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Environmental Chemical Assessment in Clinical Practice: Unveiling the Elephant in the Room

School of Health Sciences, RMIT University, Bundoora, Victoria 3083, Australia
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Environ. Res. Public Health 2016, 13(2), 181;
Submission received: 11 December 2015 / Revised: 19 January 2016 / Accepted: 27 January 2016 / Published: 2 February 2016


A growing body of evidence suggests chemicals present in air, water, soil, food, building materials and household products are toxicants that contribute to the many chronic diseases typically seen in routine medical practice. Yet, despite calls from numerous organisations to provide clinicians with more training and awareness in environmental health, there are multiple barriers to the clinical assessment of toxic environmental exposures. Recent developments in the fields of systems biology, innovative breakthroughs in biomedical research encompassing the “-omics” fields, and advances in mobile sensing, peer-to-peer networks and big data, provide tools that future clinicians can use to assess environmental chemical exposures in their patients. There is also a need for concerted action at all levels, including actions by individual patients, clinicians, medical educators, regulators, government and non-government organisations, corporations and the wider civil society, to understand the “exposome” and minimise the extent of toxic exposures on current and future generations. Clinical environmental chemical risk assessment may provide a bridge between multiple disciplines that uses new technologies to herald in a new era in personalised medicine that unites clinicians, patients and civil society in the quest to understand and master the links between the environment and human health.

1. Introduction

Human exposure to environmental chemicals has increased exponentially over the past decades and a growing body of evidence suggests that chemicals present in air, water, soil, food, building materials and household products are toxicants that contribute to many of the chronic diseases typically seen in clinical practice. Yet, despite the call from numerous organisations for regulatory reform and an increase in training on environmental health for clinicians, environmental chemical assessment is generally overlooked in clinical practice and environmental chemicals can be considered as an elephant in the room that is largely ignored.
The failure of genome-wide association studies to explain the vast majority of chronic diseases now afflicting 50% of people of working age [1], together with emerging research exploring aberrations in the epigenome and “exposome” (the total exposures seen during the organism’s life) in the aetiology of chronic disease [2], has led to a paradigm shift in our understanding of chronic “non-communicable” disease [3]. Furthermore, the “epidemiological transition” from infectious diseases in developing countries to chronic diseases in developed countries, has led to a fundamental reconsideration of the health impact of environmental exposures [4].
Innovative breakthroughs in biomedical research and technology encompassing the emerging “-omics” fields (epigenomics, nutrigenomics, metabolomics, toxicogenomics), and advances in the field of classical toxicology, have further contributed to a new understanding of the relationship between chronic diseases and exposures to environmental chemicals across the lifespan. This new understanding validates what Hippocrates stated centuries ago; that one’s diet, lifestyle and environment, has profound consequences on health and wellbeing [5], and has wide reaching ramifications for the practice of medicine that provides clinicians with unique and important roles to play in identifying and preventing environmental chemical exposures.

2. The Rise of Chemical Production and Exposures

The number of chemicals in the world is essentially unknown, yet the world’s largest database on chemical information—the Chemical Abstracts Service (CAS) RegistrySM established in 1907, currently contains more than 100 million chemicals [6] with around 200,000 new chemicals being added each week [7]. While many of these chemicals are produced by natural processes, or are inadvertently produced as by-products of fossil fuel combustion or other industrial processes [8], the number of chemicals commercially produced has increased exponentially in parallel with increasing industrialization. Commercial chemical production has risen from 1 million tons in 1930 to 400 million tons in 2001 [9], and over the past few decades the global sale of chemicals has increased by a factor of 25 from U.S. $171 billion in 1970 to US$4.1 trillion in 2012 [10]. As of 2012, the number of industrial chemicals on the global market was estimated to be around 143,835 [10].
A number of large population biomonitoring studies have revealed widespread chemical exposures from the “womb to the tomb” with levels in humans and wildlife that are known to cause adverse health effects. Such studies include the National Health and Nutrition Examination Survey in the USA [11], DEMOCOPHES survey in Europe [12], German Environmental Surveys in Germany [13], Flemish Environment and Health Study in Belgium [14], Esteban cross sectional survey in France [15], Russian Federation [16] and the BIOAMBIENT ES in Spain [17] in addition to national birth cohort studies conducted in Denmark (Danish National Birth Cohort) [18], France (French Longitudinal Study of Children Survey) [19], Norway (Norwegian Mother and Child Cohort Study [20], and Spain (The Spanish Environment and Childhood Research Network) [21]. There are also ongoing epidemiological studies such as the Cross-Mediterranean Environment and Health Network project, which aim to demonstrate an integrated methodology for the interpretation of human biomonitoring data that will allow researchers to quantitatively assess the impact of chemical exposures on human health [16]. Despite these efforts, human toxicity data is lacking for most chemicals in widespread use, even when population-wide exposures are documented [22].
Disturbingly, many environmental chemicals are found in human breast milk and the placenta where they directly affect the foetus [23]. A landmark study conducted by the Environmental Working Group identified 287 chemicals in cord blood, raising the profile of the widespread exposures to everyday chemicals [24]. More recently, the Canadian “pre-polluted study” identified 137 chemicals in cord blood, 132 of which are reported to cause cancer and 133 that cause developmental and reproductive problems in mammals [25]. The brain of a foetus and infant is particularly vulnerable as the central nervous system is the dominant repository of foetal fat and many environmental toxicants are lipophilic. Consequently the health impact of chemical exposures is most evident in paediatric medicine where chronic disease has overtaken infectious diseases as the major burden of paediatric illness [26]. The obvious and extensive impact of environmental chemicals on children’s health, has contributed to paediatrics being the first medical discipline to identify chemical exposures as an important health issue, with the American Academy of Paediatrics establishing an environmental health committee in 1958 and publishing its first edition of Paediatric Environmental Health for clinicians in 1999 [27].
While chemical exposure is ubiquitous in the general population, the Environmental Justice Hypothesis suggests that exposures are unevenly distributed. This hypothesis, which emerged in the 1980s following the publication of several studies in the USA [28,29,30,31,32] suggests that environmental hazards are inequitably distributed according to class and race [33]. Yet, the strict bifurcation of communities into categories of Environmental Justice and Non-Environmental Justice is problematic [34], because much of the literature is based on comparisons of exposure and risk between different populations, rather than on the toxicological and biological impacts of those exposures [35]. Furthermore, while some minority groups and those with lower socioeconomic (SES) status are likely to bear a greater burden of environmental toxicants given their lifestyle, proximity to waste sites, industrial emissions and poorer quality ambient air, biomonitoring studies have identified toxicants in all individuals, the type and amount of which varies depending upon lifestyle factors and geographical variation. For example higher SES individuals have been found to have higher burdens of mercury, arsenic, caesium, thallium, perfluorinated compounds, certain types of phthalates and benzophenone-3 as a result of their lifestyle (fish consumption, dental history, homegrown vegies, cosmetic and sunscreen use) [36]. In contrast, lower SES individuals have been found to have higher levels of lead, cadmium, antimony, bisphenol-A and other types of phthalates, which may be partially mediated by smoking, occupation and diet [36].

3. Environmental Chemicals and the Origins of Chronic and Complex Disease

The dramatic rise in the number of commercially produced chemicals has resulted in exposure to industrial chemicals being ubiquitous in both developed and developing nations and an increasing disease burden that is not yet fully understood. The World Health Organisation estimates that 4.9 million deaths and 86 million Disability Adjusted Life Years were attributed to environmental chemicals in 2011 [10] and that approximately one-quarter of the global disease burden, and more than one-third of the burden among children under the age of 5 is due to modifiable environmental factors [37]. A recent review further estimated that the disease burden in the European Union associated with exposure to endocrine disrupting chemicals alone, cost $209 billion or 1.23% of Europe’s GDP [38].
Many of the chronic diseases that have substantially increased in prevalence over the past 40 years, appear to be related in part to developmental factors associated with nutritional imbalance and exposures to environmental chemicals [39]. For example the “developmental obesogen” hypothesis is used to explain why the prevalence of obesity among school age children between the early 1970s and late 1990s has doubled or trebled [40]. Whilst obesity prevalence has begun to plateau, a growing number of chemical obesogens such as organochlorine pesticides [41,42,43], bisphenol A [44], PCBs and phthalates [45] have been found in-utero and are implicated in the development of obesity later in life [46,47].
The concept of early life origins of disease was first brought to light in 1934 by Kermack and colleagues who suggested that decreased death rates due to all causes were the result of improved childhood living conditions [48]. This was later expanded upon by Neel in 1962 [49], Forsdahl in the 1970s [50,51], and in the late 1980s by David Barker who associated nutritional deficits during fetal development and consequent low birth weight, to increased risks for obesity, diabetes and cardiovascular disease and thereby came to be considered as the father of the “Fetal Origins of Adult Disease” hypothesis [52]. Whilst the Developmental Origins of Health and Disease (DOHaD) has historically focused on nutrition, understanding of the role of early life experience in chronic disease aetiology requires an integrated analysis of all aspects of the environment (nutrition, psychosocial stress, drugs, microbiome and environmental pollutants) and how they interact to cause disease [53]. Thus, the DOHaD has far reaching implications in clinical practice, and implies a need for clinicians to undertake an extensive paediatric, environmental and occupational exposure history and consider the role of nutrition and environmental chemical exposures during critical windows of development to understand the development of chronic illness in later life.
The list of diseases that may be caused or exacerbated by environmental chemical exposures is extensive and growing. These diseases include diabetes [54,55], infertility [56,57,58], testicular dysgenesis syndrome [59,60] which encompasses hypospadias [61,62], cryptorchidism [63,64], testicular cancer [65], and poor semen quality [66,67,68], ovarian dysgenesis syndrome [69], neurodegenerative diseases such as Alzheimer’s Disease [70], respiratory disorders such as asthma [71] and chronic obstructive airway disease [72], as well as autoimmune diseases [8], obesity [73,74,75] and cardiovascular disease [76,77,78]. Emerging evidence is also linking industrial chemicals to a pandemic of neurodevelopmental disorders [79] the implications of which have devastating consequences on family’s and the global economy [80,81]. Whilst the cause of these neurodevelopmental problems is not yet clear, genetic factors are acknowledged as only playing a minor role [82,83] and several hypotheses point to environmental influences involving aberrations in the gastrointestinal microbiota [83], industrial chemicals [81,84,85], malnutrition [86,87], viruses and drugs [88] as potential causal agents.
Environmental factors are also believed to account for a significant portion of cancer mortality worldwide [89]. There is a growing body of evidence associating various toxicants with cancer including: air pollutants like asbestos, radon, hexavalent chromium, tobacco smoke and benzo(a)pyrene with lung cancer [90,91,92,93]; endocrine disrupting chemicals such as pesticides, dioxins, furans and PCBs with an increased risk for breast cancer [94], endometrial, testicular and prostate cancer [95,96,97,98]; arsenic and disinfection by-products with bladder cancer [99,100]; vinyl chloride with liver cancer [101], benzene with leukemia [102]; and pesticides with childhood leukaemia [103,104,105]. Even though the incidence of cancer attributable to environmental chemical exposures has not been definitively established [106,107], the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that between 7% and 19% of all cancers are attributable to toxic environmental exposures [108,109]. According to cancer biologists, this estimate is likely to be a gross underestimation, as many supposedly non-carcinogenic chemicals that are ubiquitous in the environment have been shown to exert low-dose effects that may contribute to carcinogenesis [110,111]. This is of particular concern in light of the fact that cancer has now become the world’s leading cause of mortality [112].
Clinicians are also seeing a rise in the prevalence of patients with a shopping list of ongoing seemingly unrelated persistent complaints, which some have described as a “pandemic of idiopathic multimorbidity” [113]. While multimorbidity is associated with chemical sensitivity, it presents an increasingly common and confusing primary care dilemma often labelled as Chronic Fatigue Syndrome [114,115], Systemic Exertion Intolerance Disease [114], Sensitivity-Related Illness [116], Idiopathic Environmental Intolerances [117], Fibromyalgia [118], Electromagnetic Hypersensitivity [119], Sick Building Syndrome [120] and Multiple Chemical Sensitivity [114]. These conditions are diagnoses based on exclusion rather than any specific aetiology as they have no clear aetiology, pathogenesis, or recognised genetic or metabolic markers that can be observed with standard laboratory testing. Despite the fact that the degree of hypersensitivity often parallels the intensity of the total body burden of bio-accumulated toxicants [121], patients with these conditions are relatively understudied [122] and are frequently considered to have psychogenic illness. Such patients have complex needs, and frequently present with a multitude of health complaints in different organ systems that often require attention from a range of medical specialists [123]. It has been suggested that a common aetiological pathway for a diverse range of idiopathic environmental intolerances may involve environmental chemicals inducing oxidative stress and subsequent mitochondrial dysfunction [124,125], in addition to low-grade systemic inflammation in multiple organ systems [124,126], and polymorphisms in nitric oxide synthase [125], antioxidant and/or detoxification genes [116,124], that result in a “toxicant-induced loss of tolerance” [127,128]. It is further suggested that exposures occurring during critical windows of development play an important role and that early life exposures are significant contributors to chronic diseases throughout the lifespan and across generations [96,129].

4. Chemical Risk and Chemical Risk Assessment

In contrast to the great majority of acute conditions and infectious diseases where cause and effect can easily be established, exposure to low levels of thousands of environmental chemicals over a life span requires a paradigm shift in the way in which causality is established. Chemical risk is based on the type and dose of chemical, combination effects, the timing of exposure, and individual risk factors, yet the existing chemical risk assessment framework only involves hazard identification and exposure assessment [130], where hazard identification assesses the ability of a chemical to cause harm at various dosage levels, and exposure assessment evaluates the dose that might be received at target tissue after contact. Such assessments rely heavily on data extrapolated from human epidemiology, animal testing and cell culture/in vitro laboratory studies [131] that fail to account for multiple routes of exposure, mixture effects, transgenerational epigenetic effects or individual human risk factors such as age, gender, genetics, nutrition, psychosocial determinants and comorbidities [130,132,133,134].

4.1. Dose Response and Low Dose Effects

Dose-response relationships follow the path laid by epidemiologist, Sir Austin Bradford Hill, and form the basis of most contemporary systems for chemical risk assessment and causation analysis [135]. Such assessments involve giving increasing levels of an individual chemical to a group of test animals with the key objective of providing a dose-response assessment that estimates a point of departure (traditionally the no-observed-adverse-effect (NOAEL) level or the lowest-observed-adverse-effect level), which is then used to extrapolate the quantity of substance above which adverse effects can be expected in humans [110]. Endocrine disrupting chemicals pose a particular dilemma for chemical risk assessment as these chemicals can exhibit non-monotonic dose-responses whereby the effect of low doses cannot be predicted by the effects observed at high doses [110,136]. In addition to the complexities involved with endocrine disruption, carcinogenesis is a highly complex process and a growing number of scientists are questioning the use of linear dose-response models for classifying carcinogens, as these models do not account for the complex and permutable pathogenesis of many cancers [137].

4.2. Chemical Mixtures and “Something from Nothing” Effects

The prediction of health risks based on NOAEL not only fails to account for non-monotonic dose-responses, it also fails to reflect real-life exposures which typically involves exposure to multiple chemicals [138]. This may explain why pesticide formulations such as “Roundup” have been shown to be significantly more toxic than their active principle (glyphosate), due to the inclusion of adjuvants that increase their potency yet are not accounted for in safety assessments [139]. Furthermore, the NOAEL approach does not consider “something from nothing” mixture toxicity whereby unpredictable additive, antagonistic or synergistic adverse effects may occur at doses around, or below points of departure [140]. For example, carpenters exposed to formaldehyde, terpenes and dust particles below their point of departure are reported to exhibit dyspnea, nose and throat irritation, chest tightness and productive cough [141] and complaints of headache, skin, eye, nose and throat irritation are reported in painters despite airborne exposure levels being below the known irritation levels for the single chemicals [142]. Similarly, weakly oestrogenic chemicals that are too small to be detected individually can jointly increase the actions of potent, endogenous sex steroids [143] and chemical mixtures can act synergistically to exert pro-carcinogenic and anti-carcinogenic effects that contribute to the accumulation of somatic mutations and instigate the hallmarks of cancer [110,144,145]. Inorganic arsenic is one such example. At high levels in drinking water, arsenic is a well-established human carcinogen associated with bladder, lung and skin cancer [146], however at lower doses, its cancer risk may depend upon other variables such as smoking, and on differences in individual susceptibility, either genetically based or via nutritional status or other conditions [147]. This observation parallels the well-established finding that smokers exposed to asbestos have a significant increase in lung cancer risk compared to non-smokers [148].
One theory of how chemical mixtures may elicit unexplained effects, is based on the observation that mixture effects commonly occur when chemical mixtures contain at least one lipophilic and one hydrophilic chemical [132]. Lipophilic chemicals promote the permeation of hydrophilic chemicals through mucous membranes [132]. This is important because lipophilic barriers in the body (skin and mucous membranes) serve as the body’s primary protection against the absorption of environmental chemicals [149]. The octanol-water partition coefficient, or Kow, which classifies the lipophilic character of a given chemical, is a useful parameter for environmental risk assessment that is used extensively by authorities in the European Union [150]. Most lipophilic toxicants can permeate the body’s membranes, and lipophilic chemicals with a Kow greater than 2, are frequently used by the cosmetic industry as chemical penetration enhancers, as adjuvants in pesticides to increase the solubility of the active principle and by the pharmaceutical industry in drug-delivery systems to enhance transdermal drug delivery [151].
The evaluation of mixture effects is hampered by a lack of knowledge of the molecular pathways involved along with the large numbers of pollutants and their many potential combinations [152]. Lifetime effects of exposure to chemical combinations are also largely unstudied [111], and may only become evident after people have become sick [132]. Thus, until a risk assessment paradigm is designed for mixture effects, traditional risk assessment tools need to be used with caution when evaluating chemical mixtures [153].

4.3. Timing and Transgenerational Epigenetic Effects

Compelling epidemiological, pharmacological and toxicological evidence shows that there are several vulnerable periods of growth and development. During these periods, environmental interactions with the immune system and genome can increase susceptibility to central nervous system and metabolic diseases later in life [154]. Despite the fact that transgenerational effects arising from poor nutrition and chemical exposures in utero are widely reported in the scientific literature [155,156,157,158], the impact of epigenetic factors early in life remains largely unexplored in chemical risk assessment [159]. This is made more poignant by emerging evidence that in utero and early-life exposures may lead to disordered immune responses in adulthood and lead to heritable, epigenetic modifications in the immune responses of subsequent generations [137].
The first association of transgenerational inheritance of disease was documented in the Dutch famine of 1944 to 1945 where nutritional deprivation in utero was associated with increased risks for obesity later in life [160]. Epigenetic inheritance involving environmental chemicals is documented in the daughters of mothers who took the drug diethylstilbestrol (DES) to prevent miscarriages and later went on to have a significantly higher risk of vaginal cancer and other health complaints [161]. Similarly, emerging evidence of transgenerational effects in animal models links autism spectrum disorders to an array of environmental factors such as stress or environmental enrichment, endocrine disruptors such as vinclozolin and BPA, and inadequate nutrition [162].
Whilst the mechanisms by which the effects of exposure are transmitted through the germline to the next generation are still unclear, the most plausible explanation for these associations is the occurrence of epigenetic modifications involving DNA methylation, retained histone modification, tRNA fragments, and non-coding RNAs in somatic and germ cells arising from exposure to various environmental agents during critical windows of development [163]. Genome-wide association studies, in contrast to single nucleotide polymorphisms (SNPs) are likely to provide an important tool to identify the “susceptible biomarkers” to environmental chemicals [100]. The study of gene-environment interactions however, poses special challenges for clinicians because it requires the integration of complex information derived from a comprehensive exposure history, assessment of nutritional status and detoxifications pathways, and genetic profile.

4.4. Individual Factors

There are many individual factors that determine chemical exposure and risk of adverse health outcomes. They include; age, gender, ethnicity, genetics, nutritional status, intestinal microbiota and other lifestyle factors such as diet, smoking, exercise and hobbies, psychosocial determinants and comorbidities [130,132,133,134], the co- or pre-administration of other drugs, [132,164] and epigenetic states [165]. Exposure to toxicants also varies widely amongst individuals depending upon: past and current environmental exposures; occupation and health and safety practices; place of residence, work and/or school (proximity to vehicle exhaust, industry, mining, waste sites, industrial accidents, golf courses, parks, farms, flight paths, etc.) which is likely to be influenced in part by socioeconomic factors [36]; use of household products, chemicals and pesticides and appropriate use of safety equipment; and access to clean air, water, food and soil.

4.5. New Horizons in Chemical Risk Assessment

Advances in the “omics” fields such as genomics, proteomics and metabolomics, enable the screening of effects of chemical mixtures at the molecular level and the development of more sensitive and specific methodologies for biological monitoring of combined exposures [138,166]. High-resolution metabolomics (HRM) that uses ultra-high resolution mass spectrometry with minimal sample preparation can support high-throughput relative quantification of thousands of environmental, dietary and microbial chemicals and measure metabolites in most endogenous metabolic pathways, thereby providing simultaneous measurement of environmental exposures and their biologic responses [167]. Renewed interest in the placenta as a potential biomarker of exposure and its contributions to long-term human health and disease was recently initiated by the National Institutes of Health: Human Placental Project following evidence of its impact on the health of the mother [168,169] and fetus [170,171,172,173]. Prospective follow-up birth cohorts to examine the effects of early life programming will also be important [163]. Emerging technologies are also providing a mechanism to assess the allostatic load at the clinical level. For example, biomolecular adducts formed when a xenobiotic or its metabolite binds to biological molecules (DNA or proteins), are a useful tool to assess exposures to non-persistent chemicals in blood such as organophosphates and aromatic amines before clinical consequences appear [174].
Chemical risk assessment can be vastly improved by gaining better information about the totality of exposures across the life span (exposome) [175]. Prospective, population-based cohort studies have recently started to implement these methods using the exposome framework [166]. Consequently environmental health scientists are exploring new ways to strengthen the integrity of chemical risk assessment using the principles of systematic review [176,177] and some new initiatives are contributing to the refinement and codification of methodological approaches for systematic review and meta-analysis tailored to the specificities of environmental health [178]. To date there have been several attempts at establishing systematic reviews for evaluating data on chemical toxicity [179] including The Navigation Guide [176], the Evidence-Based Toxicology Collaboration [180], the PROMETHEUS project by the European Food Safety Authority [181], Integrated Risk Information System (IRIS) and Tox21 by the joint US EPA, Food and Drug Administration and National Institute of Environmental Health Sciences [182,183], ToxRTool by the European Commission [184], REACH by the European Chemicals Agency and KIimisch Ring Test [185].
Further developments to improve toxicity testing based on animals include a new design from the National Research Council for cellular-response networks that take into consideration advances in toxicogenomics, bioinformatics, systems biology, epigenetics, and computational toxicology thereby allowing scientists to uncover how environmental chemicals may lead to toxicity [134]. Emerging tools like the maximum cumulative ratio will further help to identify a person’s cumulative exposure to multiple chemicals over a lifetime [186].

5. The Challenges and Failure of Chemical Regulation

Once an industrial chemical has been tested and its point of departure has been established, it is up to government organisations such as the Environmental Protection Agency, US National Institute for Occupational Safety and Health, Safe Work Australia, European Commission’s Scientific Committee on Occupational Exposure Limit Values and non-governmental organisations like the American Conference of Governmental Industrial Hygienists (whose guidelines have been widely adopted in English speaking countries) to develop ambient air and occupational exposure limits. This process is frequently conducted in consultation with industry, involving scientists employed by various corporations, taking into account what is easily achievable in the workplace [187,188], along with a consideration of economic output and future innovations.
Legislation and the threat of litigation is a powerful motivating force that encourages employers and manufacturers of industrial chemicals to comply with their occupational health and safety requirements. Yet, exposure standards frequently differ from country to country depending upon the approach adopted. In the USA, the “low dose linear extrapolation” approach is favoured and legislated through the Toxic Substance Control Act (TSCA), as opposed to the “margin of exposure” approach used in Europe and regulated through REACH (Registration Evaluation, Authorisation and Restriction of Chemicals) [189]. The stark difference between the two is that REACH is a preventative approach that places the burden of proof on industry to show safety, as opposed to TSCA where the burden of proof is on the government to show harm [130]. As both of these systems primarily focus on industrial chemicals, numerous regulatory authorities have been established to regulate chemicals in food, cosmetics, pesticides and medicinal products. The chemical industry has exploited the inadequacies of weak laws and regulations, inefficient enforcement, regulatory complexity and fragmented overlapping authorities, to enable the introduction of untested chemicals into the commercial products and the environment [111,190]. Furthermore, non-occupational exposure standards for indoor air quality in residential environments are lacking, despite organisations such as the World Health Organisation [191] and the US Environmental Protection Agency [192] producing numerous reports and guidelines on indoor air quality.
The wide variation in exposure standards across jurisdictions along with vast numbers of commercial chemicals in widespread use that have not been adequately assessed for neurodevelopmental toxicity, endocrine disruption or other toxic effects, points to inadequacies in current chemical risk assessment procedures. Such inadequacies were highlighted as early as the 1970s by Bruce Ames who subsequently developed the Ames test for assessing the mutagenic potential of chemical compounds [193]. More recently, existing chemical risk assessment practices have come under scrutiny from various governmental and non-governmental bodies including the US Environmental Protection Agency [194], National Resource Defence Council [190], European Union (who responded by developing REACH), the National Academy of Sciences and the Institute of Medicine [130] and medical organisations such as the American Medical Association [195] and the American Academy of Paediatrics [196].
The availability of scientific information is fundamental to the ability to understand and manage risk and form the basis for regulatory action. However, while compelling epidemiological, animal and in vitro evidence is required to prove harm from a chemical exposure [111], there is a lack of well-accepted tools to objectively, efficiently and systematically assess the quality of published toxicological studies [197] making it difficult to assess health risks associated with low level exposure to hundreds of chemicals over a life time. Thus, for almost every conclusion about chemical-related health risks, it is possible to find a dissenting view [179] and the vast majority of scientific reviews conclude that “more research is needed”.

6. What Are the Barriers for Chemical Assessment in Clinical Practice?

While chemical risk assessment requires the application of multiple scientific fields to public health and regulatory issues, it is up to individual clinicians to determine the relevance of the many issues involved to the current and future health needs of their individual patients. Environmental chemical assessment in clinical practice therefore requires the personalization of medicine using the translation of a complex knowledge base to determine an individual’s body burden of toxicants, along with their personal risk factors and health status. Yet, despite the many scientific developments occurring in the area of chemical risk assessment, the discrepancies amongst leading authorities in their interpretation for evidence of harm makes it difficult for clinicians to translate scientific information into clinical practice. Furthermore, while clinicians must deal with the consequences of environmental chemical exposures and remain one of the most often accessed and most trusted sources of information about the health and the environment [198], there is widespread agreement that clinicians lack adequate information and training with respect to environmental risks and health [199,200].

6.1. What is Environmental Medicine?

A lack of clinical training in environmental medicine may be partly due to inconsistencies in defining “environmental medicine” and the confusion as to where it fits in relation to other specialties such as public health and occupational medicine. In the mainstream scientific literature, environmental medicine is defined as the evaluation, management, and study of detectable human disease or adverse health outcomes from exposure to external physical, chemical, and biologic factors in the general environment [199,201]. This is in contrast to occupational clinicians whose definition of environmental medicine varies depending upon the country and include: “exposures arising from industrial activities at a workplace” (Australia), “embracing any influences on health and disease that are not genetic” (UK), or as “a branch of medical science which addresses the impact of chemical or physical stressors on the individual or group in a community” (USA) [202]. To add to the confusion, public health clinicians define environmental medicine more broadly as “issues in the physical environment which impact on health, encompassing quality of air, water and food” [202]. Consequently environmental medicine has become a specialty field under the guise of “occupational and/or environmental medicine” and “public health” with the majority of “environmental physicians” focusing on public health issues rather than patient-centered clinical practice [203]. Wide inconsistencies in the definition for the term “environment”, has further ramifications for establishing environmentally attributable risk estimates. For example researchers and publications that define the environment in the narrow sense (air, water, food, and soil pollutants) tend to have smaller attributable risk estimates, whereas researchers and publications that refer to the environment in the broadest sense (including lifestyle factors, occupational exposures, and pollutants) have consistently larger risk estimates [106].
Relegating environmental health to a specialty field is highly problematic when environmental chemical exposures are implicated in many of the conditions seen by clinicians on a daily basis, yet the tools and expertise to adequately assess or manage these exposures are not widely available [200]. Furthermore, few doctors take adequate occupational or exposure histories [204] or refer patients to environmental physicians [123] and therefore environmental exposures are seldom identified in disease causation [111]. Consequently the cadre of environmental oncologists, researchers and clinicians trained in environmental health are relatively small, which may explain why environmental health is largely excluded from national policy [111].

6.2. Medical Training

There is a widely acknowledged need for greater awareness about chemical assessment amongst clinicians. The need for general clinicians to familiarise themselves with the health impacts of environmental chemical exposures was highlighted in 1967 at a conference by the American Medical Association’s National Congress on Environmental Health Management, and was further highlighted by the American College of Clinicians [205,206] as well as being a focus of the International Federation of Environmental Health in 1991 [207] and 2013 [208]. Despite the recognized need for clinical education on environmental chemicals, there appears to be a severe lack of environmental health education in medical undergraduate curricula. The Institute of Medicine has been particularly vocal about the lack of environmental health training as evidenced by the publication of the book “Role of the Primary Care Physician in Occupational and Environmental Medicine” [200], and the report “Environmental Medicine—Integrating a Missing Element into Medical Education” [199], which outlined a six competency-based learning objectives for medical students. This is further reinforced by the World Health Organisation’s report “Environmental Health and the Role of Medical Professionals” [209], which highlights the medical professionals role in assessing, investigating, diagnosing, monitoring, treating and preventing environmentally-related disorders.
The lack of environmental education for clinicians can be seen to be due to competition from other disciplines in crowded medical curricula, lack of funding and a lack of appropriately trained academics [210]. A significant proportion of undergraduate medical training is devoted to pharmacology as opposed to toxicology [211] or environmental health, with the exception of medical toxicology, a specialty field involving acute high dose exposures confined to emergency clinicians [212]. Furthermore, nutrition is rarely taught in undergraduate medical training despite the fact that the nutritional state of the person affects the impact and metabolism of toxicants in key Phase 1 and 2 metabolic detoxification pathways [132]. Not surprisingly, a recent survey of medical school graduates found that more than one-third of respondents said they received “inadequate” instruction in environmental health [213].
Both the World Health Organisation [214] and the American Academy of Paediatrics [27] acknowledge the lack of training in medical schools, and recommend that children’s environmental health be incorporated into the training for health care providers. Others have noted that obstetricians and gynaecologists are well positioned to prevent hazardous exposures in light of the irreversible impacts on health arising from chemical exposures in utero [215]. Aside from nutrition, smoking and drinking during pregnancy, obstetrics-gynecology education has been largely void of environmental health [216]. A recent report by the International Federation of Gynecology and Obstetrics recommended that reproductive and other health professionals advocate for policies to prevent exposure to toxic environmental chemicals, work to ensure a healthy food system for all, make environmental health part of health care, and champion environmental justice [85]. Calls to action are starting to be heard with the Association of American Medical Colleges recent webinar on “Teaching Population Health: Innovative Medical School Curricula on Environmental Health” [217] outlining the need to educate undergraduate medical students in environmental health which included links to the American College of Medical Toxicology’s Environmental Medicine Modules [218].

6.3. Environmental Health Data and Its Relevance to Clinical Practice

The sheer number of scientific journals, non-governmental organisations, associations, professional societies, environmental medicine practitioner organisations and governmental agencies dedicated to environmental health is enough to leave clinicians overwhelmed and despondent in ever gaining a grasp of this complex and ever growing field. The number of journals dedicated to public, environmental and occupational health under the category “Clinical Medicine” in the Web of Science database grew from 101 in 2005 to 142 in 2010 yet very little of the vast amount of literature on environmental health is actually published in general medical journals. This is likely to be due to a variety of factors. Firstly, evidence about environmental exposures based on animal studies in the absence of human experimental data is considered “weak evidence” by the medical fraternity and outside the comfort zone and time constraints of most clinicians [219]. In addition, whilst epidemiological studies are important tools for determining risk, they can be limited by often failing to take into account the role of individual differences reflected in subpopulations [220]. For much of the history of clinical trials, the treatments under investigation were assumed to apply to anyone with the relevant clinically defined condition [221]. However the emerging “omics” fields and molecular cancer epidemiology, has led to the recognition that clinical trials need to be redesigned to account for individual variations (N = 1) arising from one’s genomic profile, lifestyle and environmental exposures.
How do we accommodate evidence in the context of individual patients? As it is not viable to devote resources to generate randomised clinical data on patients whose variants are so unique that they represent a small minority of the community, a shift is needed in the way we think about evidence-based medicine. Despite rapid advances in technology and the volume of literature published about the adverse health effects arising from exposure to environmental chemicals, health care systems have fallen far short in their ability to translate knowledge into practice and to apply new technology safely and appropriately [222].

7. How Can Clinicians Assess Environmental Chemical Exposures?

Whilst biomonitoring is an established approach to evaluate the internal body burden of environmental exposures, the use of biomonitoring for exposome research is limited by the high costs associated with quantification of individual chemicals [167]. Interpretation of the presence of chemicals in human tissues has also been the subject of much controversy, as its presence cannot be taken to imply that there will be adverse functional consequences [123,223]. For example blood and urine samples generally only reflect recent exposures to toxicants (heavy metals, persistent organic chemicals, organophosphate (OPs) and carbamate pesticides); hair and nails reflect past exposures (pesticides, heavy metals, polychlorinated biphenyls and polyaromatic hydrocarbons), are easily contaminated and difficult to collect in a standardized way; and many other biological matrices such as human milk, saliva, adipose tissue and meconium lack reliable reference values for human populations [138].
Resources and tools to educate clinicians and elicit personal environmental health data in the clinical setting are limited in scope and applicability. For example, the Australian NHMRC 2011 Standard for Clinical Practice Guidelines portal does not provide any guidelines on how to assess environmental chemical exposures, despite the fact there are extensive guidelines for conditions like diabetes, which are known to be influenced by chemical exposures. The lack of guidelines is compounded by a lack of conventional pathology tests to assess environmental chemical exposures. In addition, the knowledge required to understand what, how and when to assess environmental chemical exposures requires extensive knowledge on individual toxicants, their metabolites and/or the product of toxicant interactions with endogenous targets [174], which is not generally considered within the realm of most clinicians.
Tools that are available such as the EPA’s Office of Pesticide Protection questionnaire, the CDC’s Agency for Toxic Substance and Disease Registry “Taking an Exposure History Guide”, The Navigation Guide, Eco-Health Footprint Guide (Global Health and Safety Initiative), Quick Environmental Exposure and Sensitivity Inventory (QEESI), WHO Paediatric Environmental History to name but a few, are unlikely to be known by most general clinicians, and have either not been validated and/or require lengthy periods of time to complete, which may not always be practical in a clinical setting. Consequently clinicians and those specialising in idiopathic multimorbidity, are likely to have developed their own assessment procedures to assess their patient’s susceptibility or exposure to environmental toxicants. Such procedures may include extensive historical inquiries (paediatric, occupational and environmental exposure histories) along with an assessment of their patients’ metabolic, nutritional, genetic, and exposure profiles and include unconventional tests performed at pathology laboratories from around the globe such as Acumen Labs, Nutripath, Doctors Data, Genova Diagnostics, Healthscope Functional Pathology, Mycometrics, US Biotek Laboratories, Great Plains Laboratory and AsureQuality Labs, amongst others. Such assessments may come at considerable expense to their patients and as exposure standards are not available for many biomarkers, these clinicians must interpret the data without the benefit of published normal ranges or specific diagnostic criteria.
To assess environmental chemical exposures in patients, the challenge for clinicians is to ask relevant questions to elicit toxicant sources and exposure, identify the most relevant tests and to digest data from multiple streams (traditional medical data, “omics” data and quantified self-data), and place this information in the context of individual patients in a way that has measurable and meaningful outcomes. Only by doing so, can medicine shift the focus from treating disease, to prevention and wellness.

7.1. Lessons in History—Asking the Right Questions

The history of medical care is littered with examples of missed opportunities, wasted resources and counter-productive policies, due to the inability to effectively assemble and act on available evidence on toxicant exposure [179]. Environmental tobacco smoke, asbestos, lead dust, benzene, polychlorinated biphenyls, chlorofluorocarbons, lead and organochlorine pesticides are just some examples where warnings were ignored decades prior to the emergence of devastating public health issues [224]. History also provides examples of doctors whose observations at the clinical level, in addition to the power of rapid action, resulted in significant improvements in public health. For example, in the 18th century, British surgeon, Sir Percivall Pott, without knowing the cause or mechanism of action, stopped an epidemic of scrotal cancer in chimney sweeps by asking them to improve their genital hygiene [225]. Furthermore, in 1854, Dr. John Snow who is credited as the first epidemiologist, was able to prevent an outbreak of cholera by dismantling a water pump handle in Broad St, London, despite great criticism from his peers [226].

7.2. The “Omics” Revolution and Personalised Medicine: A Match Made in Heaven

Following completion of the Human Genome Project in 2003 in conjunction with the rapid advances in bioinformatics, the “omics” fields exploded onto the scene, challenging our understanding of the nature and cause of disease, whilst also shifting the focus to what it means to be well. Clinical genetic testing has transformed from being centred on mutation detection for Mendelian disorders like sickle cell disease to personal genomic data as a way to predict ancestry and assess disease risk. The emergence of hand-held devices such as the “SNIP doctor” for analysing single nucleotide polymorphisms, has bridged the gap from the bench to the bedside [227]. Whilst the brunt of these discoveries has yet to infiltrate clinical practice (because it takes an average of 17 years to incorporate scientific discovery into clinical practice [222]), the ramifications of these findings will provide more precise treatment for individuals and issue a new era in personalised medicine.
Breast cancer risk provides a good example. Whilst the aetiology of breast cancer is still not fully understood, there are several known risk factors including: the age of menarche/parity/menopause; family history of breast cancer; length of time of breast feeding; body mass index; drugs (hormone replacement therapy, oral contraceptive pill); exercise; alcohol intake; and cigarette smoking [228,229]. Given that the prevalence of gene mutations (BRCA1, BRCA2) for women diagnosed with breast cancer are low (5.3% and 3.6% respectively) [230], it has been suggested that low-penetrance susceptibility genes combined with environmental factors may be important risk factors [231]. Advances in genomics have identified several gene variants (single nucleotide polymorphisms (SNPs)) in key detoxification pathways that maybe associated with breast cancer susceptibility [232,233,234,235,236]. However few of these variants (COMT, CYP1B1, GSTP1, MnSOD, MTHFR) have been shown to contribute to breast cancer risk individually except when these polymorphisms are combined [237], or in the presence of relevant environmental chemical and lifestyle exposures [238,239]. This is significant in light of the fact that unique populations of various ethnicity have been shown to have polymorphic variants in detoxification enzymes, which may predispose them to increased adverse health effects from environmental chemical exposures [240,241]. For example, despite the low incidence of breast cancer amongst Asian women [242], a recent meta-analysis to determine the role of MTHFR C677T polymorphism in breast cancer risk, showed a strong significant association between TT genotype and breast cancer which is far more prevalent in the Asian population compared with the Caucasian population [235]. This may explain why US-born Asian women have an almost two fold higher incidence of invasive breast cancer than foreign-born Asian women [243], implying that epigenetic effects involving lifestyle, dietary, and/or environmental factors are likely to play a role. The results of these findings, may explain why so many risk factors have been implicated in breast cancer and other chronic diseases, and yet a causal relationship has not been definitively established.
As stated by Dr. Francis Collins, Director of the US National Institutes of Health “genetics loads the gun and the environment pulls the trigger”. Thus establishing an individual’s risk to environmental chemicals based on the presence of low penetrance genes (SNPs) alone is limited unless it is combined with the potential epigenetic effects of pathological, developmental, dietary and environmental chemical exposure history across the lifespan [244]. The concept that the phenotype is the consequence of gene-environment interaction was highlighted by Archibald Garrod in 1902 who suggested that individual differences in genetics could play a role in variation in response to drugs, and that this effect could be further modified by the diet [245]. However, while genetic testing is providing greater understanding of disease risk, the application of gene testing at the clinical level is fraught with challenges.
Very few of the one million plus SNPs identified in genome wide association studies have clear functional implications and actionable outcomes that are relevant to mechanisms of disease [246], which is why clinicians perceive the analysis of genetic data as requiring considerably more time and work with uncertain outcomes [247]. Secondly clinical guidelines for genomic testing is still in its infancy, such that there is a poor understanding of the effect of individual alleles, many of which appear to be non-sense mutations but may at a later date prove to be of clinical relevance especially in the context of other alleles, epialleles and environmental exposures [248]. Furthermore, the accuracy of laboratory analysis of genetic information and interpretation of results may vary amongst direct-to-consumer genetic testing companies depending upon their quality control standards [249]. Despite the remarkable advances in biomedical research and in particular, the field of genomics in the past twenty years, concerns have been raised about the lack of knowledge and skills in genetic and genomic testing, interpretation of test results, communication of results to patients and families, and basic genetic counseling amongst general non-academic clinicians [250,251]. Finally and perhaps most importantly, clinical genomics requires an understanding of the ethical, legal and social considerations associated with genomic profiling including employment and health insurance nondiscrimination, patient’s rights, informed consent, disclosure, microarray screening for pregnancy, cost/benefit ratio, drawbacks versus perceived benefits, genetic counselling, protection of privacy and data protection [252,253,254]. Clinicians will therefore need educational programs that target relevant scientific, clinical, ethical, legal, and social topics and support systems that address structural and systemic barriers to the integration of genetic medicine into clinical practice [251].

7.3. Citizen Science and Mobile Technologies

It is clear that the impact of environmental chemical exposures is an issue that requires action at many levels and must ultimately include the general community. Thus, civil society, including non-government organisations and civilian advocates can play a vital role in shedding light on the nature and extent of chemical exposures and their impacts. As such, citizen science or “participatory urbanism” is an emerging field that shows great promise in the scope of environmental awareness and regulation [255]. This became evident as early as the 1960s when a citizen science project revealed widespread contamination from radioactive fallout from atomic weapon testing through the analysis of strontium 90 in baby teeth collected from around the world, leading to the signing of the Partial Nuclear Test Ban Treaty in 1963 [256].
The potential for participatory citizen science has expanded enormously since the 1960s. Consumer’s appetite for health information is evident by the 40,000+ smartphone health applications now available [257] and the fact that almost 60% of mobile phone users have downloaded a health app [258]. Furthermore, genomic profiling is now available for as little as $99 from companies like 23andMe who have databases in excess of one million clients. With more tools at their disposal, web applications have enabled citizens to take a proactive approach to make informed health-care decisions. No longer passive recipients of health care, these “e-patients” have given birth to the quantified self-movement, and irrevocably changed the traditional doctor-patient relationship making way for the participatory medical model. Furthermore, the advent of the internet along with rapid advances in mobile computing, wearable devices, nano-biosensors, lab on a chip technology, geographical information systems, the quantified-self movement, the internet of things, big data analytics and cloud computing, represent disruptive innovations that promise to create a fundamental shift in biological discovery. Such advances, which enable the real-time measurement of physiological and psychological states along with environmental measures, offer the ability to better predict, detect and prevent disease brought on by chemical exposures and thus radically accelerate our understanding of the health impact of environmental chemical exposures [259].
Widespread adoption of information technology applications requires behavioral adaptations on the part of clinicians, organizations, and patients [222] and the ability of technology designers to build better tools and platforms that allow patients to share data with their doctors in order to augment existing medical knowledge and practices [247]. Whilst citizen science has the potential to build important bridges between scientists, clinicians and the public with positive outcomes for all [260], clinicians need to be receptive to the shift in the availability of knowledge to the public and be capable of answering questions that might arise so they can direct patients to credible and reliable resources when appropriate [261]. Engaging volunteers in rigorous science, global-scale citizen science projects also provide an excellent opportunity to promote awareness, and educate and empower individuals and clinicians to find solutions to problems that would otherwise be large and overwhelming [260].
While citizen science and mobile technology has the potential to engage the wider community in monitoring and reducing exposures to environmental pollutants, currently there is a lack of integration between data sources and a key challenge is the integration of big health data streams. Incorporating “big data” arising from traditional medical data, “omics” data and quantified self-data to routine clinical care will be a formidable and challenging task, and yet one that is vital for the emergence of personalised medicine that is predictive, personalised, preventative and participatory (4Ps). This challenge has been taken up by the field of systems biology, which uses computational mathematical tools that promise to unify multiple data sets—personal, clinical, genomic, geographical and environmental data. Systems biology therefore provides the foundation for personalised medicine where the patient becomes an integral part of the identification and modification of disease related risk factors and the clinical decision-making processes takes advantage of the most up-to-date scientific knowledge [262].

7.4. Tomorrow’s Doctor

The failure of regulatory authorities to manage risk associated with environmental chemicals, in addition to the widespread and growing number of chemicals found in the human population, provides clinicians with unique and important roles to play in identifying and preventing environmental chemical exposures. While there some clinicians who are supported by integrative/functional medicine associations that are rising to meet this challenge, there are no standard practice models and these clinicians have had to engage in continual education, develop their own clinical assessment tools, and navigate a path through the complex landscape of laboratory tests and the emerging science in multiple fields. This is an extremely challenging task, as conducting environmental chemical assessment at the clinical level includes (but is not limited to):
  • Establishing the patient’s inherent susceptibility to environmental chemicals through assessment of their demographics, ethnicity, socioeconomic status, comorbidities, nutritional and genomic profile.
  • A detailed place history that includes places of residence and work across the lifespan and throughout the week including primary modes of transportation and an assessment of the patients living conditions including their proximity to traffic and other sources of air pollution and potential sources of lead and other heavy metals, mould, dust, indoor air pollution and chemicals in building materials, furnishing and consumer products.
  • An obstetric, paediatric, environmental and occupational exposure history that includes a detailed dietary history, drinking water sources, pharmaceutical and recreational drug use and general lifestyle factors including the use of chemicals in the home and garden, cooking utensils, cleaning methods, personal care products and consumer goods.
  • A family history that includes previous generations.
  • A detailed symptom history that includes a timeline from the perinatal period and enquiry into multiple organ systems.
  • A physical examination to look for physical signs of metabolic, neurological, reproductive or other disease and co-morbidities.
  • Assessing current toxic load through performing various biomonitoring tests that include assessment of biomarkers in various body tissues to assess long term accumulation of toxicants as well as short term exposures.
  • A consideration of external data sources such as geographical information systems and governmental or non-government environmental pollution reporting, ambient air monitoring, drinking water quality and any crowd-sourced data.
  • Networking with other professionals who can assess the patient’s home and/or workplace to establish sources of exposure.
  • Keeping up with the latest regulations and scientific information on environmental chemicals and how they may be assessed as well as their interactions with each other, different diseases and individual patient factors.
To achieve this, clinicians need to possess a cluster of related knowledge, skills and attitudes in the fields of genomics, nutrigenomics, microbiology, hygiene, toxicology, occupational health, public health, epidemiology and, from a clinical perspective, nearly all fields, as well as general medicine, paediatrics and oncology. In addition to clinicians dedicating themselves to this task, the politics and economics of contemporary medicine need to support the dissemination and implementation of this kind of information. However there are many obstacles that hinder this process including the complexities involved in integrating data from numerous emerging fields, time constraints imposed on clinicians, educational requirements, the need for population and individual biomonitoring, the lack of clinical assessment tools, pathology facilities and adequate risk based regulation, profit based funding models that favor treatment over prevention, and the lack of political will to implement drastic changes in how we produce, monitor and regulate chemicals. Ultimately the issues raised by environmental chemical exposures are far greater than those that can be faced by clinicians, as they affect all people and indeed all life on earth. There is a need therefore for concerted action at all levels including actions by individual patients, clinicians, medical educators, regulators, government and non-government organisations, corporations and the wider civil society in order to understand and minimise the extent of toxic exposures on current and future generations.

8. Conclusions

Large population biomonitoring studies have revealed widespread exposures to environmental chemicals at levels in humans known to cause adverse health effects. Despite emerging evidence associating many of these chemicals with chronic diseases typically seen in general clinical practice, environmental chemical assessment has largely been overlooked in clinical practice. Part of the reason lies in the scientific complexities involved, inadequacies in chemical regulations and chemical risk assessment, inconsistencies in defining environmental medicine, a lack of information on environmental chemicals in general medical journals, inadequate pre- and post-graduate medical education on environmental medicine, the limitations of current biomarkers and laboratory tests, along with time, funding and political constraints that limit the use of available tests in clinical practice.
Assessing environmental chemicals in clinical practice may very well be the toughest challenge facing medicine today. Determining susceptibility to environmental chemicals requires a sophisticated understanding of each individual patient and the use of increasingly refined approaches that incorporate extensive paediatric, environmental, geographical, occupational and lifestyle data. The clinical assessment of environmental chemicals also involves embracing the gene-environment paradigm and moving beyond reactive disease models to one that is proactive and preventative, whilst also acknowledging the vital role patients play in their own wellbeing. Recent developments in the fields of systems biology, and the “-omics” fields and advances in peer-to-peer wireless sensor networks, may soon offer tools that provide a bridge between multiple disciplines and herald a new era in personalised medicine that unites clinicians, patients and civil society in the quest to understand and master the links between the environment and human health.


We have received no funds to publish in open access.

Author Contributions

Nicole Bijlsma and Marc M. Cohen contributed equally to the original idea for the paper and drafting, revising and approving the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Reichard, A.; Gulley, S.P.; Rasch, E.K.; Chan, L. Diagnosis isn’t enough: Understanding the connections between high health care utilization, chronic conditions and disabilities among U.S. working age adults. Disabil. Health J. 2015, 8, 535–546. [Google Scholar] [CrossRef] [PubMed]
  2. Paoloni-Giacobino, A. Post genomic decade—The epigenome and exposome challenges. Swiss Med. Wkly. 2011. [Google Scholar] [CrossRef] [PubMed]
  3. Lopez, A.D.; Williams, T.N.; Levin, A.; Tonelli, M.; Singh, J.A.; Burney, P.; Rehm, J.; Volkow, N.D.; Koob, G.; Ferri, C.P. Remembering the forgotten non-communicable diseases. BMC Med. 2014. [Google Scholar] [CrossRef] [PubMed]
  4. Laborde, A.; Tomasina, F.; Bianchi, F.; Brune, M.N.; Buka, I.; Comba, P.; Corra, L.; Cori, L.; Duffert, C.M.; Harari, R. Children’s Health in Latin America: The Influence of Environmental Exposures. Environ. Health Perspect. 2015, 123, 201–209. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Kleisiaris, C.F.; Sfakianakis, C.; Papathanasiou, I.V. Health care practices in ancient Greece: The hippocratic ideal. J. Med. Ethics Hist. Med. 2014, 7, 6. [Google Scholar]
  6. CAS. CAS REGISTRY—The Gold Standard for Chemical Substance Information. 2015. Available online: (accessed on 24 June 2015).
  7. Obodovskiy, I. 5—The effect of chemicals on biological structures. In Fundamentals of Radiation and Chemical Safetyl; Obodovskiy, I., Ed.; Elsevier: Amsterdam, The Netherlands, 2015; pp. 133–179. [Google Scholar]
  8. Rosenthal, G.J. Toxicological assessment of the immune system. In Toxicological Testing Handbook: Principles, Applications, and Data Implementation; CRC Press: Boca Raton, FL, USA, 2000; p. 291. [Google Scholar]
  9. Walters, D.; Grodzki, K. Beyond limits? Dealing with Chemical Risks at Work in Europe; Elsevier: Philadelphia, PA, USA, 2006. [Google Scholar]
  10. United Nations Environment Programme (UNEP). Global Chemicals Outlook. Towards Sound Management of Chemicals; UNEP: Geneva, Switzerland, 2012. [Google Scholar]
  11. Calafat, A.M. The U.S. National Health and Nutrition Examination Survey and human exposure to environmental chemicals. Int. J. Hyg. Environ. Health 2012, 215, 99–101. [Google Scholar] [CrossRef] [PubMed]
  12. Schindler, B.K.; Esteban, M.; Koch, H.M.; Castano, A.; Koslitz, S.; Cañas, A.; Casteleyn, L.; Kolossa-Gehring, M.; Schwedler, G.; Schoeters, G.; et al. The European COPHES/DEMOCOPHES project: Towards transnational comparability and reliability of human biomonitoring results. Int. J. Hyg. Environ. Health 2014, 217, 653–661. [Google Scholar] [CrossRef] [PubMed]
  13. Schulz, C.; Seiwert, M.; Babisch, W.; Becker, K.; Conrad, A.; Szewzyk, R.; Kolossa-Gehring, M. Overview of the study design, participation and field work of the German Environmental Survey on Children 2003–2006 (GerES IV). Int. J. Hyg. Environ. Health 2012, 215, 435–448. [Google Scholar] [CrossRef] [PubMed]
  14. Schoeters, G.; Hond, E.D.; Colles, A.; Loots, I.; Morrens, B.; Keune, H.; Bruckers, L.; Nawrot, T.; Sioen, I. Concept of the Flemish human biomonitoring programme. Int. J. Hyg. Environ. Health 2012, 215, 102–108. [Google Scholar] [CrossRef] [PubMed]
  15. Fréry, N.; Vandentorren, S.; Etchevers, A.; Fillol, C. Highlights of recent studies and future plans for the French human biomonitoring (HBM) programme. Int. J. Hyg. Environ. Health 2012, 215, 127–132. [Google Scholar] [CrossRef]
  16. WHO. Human Biomonitoring: Facts and Figures; WHO: Copenhagen, Denmark, 2015. [Google Scholar]
  17. Pérez-gómez, B.; Pastor-barriuso, R.; Cervantes-amat, M.; Esteban, M.; Ruiz-moraga, M.; Aragonés, N.; Pollán, M.; Navarro, C.; Calvo, E.; Román, J.; et al. BIOAMBIENT.ES study protocol: Rationale and design of a cross-sectional human biomonitoring survey in Spain. Environ. Sci. Pollut. Res. Int. 2013, 20, 1193–1202. [Google Scholar]
  18. Olsen, J.; Melbye, M.; Olsen, S.F.; Sorensen, T.I.; Aaby, P.; Andersen, A.M.; Taxbol, D.; Hansen, K.D.; Juhl, M.; Schow, T.B.; et al. The Danish National Birth Cohort—Its background, structure and aim. Scand. J. Public Health 2001, 29, 300–307. [Google Scholar] [CrossRef] [PubMed]
  19. Vandentorren, S.; Bois, C.; Pirus, C.; Sarter, H.; Salines, G.; Leridon, H. Rationales, design and recruitment for the Elfe longitudinal study. BMC Pediatr. 2009, 9, 58. [Google Scholar] [CrossRef] [PubMed]
  20. Magnus, P.; Irgens, L.M.; Haug, K.; Nystad, W.; Skjaerven, R.; Stoltenberg, C. Cohort profile: The Norwegian Mother and Child Cohort Study (MoBa). Int. J. Epidemiol. 2006, 35, 1146–1150. [Google Scholar] [CrossRef]
  21. Fernandez, M.F.; Sunyer, J.; Grimalt, J.; Rebagliato, M.; Ballester, F.; Ibarluzea, J.; Ribas-Fitó, N.; Tardon, A.; Fernandez-Patier, R.; Torrent, M.; et al. The Spanish Environment and Childhood Research Network (INMA study). Int. J. Hyg. Environ. Health 2007, 210, 491–493. [Google Scholar] [CrossRef] [PubMed]
  22. Nuclear Regulatory Commission (NRC). Acute Exposure Guideline Levels for Selected Airborne Chemicals; National Academies Press: Washington, DC, USA, 2015; Volume 19. [Google Scholar]
  23. WHO. Fourth WHO-Coordinated Survey of Human Milk for Persistent Organic Pollutants in Cooperation with UNEP; Guidelines for Developing a National Protocol; WHO: Geneva, Switzerland, 2007. [Google Scholar]
  24. EWG. Body Burden: The Pollution in Newborns. A Benchmark Investigation of Industriacl Chemicals, Pollutants and Pesticides in Umbilical Cord Blood. 2005. Available online: (accessed on 25 June 2015).
  25. Defence, E. Pre-Polluted: A Report on Toxic Substances in the Umbilical Cord of Canadian Newborns; Environmental Defence Canada: Toronto, ON, Canada, 2013. [Google Scholar]
  26. Genuis, S.J. Evolution in pediatric health care. Pediatr. Int. 2010, 52, 640–643. [Google Scholar] [CrossRef] [PubMed]
  27. American Academy of Pediatrics. Pediatric Environmental Health, 3rd ed.; American Academy of Pediatrics: Elk Grove Village, IL, USA, 2012. [Google Scholar]
  28. Mohai, P.; Bryant, B. Environmental racism: Reviewing the evidence. In Race and the Incidence of Environmental Hazards: A Time for Discourse; Westview press: Boulder, CO, USA, 1992; p. 164. [Google Scholar]
  29. White, H.L. Hazardous waste incineration and minority communities. In Race and the Incidence of Environmental Hazards: A Time for Discourse; Westview press: Boulder, CO, USA, 1992; pp. 126–139. [Google Scholar]
  30. Hird, J.A. Environmental policy and equity: The case of Superfund. J. Policy Anal. Manag. 1993, 12, 323–343. [Google Scholar] [CrossRef]
  31. Zimmerman, R. Social Equity and Environmental Risk1. Risk Anal. 1993, 13, 649–666. [Google Scholar] [CrossRef]
  32. U.S. Government Accountability Office (GAO). Hazardous and Non-Hazardous Waste: Demographics of People Living Near Waste Facilities; GAO: Washington, DC, USA, 1995.
  33. Brown, P. Race, class, and environmental health: A review and systematization of the literature. Environ. Res. 1995, 69, 15–30. [Google Scholar] [CrossRef] [PubMed]
  34. Krieg, E.J.; Faber, D.R. Not so black and white: Environmental justice and cumulative impact assessments. Environ. Impact Assess. Rev. 2004, 24, 667–694. [Google Scholar] [CrossRef]
  35. Bryant, B. Issues and potential policies and solutions for environmental justice: An overview. In Environmental Justice: Issues, Policies, and Solutions; Island Press: Covelo, CA, USA, 1995; pp. 8–34. [Google Scholar]
  36. Tyrrell, J.; Melzer, D.; Henley, W.; Galloway, T.S.; Osborne, N.J. Associations between socioeconomic status and environmental toxicant concentrations in adults in the USA: NHANES 2001–2010. Environ. Int. 2013, 59, 328–335. [Google Scholar] [CrossRef] [PubMed]
  37. WHO. Preventing Disease through Healthy Environments. Towards an Estimate of the Environmental Burden of Disease; WHO: Geneva, Switzerland, 2006. [Google Scholar]
  38. Trasande, L.; Zoeller, R.T.; Hass, U.; Kortenkamp, A.; Grandjean, P.; Myers, J.P.; DiGangi, J.; Bellanger, M.; Hauser, R.; Legler, J.; et al. Estimating burden and disease costs of exposure to endocrine-disrupting chemicals in the European union. J. Clin. Endocrinol. Metab. 2015, 100, 1245–1255. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Barouki, R.; Gluckman, P.D.; Grandjean, P.; Hanson, M.; Heindel, J.J. Developmental origins of non-communicable disease: Implications for research and public health. Environ. Health 2012, 11, 42. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  40. Wang, Y.; Lobstein, T. Worldwide trends in childhood overweight and obesity. Int. J. Pediatr. Obes. 2006, 1, 11–25. [Google Scholar] [CrossRef] [PubMed]
  41. Konkel, L. Obesogen holdover: Prenatal exposure predicts cardiometabolic risk factors in childhood. Environ. Health Perspect. 2015. [Google Scholar] [CrossRef] [PubMed]
  42. Agay-Shay, K.; Martinez, D.; Valvi, D.; Garcia-Esteban, R.; Basagana, X.; Robinson, O.; Casas, M.; Sunyer, J.; Vrijheid, M. Exposure to endocrine-disrupting chemicals during pregnancy and weight at 7 years of age: A multi-pollutant approach. Environ. Health Perspect. 2015, 123, 1030–1037. [Google Scholar] [CrossRef] [PubMed]
  43. Mendez, M.A.; Garcia-Esteban, R.; Guxens, M.; Vrijheid, M.; Kogevinas, M.; Goñi, F.; Fochs, S.; Sunyer, J. Prenatal organochlorine compound exposure, rapid weight gain, and overweight in infancy. Environ. Health Perspect. 2011, 119, 272–278. [Google Scholar] [CrossRef] [PubMed]
  44. Bhandari, R.; Xiao, J.; Shankar, A. Urinary bisphenol A and obesity in US children. Am. J. Epidemiol. 2013, 177, 1263–1270. [Google Scholar] [CrossRef] [PubMed]
  45. Tang-Peronard, J.L.; Andersen, H.R.; Jensen, T.K.; Heitmann, B.L. Endocrine-disrupting chemicals and obesity development in humans: A review. Obes. Rev. 2011, 12, 622–636. [Google Scholar] [CrossRef] [PubMed]
  46. Iughetti, L.; Lucaccioni, L.; Predieri, B. Childhood obesity and environmental pollutants: A dual relationship. Acta Biomed. 2015, 86, 5–16. [Google Scholar] [PubMed]
  47. Janesick, A.; Blumberg, B. Obesogens, stem cells and the developmental programming of obesity. Int. J. Androl. 2012, 35, 437–448. [Google Scholar] [CrossRef] [PubMed]
  48. Kermack, W.O.; McKendrick, A.G.; McKinlay, P.L. Death-rates in Great Britain and Sweden: Expression of specific mortality rates as products of two factors, and some consequences thereof. J. Hyg. (Lond.) 1934, 34, 433–457. [Google Scholar] [CrossRef] [PubMed]
  49. Neel, J.V. Diabetes mellitus: A “thrifty” genotype rendered detrimental by “progress”? Am. J. Hum. Genet. 1962, 14, 353–362. [Google Scholar] [PubMed]
  50. Forsdahl, A. Are poor living conditions in childhood and adolescence an important risk factor for arteriosclerotic heart disease? Br. J. Prev. Soc. Med. 1977, 31, 91–95. [Google Scholar] [CrossRef] [PubMed]
  51. Forsdahl, A. Living conditions in childhood and subsequent development of risk factors for arteriosclerotic heart disease. The cardiovascular survey in Finnmark 1974–1975. J. Epidemiol. Commun. Health 1978, 32, 34–37. [Google Scholar] [CrossRef]
  52. Barker, D.J.P.; Gluckman, P.D.; Robinson, J.S. Conference report: Fetal origins of adult disease—Report of the first international study group, Sydney, 29–30 October 1994. Placenta 1995, 16, 317–320. [Google Scholar] [CrossRef]
  53. Heindel, J.J.; Balbus, J.; Birnbaum, L.; Brune-Drisse, M.N.; Grandjean, P.; Gray, K.; Landrigan, P.J.; Sly, P.D.; Suk, W.; Slechta, D.C.; et al. Developmental origins of health and disease: Integrating environmental influences. Endocrinology 2015, 156, 3416–3421. [Google Scholar] [CrossRef] [PubMed]
  54. Chevalier, N.; Fénichel, P. Endocrine disruptors: New players in the pathophysiology of type 2 diabetes? Diabetes Metabo. 2015, 41, 107–115. [Google Scholar] [CrossRef] [PubMed]
  55. Turyk, M.; Fantuzzi, G.; Persky, V.; Freels, S.; Lambertino, A.; Pini, M.; Rhodes, D.H.; Anderson, H.A. Persistent organic pollutants and biomarkers of diabetes risk in a cohort of Great Lakes sport caught fish consumers. Environ. Res. 2015, 140, 335–344. [Google Scholar] [CrossRef] [PubMed]
  56. Zama, A.M.; Uzumcu, M. Epigenetic effects of endocrine-disrupting chemicals on female reproduction: An ovarian perspective. Front. Neuroendocrinol. 2010, 31, 420–439. [Google Scholar] [CrossRef] [PubMed]
  57. Zeliger, H.I. 23—Toxic Infertility. In Human Toxicology of Chemical Mixtures, 2nd ed.; Zeliger, H.I., Ed.; William Andrew Publishing: Oxford, UK, 2011; pp. 323–340. [Google Scholar]
  58. Buck Louis, G.M.; Sundaram, R.; Schisterman, E.F.; Sweeney, A.M.; Lynch, C.D.; Gore-Langton, R.E.; Maisog, J.; Kim, S.; Chen, Z.; Barr, D.B. Persistent environmental pollutants and couple fecundity: The LIFE study. Environ. Health Perspect. 2013, 121, 231–236. [Google Scholar] [PubMed]
  59. Skakkebaek, N.E.; Meyts, E.R.; Main, K.M. Testicular dysgenesis syndrome: An increasingly common developmental disorder with environmental aspects. Hum. Reprod. 2001, 16, 972–978. [Google Scholar] [CrossRef] [PubMed]
  60. Nordkap, L.; Joensen, U.N.; Jensen, M.B.; Jørgensen, N. Regional differences and temporal trends in male reproductive health disorders: Semen quality may be a sensitive marker of environmental exposures. Mol. Cell. Endocrinol. 2012, 355, 221–230. [Google Scholar] [CrossRef] [PubMed]
  61. Kalfa, N.; Paris, F.; Philibert, P.; Orsini, M.; Broussous, S.; Fauconnet-Servant, N.; Audran, F.; Gaspari, L.; Lehors, H.; Haddad, M.; et al. Is hypospadias associated with prenatal exposure to endocrine disruptors? A French collaborative controlled study of a cohort of 300 consecutive children without genetic defect. Eur. Urol. 2015, 68, 1023–1030. [Google Scholar] [CrossRef]
  62. Michalakis, M.; Tzatzarakis, M.N.; Kovatsi, L.; Alegakis, A.K.; Tsakalof, A.K.; Heretis, I.; Tsatsakis, A. Hypospadias in offspring is associated with chronic exposure of parents to organophosphate and organochlorine pesticides. Toxicol. Lett. 2014, 230, 139–145. [Google Scholar] [CrossRef]
  63. Virtanen, H.E.; Adamsson, A. Cryptorchidism and endocrine disrupting chemicals. Mol. Cell. Endocrinol. 2012, 355, 208–220. [Google Scholar] [CrossRef] [PubMed]
  64. Voigt, K.; Brueggemann, R.; Scherb, H.; Shen, H.; Schramm, K.W. Evaluating the relationship between chemical exposure and cryptorchidism. Environ. Model. Softw. 2010, 25, 1801–1812. [Google Scholar] [CrossRef]
  65. Meeks, J.J.; Sheinfeld, J.; Eggener, S.E. Environmental toxicology of testicular cancer. Urol. Oncol. 2012, 30, 212–215. [Google Scholar] [CrossRef] [PubMed]
  66. Carlsen, E.; Giwercman, A.; Keiding, N.; Skakkebaek, N.E. Evidence for decreasing quality of semen during past 50 years. Int. J. Gynecol. Obstet. 1993, 41, 112–113. [Google Scholar] [CrossRef]
  67. Fathi Najafi, T.; Roudsari, R.L.; Namvar, F.; Ghanbarabadi, V.G.; Talasaz, Z.H.; Esmaeli, M. Air pollution and quality of sperm: A meta-analysis. Iran Red Crescent Med. J. 2015. [Google Scholar] [CrossRef]
  68. Vrooman, L.A.; Oatley, J.M.; Griswold, J.E.; Hassold, T.J.; Hunt, P.A. Estrogenic exposure alters the spermatogonial stem cells in the developing testis, permanently reducing crossover levels in the adult. PLoS Genet. 2015. [Google Scholar] [CrossRef] [PubMed]
  69. Fowler, P.A.; Bellingham, M.; Sinclair, K.D.; Evans, N.P.; Pocar, P.; Fischer, B.; Schaedlich, K.; Schmidt, J.S.; Amezaga, M.R.; Bhattacharya, S.; et al. Impact of endocrine-disrupting compounds (EDCs) on female reproductive health. Mol. Cell. Endocrinol. 2012, 355, 231–239. [Google Scholar] [CrossRef] [PubMed]
  70. Genuis, S.J.; Kelln, K.L. Toxicant exposure and bioaccumulation: A common and potentially reversible cause of cognitive dysfunction and dementia. Behav. Neurol. 2015. [Google Scholar] [CrossRef] [PubMed]
  71. McGwin, G.; Lienert, J.; Kennedy, J.I. Formaldehyde exposure and asthma in children: A systematic review. Environ. Health Perspect. 2010, 118, 313–317. [Google Scholar] [CrossRef] [PubMed]
  72. Miller, M.D.; Marty, M.A. Impact of environmental chemicals on lung development. Environ. Health Perspect. 2010, 118, 1155–1164. [Google Scholar] [CrossRef] [PubMed]
  73. Heindel, J.J.; vom Saal, F.S. Role of nutrition and environmental endocrine disrupting chemicals during the perinatal period on the aetiology of obesity. Mol. Cell. Endocrinol. 2009, 304, 90–96. [Google Scholar] [CrossRef] [PubMed]
  74. Newbold, R.R.; Padilla-Banks, E.; Jefferson, W.N. Environmental estrogens and obesity. Mol. Cell. Endocrinol. 2009, 304, 84–89. [Google Scholar] [CrossRef] [PubMed]
  75. Grün, F.; Blumberg, B. Endocrine disrupters as obesogens. Mol. Cell. Endocrinol. 2009, 304, 19–29. [Google Scholar] [CrossRef] [PubMed]
  76. Xu, X.; Freeman, N.C.; Dailey, A.B.; Ilacqua, V.A.; Kearney, G.D.; Talbott, E.O. Association between exposure to alkylbenzenes and cardiovascular disease among national health and nutrition examination survey (NHANES) participants. Int. J. Occup. Environ. Health 2009, 15, 385–391. [Google Scholar] [CrossRef] [PubMed]
  77. Hoek, G.; Krishnan, R.M.; Beelen, R.; Peters, A.; Ostro, B.; Brunekreef, B.; Kaufman, J.D. Long-term air pollution exposure and cardio-respiratory mortality: A review. Environ. Health 2013. [Google Scholar] [CrossRef] [PubMed]
  78. Zeliger, H.I. Lipophilic chemical exposure as a cause of cardiovascular disease. Interdiscip. Toxicol. 2013, 6, 55–62. [Google Scholar] [CrossRef] [PubMed]
  79. Grandjean, P.; Landrigan, P.J. Neurobehavioural effects of developmental toxicity. Lancet Neurol. 2014, 13, 330–338. [Google Scholar] [CrossRef]
  80. Grandjean, P.; Landrigan, P.J. Developmental neurotoxicity of industrial chemicals. Lancet 2006, 368, 2167–2178. [Google Scholar] [CrossRef]
  81. Grandjean, P. Only One Chance. How Environmental Pollution Impairs Brain Development—And How to Protect the Brains of the Next Generation; Oxford University Press: Oxford, UK, 2013. [Google Scholar]
  82. Sutcliffe, J.S. Genetics: Insights into the pathogenesis of autism. Science 2008, 321, 208–209. [Google Scholar] [CrossRef] [PubMed]
  83. Rosenfeld, C.S. Microbiome disturbances and autism spectrum disorders. Drug Metab. Dispos. 2015, 43, 1557–1571. [Google Scholar] [CrossRef] [PubMed]
  84. Ross, S.M.; McManus, I.C.; Harrison, V.; Mason, O. Neurobehavioral problems following low-level exposure to organophosphate pesticides: A systematic and meta-analytic review. Crit. Rev. Toxicol. 2012, 43, 21–44. [Google Scholar] [CrossRef]
  85. Di Renzo, G.C.; Conry, J.A.; Blake, J.; DeFrancesco, M.S.; DeNicola, N.; Martin, J.N., Jr.; McCue, K.A.; Richmond, D.; Shah, A.; Sutton, P.; et al. International federation of gynecology and obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals. Int. J. Gynaecol. Obstet. 2015, 131, 219–225. [Google Scholar] [CrossRef] [PubMed]
  86. Goldschmidt, J.; Song, H.J. At-risk and underserved: A proposed role for nutrition in the adult trajectory of Autism. J. Acad. Nutr. Diet 2015, 115, 1041–1047. [Google Scholar] [CrossRef] [PubMed]
  87. Van De Sande, M.M.; van Buul, V.J.; Brouns, F.J. Autism and nutrition: The role of the gut-brain axis. Nutr. Res. Rev. 2014, 27, 199–214. [Google Scholar] [CrossRef] [PubMed]
  88. Yap, I.K.S.; Li, J.V.; Saric, J.; Martin, F.P.; Davies, H.; Wang, Y.; Wilson, I.D.; Nicholson, J.K.; Utzinger, J.; Marchesi, J.R.; et al. Metabonomic and microbiological analysis of the dynamic effect of vancomycin-lnduced gut microbiota modification in the mouse. J. Proteome Res. 2008, 7, 3718–3728. [Google Scholar] [CrossRef] [PubMed]
  89. Abel, E.L.; DiGiovanni, J. 7—Environmental carcinogenesis. In The Molecular Basis of Cancer, 4th ed.; Saunders: Philadelphia, PA, USA, 2015; pp. 103–128. [Google Scholar]
  90. Kim, K.H.; Jahan, S.A.; Kabir, E.; Brown, R.J. A review of airborne polycyclic aromatic hydrocarbons (PAHs) and their human health effects. Environ. Int. 2013, 60, 71–80. [Google Scholar] [CrossRef] [PubMed]
  91. Cao, J.; Yang, C.; Li, J.; Chen, R.; Chen, B.; Gu, D.; Kan, H. Association between long-term exposure to outdoor air pollution and mortality in China: A cohort study. J. Hazard. Mater. 2011, 186, 1594–1600. [Google Scholar] [CrossRef] [PubMed]
  92. Yang, W.S.; Zhao, H.; Wang, X.; Deng, Q.; Fan, W.Y.; Wang, L. An evidence-based assessment for the association between long-term exposure to outdoor air pollution and the risk of lung cancer. Eur. J. Cancer Prev. 2015. [Google Scholar] [CrossRef] [PubMed]
  93. Halasova, E.; Matakova, T.; Kavcova, E.; Musak, L.; Letkova, L.; Adamkov, M.; Ondrusova, M.; Bukovska, E.; Singliar, A. Human lung cancer and hexavalent chromium exposure. Neuro Endocrinol. Lett. 2009, 30, 182–185. [Google Scholar] [PubMed]
  94. Teitelbaum, S.L.; Belpoggi, F.; Reinlib, L. Advancing research on endocrine disrupting chemicals in breast cancer: Expert panel recommendations. Reprod. Toxicol. 2015, 54, 141–147. [Google Scholar] [CrossRef] [PubMed]
  95. Kim, H.S.; Lee, B.M. Endocrine disrupting chemicals and human cancer. In Encyclopedia of Environmental Health; Nriagu, J.O., Ed.; Elsevier: Burlington, MA, USA, 2011; pp. 296–305. [Google Scholar]
  96. WHO. State of the Science of Endocrine Disrupting Chemicals—2012. An Assessment of the State of the Science of Endocrine Disruptors Prepared by a Group of Experts for the United Nations Environment Programme (UNEP) and WHO. 2013. Available online: (accessed on 25 June 2015).
  97. Darbre, P.D.; Williams, G. Chapter 10—Endocrine disruption and cancer of reproductive tissues. In Endocrine Disruption and Human Health; Darbre, P.D., Ed.; Academic Press: Boston, MA, USA, 2015; pp. 177–200. [Google Scholar]
  98. Le Moal, J.; Sharpe, R.M.; Jvarphirgensen, N.; Levine, H.; Jurewicz, J.; Mendiola, J.; Swan, S.H.; Virtanen, H.; Christin-Maitre, S.; Cordier, S.; et al. Toward a multi-country monitoring system of reproductive health in the context of endocrine disrupting chemical exposure. Eur. J. Public Health 2015. [Google Scholar] [CrossRef] [PubMed]
  99. Villanueva, C.M.; Fernandez, F.; Malats, N.; Grimalt, J.O.; Kogevinas, M. Meta-analysis of studies on individual consumption of chlorinated drinking water and bladder cancer. J. Epidemiol. Commun. Health 2003, 57, 166–173. [Google Scholar] [CrossRef]
  100. Bhattacharjee, P.; Chatterjee, D.; Singh, K.K.; Giri, A.K. Systems biology approaches to evaluate arsenic toxicity and carcinogenicity: An overview. Int. J. Hyg. Environ. Health 2013, 216, 574–586. [Google Scholar] [CrossRef]
  101. Dogliotti, E. Molecular mechanisms of carcinogenesis by vinyl chloride. Ann. Ist. Super. Sanita 2006, 42, 163–169. [Google Scholar] [PubMed]
  102. Andreoli, R.; Spatari, G.; Pigini, D.; Poli, D.; Banda, I.; Goldoni, M.; Riccelli, M.G.; Petyx, M.; Protano, C.; Vitali, M.; et al. Urinary biomarkers of exposure and of oxidative damage in children exposed to low airborne concentrations of benzene. Environ. Res. 2015, 142, 264–272. [Google Scholar] [CrossRef] [PubMed]
  103. Chen, M.; Chang, C.H.; Tao, L.; Lu, C. Residential exposure to pesticide during childhood and childhood cancers: A meta-analysis. Pediatrics 2015. [Google Scholar] [CrossRef] [PubMed]
  104. Turner, M.C.; Wigle, D.T.; Krewski, D. Residential pesticides and childhood leukemia: A systematic review and meta-analysis. Environ. Health Perspect. 2010, 118, 33–41. [Google Scholar] [PubMed]
  105. Van Maele-Fabry, G.; Lantin, A.C.; Hoet, P.; Lison, D. Residential exposure to pesticides and childhood leukaemia: A systematic review and meta-analysis. Environ. Int. 2011, 37, 280–291. [Google Scholar] [CrossRef] [PubMed]
  106. McGuinn, L.A.; Ghazarian, A.A.; Ellison, G.L.; Harvey, C.E.; Kaefer, C.M.; Reid, B.C. Cancer and environment: Definitions and misconceptions. Environ. Res. 2012, 112, 230–234. [Google Scholar] [CrossRef] [PubMed]
  107. Christiani, D.C. Combating environmental causes of cancer. N. Engl. J. Med. 2011, 364, 791–793. [Google Scholar] [CrossRef]
  108. WHO. Global health risks: Mortality and burden of disease attributable to selected major risks. World Health Organization: Geneva, Switzerland, 2009. [Google Scholar]
  109. Straif, K. The burden of occupational cancer. Occup. Environ. Med. 2008, 65, 787–788. [Google Scholar] [CrossRef] [PubMed]
  110. Goodson, W.H., 3rd; Lowe, L.; Carpenter, D.O.; Gilbertson, M.; Ali, A.M.; Salsamendi, A.L.D.; Lasfar, A.; Carnero, A.; Azqueta, A.; Amedei, A.; et al. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: The challenge ahead. Carcinogenesis 2015, 36, 254–296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  111. Reuben, S. Reducing Environmental Cancer Risk, What We Can Do Now; 2008–2009 Annual Report; US Department of Health and Human Services, National Institutes of Health, National Cancer Institute: Rockville, MD, USA, 2010.
  112. International Agency for Research on Cancer (IARC). World Cancer Report 2014; World Health Organisation: Lyon, France, 2014. [Google Scholar]
  113. Genuis, S.J.; Tymchak, M.G. Approach to patients with unexplained multimorbidity with sensitivities. Can. Fam. Physician 2014, 60, 533–538. [Google Scholar] [PubMed]
  114. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue. National Institutes of Health, in Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness; National Academies Press: New York, NY, USA, 2015. [Google Scholar]
  115. Fukuda, K.; Straus, S.E.; Hickie, I.; Sharpe, M.C.; Dobbins, J.G.; Komaroff, A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann. Intern. Med. 1994, 121, 953–959. [Google Scholar] [CrossRef] [PubMed]
  116. Gugliandolo, A.; Gangemi, C.; Calabrò, C.; Vecchio, M.; Di Mauro, D.; Renis, M.; Ientile, R.; Currò, M.; Caccamo, D. Assessment of glutathione peroxidase-1 polymorphisms, oxidative stress and DNA damage in sensitivity-related illnesses. Life Sci. 2016, 145, 27–33. [Google Scholar] [CrossRef] [PubMed]
  117. De Luca, C.; Scordo, G.; Cesareo, E.; Raskovic, D.; Genovesi, G.; Korkina, L. Idiopathic environmental intolerances (IEI): From molecular epidemiology to molecular medicine. Indian J. Exp. Biol. 2010, 48, 625–635. [Google Scholar] [PubMed]
  118. McCarthy, J. Myalgias and Myopathies: Fibromyalgia. FP Essent 2016, 440, 11–15. [Google Scholar]
  119. Belyaev, I.; Dean, A.; Eger, H.; Hubmann, G.; Jandrisovits, R.; Johansson, O.; Kern, M.; Kundi, M.; Lercher, P.; Mosgöller, W.; et al. EUROPAEM EMF Guideline 2015 for the prevention, diagnosis and treatment of EMF-related health problems and illnesses. Rev. Environ. Health 2015, 30, 337–371. [Google Scholar] [CrossRef] [PubMed]
  120. Jafari, M.J.; Khajevandi, A.A.; Mousavi-Najarkola, S.A.; Yekaninejad, M.S.; Pourhoseingholi, M.A.; Omidi, L.; Kalantary, S. Association of sick building syndrome with indoor air parameters. Tanaffos 2015, 14, 55–62. [Google Scholar] [PubMed]
  121. Rea, W.J. Chemical Sensitivity: Tools of Diagnosis and Methods of Treatment; Lewis Publishers: Boca Raton, FL, USA, 1997; Volume 4. [Google Scholar]
  122. Fraccaro, P.; Casteleiro, M.A.; Ainsworth, J.; Buchan, I. Adoption of clinical decision support in multimorbidity: A systematic review. JMIR Med. Inform. 2015. [Google Scholar] [CrossRef] [PubMed]
  123. Herr, C.; Eikmann, T. Environmental health practice: Environmental medicine. In Encyclopedia of Environmental Health; Nriagu, J.O., Ed.; Elsevier: Burlington, MA, USA, 2011; pp. 419–423. [Google Scholar]
  124. De Luca, C.; Raskovic, D.; Pacifico, V.; Thai, J.C.S.; Korkina, L. The search for reliable biomarkers of disease in multiple chemical sensitivity and other environmental intolerances. Int. J. Environ. Res. Public Health 2011, 8, 2770–2797. [Google Scholar] [CrossRef] [PubMed]
  125. De Luca, C.; Gugliandolo, A.; Calabro, C.; Curro, M.; Ientile, R.; Raskovic, D.; Korkina, L.; Caccamo, D. Role of polymorphisms of inducible nitric oxide synthase and endothelial nitric oxide synthase in idiopathic environmental intolerances. Mediat. Inflamm. 2015. [Google Scholar] [CrossRef] [PubMed]
  126. Dantoft, T.M.; Elberling, J.; Brix, S.; Szecsi, P.B.; Vesterhauge, S.; Skovbjerg, S. An elevated pro-inflammatory cytokine profile in multiple chemical sensitivity. Psychoneuroendocrinology 2014, 40, 140–150. [Google Scholar] [CrossRef] [PubMed]
  127. Ashford, N.A.; Miller, C.S. Chemical Exposures. Low Levels and High Stakes, 2nd ed.; John Wiley & Sons: Hoboken, NJ, USA, 1998. [Google Scholar]
  128. Miller, C.S. Toxicant-induced loss of tolerance—An emerging theory of disease? Environ. Health Perspect. 1997, 105, 445–453. [Google Scholar] [PubMed]
  129. Diamanti-Kandarakis, E.; Bourguignon, J.P.; Giudice, L.C.; Hauser, R.; Prins, G.S.; Soto, A.M.; Zoeller, R.T.; Gore, A.C. Endocrine-disrupting chemicals: An Endocrine Society scientific statement. Endocr. Rev. 2009, 30, 293–342. [Google Scholar] [CrossRef] [PubMed]
  130. Pool, R.; Rusch, E. Identifying and Reducing Environmental Health Risks of Chemicals in Our Society: Workshop Summary; National Academies Press: Washington, DC, USA, 2014. [Google Scholar]
  131. Darbre, P.D. Chapter 16—An introduction to the challenges for risk assessment of endocrine disrupting chemicals. In Endocrine Disruption and Human Health; Darbre, P.D., Ed.; Academic Press: Boston, MA, USA, 2015; pp. 289–300. [Google Scholar]
  132. Zeliger, H. Human Toxicology of Chemical Mixtures, 2nd ed.; William Andrew: Binghamton, NY, USA, 2011. [Google Scholar]
  133. Amiard, J.C.; Amiard-Triquet, C. Chapter 2—Conventional risk assessment of environmental contaminants. In Aquatic Ecotoxicology; Mouneyrac, C.A., Ed.; Academic Press: Cambridge, MA, USA, 2015; pp. 25–49. [Google Scholar]
  134. National Research Council of The National Academies. Toxicity Testing in the 21st Century: A Vision and a Strategy; National Academies Press: Washington, DC, USA, 2007. [Google Scholar]
  135. Hill, A.B. The Environment and Disease: Association or Causation? Proc. R. Soc. Med. 1965, 58, 295–300. [Google Scholar] [CrossRef] [PubMed]
  136. Darbre, P.D. Chapter 7—Nonmonotonic Responses in Endocrine Disruption. In Endocrine Disruption and Human Health; Darbre, P.D. Academic Press: Boston, MA, USA, 2015; pp. 123–140. [Google Scholar]
  137. Thompson, P.A.; Khatami, M.; Baglole, C.J.; Sun, J.; Harris, S.A.; Moon, E.Y.; Al-Mulla, F.; Al-Temaimi, R.; Brown, D.G.; Colacci, A.; et al. Environmental immune disruptors, inflammation and cancer risk. Carcinogenesis 2015, 36, 232–253. [Google Scholar] [CrossRef] [PubMed]
  138. Hernández, A.F.; Gil, F.; Tsatsakis, A.M. Chapter 38—Biomarkers of chemical mixture toxicity. In Biomarkers in Toxicology; Gupta, R.C., Ed.; Academic Press: Boston, MA, USA, 2014; pp. 655–669. [Google Scholar]
  139. Mesnage, R.; Defarge, N.; de Vendômois, J.S.; Séralini, G.E. Major pesticides are more toxic to human cells than their declared active principles. BioMed Res. Int. 2014. [Google Scholar] [CrossRef] [PubMed]
  140. Kortenkamp, A.; Backhaus, T.; Faust, M. State of the Art Review on Mixture Toxicity—Final Report, Executive Summary; European Commission: Brussels, Belgium, 2009. [Google Scholar]
  141. Alexandersson, R.; Kolmodin-Hedman, B.; Hedenstierna, G. Exposure to formaldehyde: Effects on pulmonary function. Arch. Environ. Health Int. J. 1982, 37, 279–284. [Google Scholar] [CrossRef]
  142. Hansen, M.K.; Larsen, M.; Cohr, K.H. Waterborne paints. A review of their chemistry and toxicology and the results of determinations made during their use. Scand. J. Work Environ. Health 1987, 13, 473–485. [Google Scholar] [CrossRef]
  143. Rajapakse, N.; Silva, E.; Kortenkamp, A. Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action. Environ. Health Perspect. 2002, 110, 917–921. [Google Scholar] [CrossRef] [PubMed]
  144. Brisson, G.D.; Alves, L.R.; Pombo-de-Oliveira, M.S. Genetic susceptibility in childhood acute leukaemias: A systematic review. Ecancermedicalscience 2015. [Google Scholar] [CrossRef]
  145. Czarnota, J.; Gennings, C.; Colt, J.S.; de Roos, A.J.; Cerhan, J.R.; Severson, R.K.; Hartge, P.; Ward, M.H.; Wheeler, D.C. Analysis of environmental chemical mixtures and non-hodgkin lymphoma risk in the nci-seer NHL study. Environ. Health Perspect. 2015. [Google Scholar] [CrossRef] [PubMed]
  146. International Agency for Research on Cancer (IARC). Arsenic in drinking water. In IARC Monographs on the Evaluation of Carcinogenic Risks to Humans; World Health Organization (WHO): Geneva, Switzerland, 2012. [Google Scholar]
  147. Tsuji, J.S.; Alexander, D.D.; Perez, V.; Mink, P.J. Arsenic exposure and bladder cancer: Quantitative assessment of studies in human populations to detect risks at low doses. Toxicology 2014, 317, 17–30. [Google Scholar] [CrossRef] [PubMed]
  148. Ngamwong, Y.; Tangamornsuksan, W.; Lohitnavy, O.; Chaiyakunapruk, N.; Scholfield, C.N.; Reisfeld, B.; Lohitnavy, M. Additive synergism between asbestos and smoking in lung cancer risk: A systematic review and meta-analysis. PLoS ONE 2015. [Google Scholar] [CrossRef] [PubMed]
  149. Rea, W.J. Chemical Sensitivity; CRC Press: Boca Raton, FL, USA, 1992; Volume 1. [Google Scholar]
  150. European Commission Joint Research Centre. Technical Guidance Document on Risk Assessment. Support of Commission Directive 93/67/EEC on Risk Assessment for New Notified Substances, Commission Regulation (EC) No 1488/94 on Risk Assessment for Existing Substances—Directive 98/8/EC of the European Parliament and of the Council Concerning the Placing of Biocidal Products on the Market, European Chemicals Bureau (ECB): JRC-Ispra, Italy, 2003. [Google Scholar]
  151. Wiedersberg, S.; Guy, R.H. Transdermal drug delivery: 30+ years of war and still fighting! J. Control. Release 2014, 190, 150–156. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Delfosse, V.; Dendele, B.; Huet, T.; Grimaldi, M.; Boulahtouf, A.; Gerbal-Chaloin, S.; Beucher, B.; Roecklin, D.; Muller, C.; Rahmani, R.; et al. Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds. Nat. Commun. 2015. [Google Scholar] [CrossRef] [PubMed]
  153. Futran Fuhrman, V.; Tal, A.; Arnon, S. Why endocrine disrupting chemicals (EDCs) challenge traditional risk assessment and how to respond. J. Hazard. Mater. 2015, 286, 589–611. [Google Scholar] [CrossRef]
  154. Fox, D.A.; Grandjean, P.; de Groot, D.; Paule, M.G. Developmental origins of adult diseases and neurotoxicity: Epidemiological and experimental studies. Neurotoxicology 2012, 33, 810–816. [Google Scholar] [CrossRef] [PubMed]
  155. Barker, D.J.; Bagby, S.P.; Hanson, M.A. Mechanisms of disease: In utero programming in the pathogenesis of hypertension. Nat. Clin. Pract. Nephrol. 2006, 2, 700–707. [Google Scholar] [CrossRef] [PubMed]
  156. Delisle, H. Foetal programming of nutrition-related chronic diseases. Sante 2002, 12, 56–63. [Google Scholar] [PubMed]
  157. Fernandez-Twinn, D.S.; Constancia, M.; Ozanne, S.E. Intergenerational epigenetic inheritance in models of developmental programming of adult disease. Semin. Cell Dev. Biol. 2015, 43, 85–95. [Google Scholar] [CrossRef] [PubMed]
  158. Rice, D.; Barone, S., Jr. Critical periods of vulnerability for the developing nervous system: Evidence from humans and animal models. Environ. Health Perspect. 2000, 108, 511–533. [Google Scholar] [CrossRef]
  159. Wang, G.; Walker, S.O.; Hong, X.; Bartell, T.R.; Wang, X. Epigenetics and early life origins of chronic noncommunicable diseases. J. Adolesc. Health 2013, 52, 14–21. [Google Scholar] [CrossRef]
  160. Ravelli, G.P.; Stein, Z.A.; Susser, M.W. Obesity in young men after famine exposure in utero and early infancy. N. Engl. J. Med. 1976, 295, 349–353. [Google Scholar] [CrossRef] [PubMed]
  161. Herbst, A.L.; Ulfelder, H.; Poskanzer, D.C. Adenocarcinoma of the Vagina. N. Engl. J. Med. 1971, 284, 878–881. [Google Scholar] [CrossRef] [PubMed]
  162. LaSalle, J.M. Epigenomic strategies at the interface of genetic and environmental risk factors for autism. J. Hum. Genet. 2013, 58, 396–401. [Google Scholar] [CrossRef] [PubMed]
  163. Grandjean, P.; Barouki, R.; Bellinger, D.C.; Casteleyn, L.; Chadwick, L.H.; Cordier, S.; Etzel, R.A.; Gray, K.A.; Ha, E.H.; Junien, C.; et al. Life-long implications of developmental exposure to environmental stressors: New perspectives. Endocrinology 2015, 156, 3408–3415. [Google Scholar] [CrossRef] [PubMed]
  164. Clayton, T.A.; Lindon, J.C.; Cloarec, O.; Antti, H.; Charuel, C.; Hanton, G.; Provost, J.P.; le Net, J.L.; Baker, D.; Walley, R.J.; et al. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature 2006, 440, 1073–1077. [Google Scholar] [CrossRef] [PubMed]
  165. Latham, K.E.; Sapienza, C.; Engel, N. The epigenetic lorax: Gene-environment interactions in human health. Epigenomics 2012, 4, 383–402. [Google Scholar] [CrossRef] [PubMed]
  166. Thomas, R.; Sanders, S.; Doust, J.; Beller, E.; Glasziou, P. Prevalence of attention-deficit/hyperactivity disorder: A systematic review and meta-analysis. Pediatrics 2015, 135, 994–1001. [Google Scholar] [CrossRef] [PubMed]
  167. Go, Y.M.; Walker, D.I.; Liang, Y.; Uppal, K.; Soltow, Q.A.; Tran, V.; Strobel, F.; Quyyumi, A.A.; Ziegler, T.R.; Pennell, K.D.; et al. Reference standardization for mass spectrometry and high-resolution metabolomics applications to exposome research. Toxicol. Sci. 2015. [Google Scholar] [CrossRef] [PubMed]
  168. Lacroix, M.; Kina, E.; Hivert, M.F. Maternal/fetal determinants of insulin resistance in women during pregnancy and in offspring over life. Curr. Diab. Rep. 2013, 13, 238–244. [Google Scholar] [CrossRef] [PubMed]
  169. Fisher, S.J. Why is placentation abnormal in preeclampsia? Am. J. Obstet. Gynecol. 2015, 213, 115–122. [Google Scholar] [CrossRef] [PubMed]
  170. Kroener, L.; Wang, E.T.; Pisarska, M.D. Predisposing factors to abnormal first trimester placentation and the impact on fetal outcomes. Semin Reprod. Med. 2016, 34, 27–35. [Google Scholar] [CrossRef] [PubMed]
  171. Rees, S.; Inder, T. Fetal and neonatal origins of altered brain development. Early Hum. Dev. 2005, 81, 753–761. [Google Scholar] [CrossRef] [PubMed]
  172. Barker, D.J.; Thornburg, K.L. Placental programming of chronic diseases, cancer and lifespan: A review. Placenta 2013, 34, 841–845. [Google Scholar] [CrossRef] [PubMed]
  173. Barker, D.J.; Bull, A.R.; Osmond, C.; Simmonds, S.J. Fetal and placental size and risk of hypertension in adult life. BMJ 1990, 301, 259–262. [Google Scholar] [CrossRef]
  174. Sogorb, M.A.; Estévez, J.; Vilanova, E. Chapter 57—Biomarkers in biomonitoring of xenobiotics. In Biomarkers in Toxicology; Gupta, R.C., Ed.; Academic Press: Boston, MA, USA, 2014; pp. 965–973. [Google Scholar]
  175. Lioy, P.J.; Rappaport, S.M. Exposure science and the exposome: An opportunity for coherence in the environmental health sciences. Environ. Health Perspect. 2011, 119, 466–467. [Google Scholar] [CrossRef]
  176. Woodruff, T.J.; Sutton, P. The Navigation Guide systematic review methodology: A rigorous and transparent method for translating environmental health science into better health outcomes. Environ. Health Perspect. 2014, 122, 1007–1014. [Google Scholar] [CrossRef] [PubMed]
  177. Rooney, A.A.; Boyles, A.L.; Wolfe, M.S.; Bucher, J.R.; Thayer, K.A. Systematic review and evidence integration for literature-based environmental health science assessments. Environ. Health Perspect. 2014, 122, 711–718. [Google Scholar] [CrossRef] [PubMed]
  178. Sheehan, M.C.; Lam, J. Use of systematic review and meta-analysis in environmental health epidemiology: A systematic review and comparison with guidelines. Curr. Environ. Health Rep. 2015, 2, 272–283. [Google Scholar] [CrossRef] [PubMed]
  179. Whaley, P. Systematic Review and the Future of Evidence in Chemicals Policy (Report); Policy from Science Project (Lancaster University): Lancaster, UK, 2013. [Google Scholar]
  180. Hoffmann, S.; Hartung, T. Toward an evidence-based toxicology. Hum. Exp. Toxicol. 2006, 25, 497–513. [Google Scholar] [CrossRef] [PubMed]
  181. European Food Safety Authority (EFSA). Tools for Critically Appraising Different Study Designs, Systematic Review and Literature Searches; EFSA: Parma, Italy, 2015. [Google Scholar]
  182. Attene-Ramos, M.S.; Miller, N.; Huang, R.; Michael, S.; Itkin, M.; Kavlock, R.J.; Austin, C.P.; Shinn, P.; Simeonov, A.; Tice, R.R.; et al. The Tox21 robotic platform for assessment of environmental chemicals—From vision to reality. Drug Discov. Today 2013, 18, 716–723. [Google Scholar] [CrossRef] [PubMed]
  183. Shukla, S.J.; Huang, R.; Austin, C.P.; Xia, M. The future of toxicity testing: A focus on in vitro methods using a quantitative high-throughput screening platform. Drug Discov. Today 2010, 15, 997–1007. [Google Scholar] [CrossRef] [PubMed]
  184. Schneider, K.; Schwarz, M.; Burkholder, I.; Kopp-Schneider, A.; Edler, L.; Kinsner-Ovaskainen, A.; Hartung, T.; Hoffmann, S. “ToxRTool”, a new tool to assess the reliability of toxicological data. Toxicol. Lett. 2009, 189, 138–144. [Google Scholar] [CrossRef] [PubMed]
  185. Klimisch, H.J.; Andreae, M.; Tillmann, U. A systematic approach for evaluating the quality of experimental toxicological and ecotoxicological data. Regul. Toxicol. Pharmacol. 1997, 25, 1–5. [Google Scholar] [CrossRef] [PubMed]
  186. Han, X.; Price, P.S. Applying the maximum cumulative ratio methodology to biomonitoring data on dioxin-like compounds in the general public and two occupationally exposed populations. J. Expo. Sci. Environ. Epidemiol. 2013, 23, 343–349. [Google Scholar] [CrossRef] [PubMed]
  187. Castleman, B.I.; Ziem, G.E. American conference of governmental industrial hygienists: Low threshold of credibility. Am. J. Ind. Med. 1994, 26, 133–143. [Google Scholar] [CrossRef] [PubMed]
  188. Castleman, B.I.; Ziem, G.E. Corporate influence on threshold limit values. Am. J. Ind. Med. 1988, 13, 531–559. [Google Scholar] [CrossRef] [PubMed]
  189. Boobis, A.R. Mode of action considerations in the quantitative assessment of tumour responses in the liver. Basic Clin. Pharmacol. Toxicol. 2010, 106, 173–179. [Google Scholar] [CrossRef] [PubMed]
  190. Sass, J. The Delay Game: How the Chemical Industry Ducks Regulation of hte Most Toxic Substances; Natural Resources Defense Council: New York, NY, USA, 2011. [Google Scholar]
  191. WHO. WHO Guidelines for Indoor Air Quality. Available online: (accessed on 11 October 2015).
  192. EPA. Indoor Air Quality. Publications about Indoor Air Quality. 2015. Available online: (accessed on 25 June 2015). [Google Scholar]
  193. Ames, B.N. Identifying environmental chemicals causing mutations and cancer. Science 1979, 204, 587–593. [Google Scholar] [CrossRef] [PubMed]
  194. EPA. Essential Principles for Reform of Chemicals Management Legislation. Available online: (accessed on 25 June 2015).
  195. American Medical Association House of Delegates. Resolution 427: Encouraging Safer Chemicals Policies and Regulatory Reform of Industrial Chemicals to Protect and Improve Human Health; American Medical Association House of Delegates: Chicago, IL, USA, 2008. [Google Scholar]
  196. Pediatrics, A.A.O. Policy statement—Chemical-management policy: Prioritising children’s health. Pediatrics 2011, 127, 983–992. [Google Scholar]
  197. Segal, D.; Makris, S.L.; Kraft, A.D.; Bale, A.S.; Fox, J.; Gilbert, M.; Bergfelt, D.R.; Raffaele, K.C.; Blain, R.B.; Fedak, K.M.; et al. Evaluation of the ToxRTool’s ability to rate the reliability of toxicological data for human health hazard assessments. Regul. Toxicol. Pharmacol. 2015, 72, 94–101. [Google Scholar] [CrossRef] [PubMed]
  198. Gomez, A.; Balsari, S.; Nusbaum, J.; Heerboth, A.; Lemery, J. Perspective: Environment, biodiversity, and the education of the physician of the future. Acad. Med. 2013, 88, 168–172. [Google Scholar] [CrossRef] [PubMed]
  199. Pope, A.M.; Rall, D.P. Environmental Medicine: Integrating a Missing Element into Medical Education; National Academies Press (US): Washington, DC, USA, 1995. [Google Scholar]
  200. Institute of Medicine. Role of the Primary Care Physician in Occupational and Environmental Medicine; National Academies Press (US): Washington, DC, USA, 1988. [Google Scholar]
  201. Ducatman, A.M. Occupational Physicians and Environmental Medicine. J. Occup. Environ. Med. 1993, 35, 251–259. [Google Scholar]
  202. Royal Australasian College of Physicians. Environmental Medicine Working Group; Review Paper; Australasian Faculty of Occupational and Environmental Medicine: Sydney, Australia, 2012. [Google Scholar]
  203. Schwartz, B.S.; Rischitelli, G.; Hu, H. Editorial: The future of environmental medicine in environmental health perspectives: Where should we be headed? Environ. Health Perspect. 2005, 113, A574–A576. [Google Scholar] [CrossRef] [PubMed]
  204. Politi, B.J.; Arena, V.C.; Schwerha, J.; Sussman, N. Occupational medical history taking: How are today’s physicians doing? A cross-sectional investigation of the frequency of occupational history taking by physicians in a major US teaching center. J. Occup. Environ. Med. 2004, 46, 550–555. [Google Scholar] [CrossRef] [PubMed]
  205. American College of Physicians. The role of the internist in occupational medicine: A position paper of the American College of Physicians (14 September 1984). Am. J. Ind. Med. 1985, 8, 95–99. [Google Scholar]
  206. American College of Physicians (ACP). Occupational and environmental medicine: The internist’s role. Ann. Intern. Med. 1990, 113, 974–982. [Google Scholar]
  207. O’Brien, F. Networking, Technology Centres and Environmental Health: Towards a Science of the Heart. In Proceedings of the European Conference on Cooperation in Environmental Technology, Cologne, Germany, 13–15 November 1991.
  208. O’Connor, J. Environmental health education: A global perspective. IFEH Mag. Int. Fed. Environ. Health 2013, 14, 48–56. [Google Scholar]
  209. WHO. Environmental Health and the Role of Medical Professionals: Report on a WHO Consultation; WHO: Geneva, Switzerland, 1996. [Google Scholar]
  210. Shanahan, E.M.; Lindemann, I.; Ahern, M.J. Engaging medical students in occupational and environmental medicine—A new approach. Occup. Med. (Lond.) 2010, 60, 566–568. [Google Scholar] [CrossRef] [PubMed]
  211. Hays, E.P., Jr.; Schumacher, C.; Ferrario, C.G.; Vazzana, T.; Erickson, T.; Hryhorczuk, D.O.; Leikin, J.B. Toxicology training in US and Canadian medical schools. Am. J. Emerg. Med. 1992, 10, 121–123. [Google Scholar] [CrossRef]
  212. Thompson, T.M. Diversity in medical toxicology: Why this is important. J. Med. Toxicol. 2013, 9, 215–216. [Google Scholar] [CrossRef] [PubMed]
  213. Association of American Medical Colleges. Medical School Graduation Questionnaire. 2013 All Schools Summary Report. Available online: (accessed on 25 June 2015).
  214. WHO. International Conference on Environmental Threats to the Health of Children: Hazards and Vulnerability; WHO: Geneva, Switzerland, 2002. [Google Scholar]
  215. Tinney, V.A.; Paulson, J.A.; Bathgate, S.L.; Larsen, J.W. Medical education for obstetricians and gynecologists should incorporate environmental health. Am. J. Obstet. Gynecol. 2015, 212, 163–166. [Google Scholar] [CrossRef] [PubMed]
  216. Schenk, M.; Popp, S.M.; Neale, A.V.; Demers, R.Y. Environmental medicine content in medical school curricula. Acad. Med. 1996, 71, 499–501. [Google Scholar] [CrossRef] [PubMed]
  217. Association of American Medical Colleges. Teaching Population Health: Innovative Medical School Curricula on Environmental Health. Available online: (accessed on 25 June 2015).
  218. American College of Medical Toxicology (ACMT). ACMT Environmental Medicine Modules; ACMT: Phoenix, AZ, USA, 2015. [Google Scholar]
  219. Sutton, P.; Woodruff, T. The Navigation Guide. J. San Franc. Med. Soc. 2010, 83, 25–26. [Google Scholar]
  220. Alam, G.; Jones, B.C. Toxicogenetics: In search of host susceptibility to environmental toxicants. Front. Genet. 2014. [Google Scholar] [CrossRef] [PubMed]
  221. Biankin, A.V.; Piantadosi, S.; Hollingsworth, S.J. Patient-centric trials for therapeutic development in precision oncology. Nature 2015, 526, 361–370. [Google Scholar] [CrossRef]
  222. Committee on Quality of Health Care in America. Crossing the Quality Chasm: A New Health System for the 21st Century; National Academy Press: Washington, DC, USA, 2001. [Google Scholar]
  223. Darbre, P.D. Chapter 2—How could endocrine disrupters affect human health? In Endocrine Disruption and Human Health; Darbre, P.D., Ed.; Academic Press: Boston, MA, USA, 2015; pp. 27–45. [Google Scholar]
  224. Harremoës, P.; Gee, D.; MacGarvin, M.; Stirling, A.; Keys, J.; Wynne, B.; Vaz, S.G. Late Lessons from Early Warnings: The Precautionary Principle 1896–2000; Office for Official Publications of the European Communities: Luxembourg City, Luxembourg, 2001. [Google Scholar]
  225. Pott, P. Chirurgical Works of Percival Pott, FRS and Surgeon to St. Bartholomew’s Hospital; Hawes, Clarke, Collins: London, UK, 1775. [Google Scholar]
  226. Snow, J. On the origin of the recent outbreak of cholera at West Ham. Br. Med. J. 1857, 1, 934–935. [Google Scholar] [CrossRef]
  227. Harvey, A.; Brand, A.; Holgate, S.T.; Kristiansen, L.V.; Lehrach, H.; Palotie, A.; Prainsack, B. The future of technologies for personalised medicine. N. Biotechnol. 2012, 29, 625–633. [Google Scholar] [CrossRef] [PubMed]
  228. Johnson, K.C.; Miller, A.B.; Collishaw, N.E.; Palmer, J.R.; Hammond, S.K.; Salmon, A.G.; Cantor, K.P.; Miller, M.D.; Boyd, N.F.; Millar, J. Active smoking and secondhand smoke increase breast cancer risk: The report of the Canadian expert panel on tobacco smoke and breast cancer risk (2009). Tob. Control 2010. [Google Scholar] [CrossRef] [PubMed]
  229. Hankinson, S.E.; Colditz, G.A.; Willett, W.C. Towards an integrated model for breast cancer etiology: The lifelong interplay of genes, lifestyle, and hormones. Breast Cancer Res. 2004, 6, 213–218. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  230. Lerner-Ellis, J.; Khalouei, S.; Sopik, V.; Narod, S.A. Genetic risk assessment and prevention: The role of genetic testing panels in breast cancer. Expert Rev. Anticancer Ther. 2015, 15, 1315–1326. [Google Scholar] [CrossRef] [PubMed]
  231. Zhang, J.; Qiu, L.X.; Wang, Z.H.; Wu, X.H.; Liu, X.J.; Wang, B.Y.; Hu, X.C. MTHFR C677T polymorphism associated with breast cancer susceptibility: A meta-analysis involving 15,260 cases and 20,411 controls. Breast Cancer Res. Treat. 2010, 123, 549–555. [Google Scholar] [CrossRef]
  232. Ünlü, A.; Ates, N.A.; Tamer, L.; Ates, C. Relation of glutathione S-transferase T1, M1 and P1 genotypes and breast cancer risk. Cell Biochem. Funct. 2008, 26, 643–647. [Google Scholar] [CrossRef] [PubMed]
  233. Šarmanová, J.; Šůsová, S.; Gut, I.; Mrhalová, M.; Kodet, R.; Adámek, J.; Roth, Z.; Souček, P. Breast cancer: Role of polymorphisms in biotransformation enzymes. Eur. J. Hum. Genet. 2004, 12, 848–854. [Google Scholar] [CrossRef] [PubMed]
  234. Oliveira, A.; Rodrigues, F.; Santos, R.; Aoki, T.; Rocha, M.; Longui, C.; Melo, M. GSTT1, GSTM1, and GSTP1 polymorphisms and chemotherapy response in locally advanced breast cancer. Genet. Mol. Res. 2010, 9, 1045–1053. [Google Scholar] [CrossRef] [PubMed]
  235. Kumar, P.; Yadav, U.; Rai, V. Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: Evidence for genetic susceptibility. Meta Gene 2015, 6, 72–84. [Google Scholar] [CrossRef] [PubMed]
  236. Meplan, C.; Dragsted, L.O.; Ravn-Haren, G.; Tjonneland, A.; Vogel, U.; Hesketh, J. Association between polymorphisms in glutathione peroxidase and selenoprotein P genes, glutathione peroxidase activity, HRT use and breast cancer risk. PLoS ONE 2013. [Google Scholar] [CrossRef] [PubMed]
  237. Cerne, J.Z.; Pohar-Perme, M.; Novakovic, S.; Frkovic-Grazio, S.; Stegel, V.; Gersak, K. Combined effect of CYP1B1, COMT, GSTP1, and MnSOD genotypes and risk of postmenopausal breast cancer. J. Gynecol. Oncol. 2011, 22, 110–119. [Google Scholar] [CrossRef] [PubMed]
  238. Liu, G.; Sun, G.; Wang, Y.; Wang, D.; Hu, W.; Zhang, J. Association between manganese superoxide dismutase gene polymorphism and breast cancer risk: A meta-analysis of 17,842 subjects. Mol. Med. Rep. 2012, 6, 797–804. [Google Scholar]
  239. Lin, W.Y.; Chou, Y.C.; Wu, M.H.; Jeng, Y.L.; Huang, H.B.; You, S.L.; Chu, T.Y.; Chen, C.J.; Sun, C.A. Polymorphic catechol-O-methyltransferase gene, duration of estrogen exposure, and breast cancer risk: A nested case-control study in Taiwan. Cancer Detect. Prev. 2005, 29, 427–432. [Google Scholar] [CrossRef] [PubMed]
  240. Vogel, U.; Bonefeld-Jørgensen, E.C. Polymorphism and gene-environment interactions in environmental cancer. In Encyclopedia of Environmental Health; Nriagu, J.O., Ed.; Elsevier: Burlington, MA, USA, 2011; pp. 631–639. [Google Scholar]
  241. Piacentini, S.; Polimanti, R.; Porreca, F.; Martínez-Labarga, C.; de Stefano, G.F.; Fuciarelli, M. GSTT1 and GSTM1 gene polymorphisms in European and African populations. Mol. Biol. Rep. 2011, 38, 1225–1230. [Google Scholar] [CrossRef] [PubMed]
  242. Ziegler, R.G.; Hoover, R.N.; Pike, M.C.; Hildesheim, A.; Nomura, A.M.; West, D.W.; Wu-Williams, A.H.; Kolonel, L.N.; Horn-Ross, P.L.; Rosenthal, J.F.; et al. Migration patterns and breast cancer risk in Asian-American women. J. Natl. Cancer Inst. 1993, 85, 1819–1827. [Google Scholar] [CrossRef] [PubMed]
  243. Gomez, S.L.; Quach, T.; Horn-Ross, P.L.; Pham, J.T.; Cockburn, M.; Chang, E.T.; Keegan, T.H.M.; Glaser, S.L.; Clarke, C.A. Hidden breast cancer disparities in asian women: Disaggregating incidence rates by ethnicity and migrant status. Am. J. Public Health 2010, 100, 125–131. [Google Scholar] [CrossRef]
  244. Barrett, J.C.; Vainio, H.; Peakall, D.; Goldstein, B.D. 12th meeting of the Scientific Group on Methodologies for the Safety Evaluation of Chemicals: Susceptibility to environmental hazards. Environ. Health Perspect. 1997, 105, 699–737. [Google Scholar] [CrossRef]
  245. Garrod, A. The incidence of alkaptonuria: A study in chemical individuality. Lancet 1902, 160, 1616–1620. [Google Scholar] [CrossRef]
  246. Bland, J. Functional Medicine & “Omics”: A Match Made in Heaven. In Proceedings of the Annual International Conference of The Omics Revolution Nature And Nurture, San Diego, CA, USA, 28 May 2015.
  247. Neff, G. Why big data won’t cure us. Big Data 2013, 1, 117–123. [Google Scholar] [CrossRef] [PubMed]
  248. Katsanis, S.H.; Katsanis, N. Molecular genetic testing and the future of clinical genomics. Nat. Rev. Genet. 2013, 14, 415–426. [Google Scholar] [CrossRef] [PubMed]
  249. National Health and Medical Research Council (NHMRC). Direct-to-Consumer DNA Genetic Testing; NHMRC: Canberra, Australia, 2011. [Google Scholar]
  250. Sawhney, V.S.R.; O’Brien, B. Genetics to genomics in clinical medicine. Indian J. Med. Res. 2014, 4, 4926–4938. [Google Scholar] [CrossRef] [PubMed]
  251. Botkin, J.R.; Belmont, J.W.; Berg, J.S.; Berkman, B.E.; Bombard, Y.; Holm, I.A.; Levy, H.P.; Ormond, K.E.; Saal, H.M.; Spinner, N.B.; et al. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am. J. Hum. Genet. 2015, 97, 6–21. [Google Scholar] [CrossRef] [PubMed]
  252. Nys, H. Genetic Testing: Patients’ Rights, Insurance and Employment: A Survey of Regulations in the European Union; Office for the Official Publications of the European Communities: Brussels, Belgium, 2002. [Google Scholar]
  253. Chow-White, P.A. From the bench to the bedside in the big data age: Ethics and practices of consent and privacy for clinical genomics and personalized medicine. Ethics Informa. Technol. 2015, 17, 189–200. [Google Scholar] [CrossRef]
  254. Solomon, S. Chapter 24—Ethical Challenges to Next-Generation Sequencing, in Clinical Genomics; Pfeifer, S.K., Ed.; Academic Press: Boston, MA, USA, 2015; pp. 403–434. [Google Scholar]
  255. Paulos, E.; Honicky, R.; Hooker, B. Citizen science: Enabling participatory urbanism. In Handbook of Research on Urban Informatics: The Practice and Promise of the Real-Time City; Foth, M., Ed.; IGI GLobal: Hershey, PA, USA, 2009; pp. 414–436. [Google Scholar]
  256. Logan, Y. The Story of the baby tooth survey. Sci. Citiz. 1964, 6, 38–39. [Google Scholar] [CrossRef]
  257. Aitken, M.; Gauntlett, C. Patient Apps for Improved Healthcare: From Novelty to Mainstream; IMS Institute for Healthcare Informatics: Parsippany, NJ, USA, 2013. [Google Scholar]
  258. Krebs, P.; Duncan, D.T. Health app use among US mobile phone owners: A national survey. JMIR Mhealth Uhealth 2015. [Google Scholar] [CrossRef] [PubMed]
  259. Marcus, F. Handbook of Research on Urban Informatics: The Practice and Promise of the Real-Time City; IGI Global: Hershey, PA, USA, 2009; pp. 1–506. [Google Scholar]
  260. Louv, R.; Fitzpatrick, J.W.; Dickinson, J.L.; Bonney, R. Citizen Science: Public Participation in Environmental Research; Cornell University Press: Ithaca, NY, USA, 2012. [Google Scholar]
  261. Kurup, V. E-patients-Revolutionizing the Practice of Medicine. Int. Anesthesiol. Clin. 2010, 48, 123–129. [Google Scholar] [CrossRef] [PubMed]
  262. Payne, P.R.O.; Marsh, C.B. Towards a “4I” approach to personalized healthcare. Clin. Transl. Med. 2012. [Google Scholar] [CrossRef] [PubMed]

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Bijlsma, N.; Cohen, M.M. Environmental Chemical Assessment in Clinical Practice: Unveiling the Elephant in the Room. Int. J. Environ. Res. Public Health 2016, 13, 181.

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Bijlsma N, Cohen MM. Environmental Chemical Assessment in Clinical Practice: Unveiling the Elephant in the Room. International Journal of Environmental Research and Public Health. 2016; 13(2):181.

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Bijlsma, Nicole, and Marc M. Cohen. 2016. "Environmental Chemical Assessment in Clinical Practice: Unveiling the Elephant in the Room" International Journal of Environmental Research and Public Health 13, no. 2: 181.

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