human bronchial epithelial cells were grown at air–liquid interface until they reached mucociliary differentiation. After treating the cells with 10 μg/cm² DEP for 24 hr, we analyzed total RNA for miRNA expression using microarray profile analysis and quantitative real-time polymerase chain reaction.

Results

DEP exposure changed the miRNA expression profile in human airway epithelial cells. Specifically, 197 of 313 detectable miRNAs (62.9%) were either up-regulated or down-regulated by 1.5-fold. Molecular network analysis of putative targets of the 12 most altered miRNAs indicated that DEP exposure is associated with inflammatory responses pathways and a strong tumorigenic disease signature.

Conclusions

Alteration of miRNA expression profiles by environmental pollutants such as DEP can modify cellular processes by regulation of gene expression, which may lead to disease pathogenesis.     

The Dichloroacetate Dilemma: Environmental Hazard versus Therapeutic Goldmine—Both or Neither?

Background

Dichloroacetate (DCA) is known to environmental scientists as a by-product of water chlorination and as a metabolite of industrial solvents, including Superfund chemicals. In contrast, DCA is studied by clinical investigators for its therapeutic potential in several life-threatening conditions, including genetic mitochondrial diseases, pulmonary arterial hypertension, and cancer. Thus, DCA holds an almost unique position at the interface between environmental science and allopathic medicine.

Objective

I critically reviewed laboratory and clinical pharmacological research on DCA to address questions about the current and future status of DCA in relation to human health.

Discussion

Recent information on the clinical toxicogenetics of DCA is interpreted particularly in light of its use as an investigational drug. Adverse effects from chronic DCA exposure have been identified in several target organs in animals. However, in humans, toxicity has so far been limited to reversible effects on the nervous system and liver. DCA is primarily biotransformed to glyoxylate by the bifunctional enzyme glutathione transferase zeta1 and maleylacetoacetate isomerase (GSTz1/MAAI), which also catalyzes the penultimate step in the phenylalanine and tyrosine catabolic pathway. DCA is a suicide inhibitor of GSTz1/MAAI, which can result in delayed plasma clearance of DCA and the accumulation of potentially toxic tyrosine intermediates. Age and GSTz1/MAAI haplotype can markedly affect the toxicokinetics of DCA in humans and rodents.

Conclusions

I have defined new potential avenues of research that focus on discrete human populations that may be at increased health risk or that may receive increased health benefit from chronic exposure to DCA at both environmentally and clinically relevant concentrations.