Systems Toxicology and the Exposome
Systems toxicology is a relatively new multidisciplinary approach to toxicology that aims to include all factors contributing to the potential toxicity of a substance, at multiple levels within the body, including molecular, cellular and organismal (e.g. whole human being), throughout time and space. [1] A systems science approach to toxicology delivers better, more realistic data to improve understanding of dynamic, complex mechanisms, prediction of adverse outcomes and guidance for risk assessment. [2]
However, it is common practice in toxicology to study potentially toxic substances in isolation, separate from the mixtures from which they are commonly found, using relatively sterile laboratory conditions and in vitro and/or animal models. Moreover, the toxicity of single substances is commonly inferred by their effects on single targets, such as genes, enzymes or transporters, within isolated molecular pathways.
Standardized, reductionist procedures provide a basic understanding of the mode-of-action and potential toxicity of isolated substances but do not accurately reflect conditions of real-world exposure. In almost all instances of human, animal or plant exposure to potentially toxic substances, the substance is present in a mixture and/ or subject to other external or internal environmental pressures that influence its biological activity. [1] Regulatory policies based on studying environmental toxicants in isolation often give estimates of potential toxicity with limited value when extrapolated to living systems.
Moreover, the multiple parallel hits hypothesis posits that the pathophysiology of certain chronic diseases (e.g. obesity, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD/ MASLD [2]) involves several different contributing factors occurring either simultaneously or closely following each other. In other words, there is no one factor that causes disease but the totality of all negative contributing factors acting together in time and space to overwhelm the capacity of an individual’s body and physiology.
[1] The biological activity of a single substance when placed in a mixture is either synergistically or additively enhanced, reduced or unchanged.
[2] NAFLD recently was renamed to metabolic dysfunction-associated steatotic liver disease (MASLD). Eslam M, Sanyal AJ, George J; International Consensus Panel. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology. 2020 May;158(7):1999-2014
The exposome, defined as ‘a measure of the totality of human environmental (meaning all non-genetic) exposures from conception onwards’ [3] [4] is a concept that was introduced in 2005 to overcome limitations of reductionist views and methodology in research on environmental exposures. Systems toxicology incorporates the exposome concept and includes a framework to study and test environmental chemicals and exposures in a manner that is more aligned with current knowledge of the dynamic, time- and space-dependent complexity of environmental influences on human health and disease. The Human Toxome project [5] was established in 2011 to use modern ‘omics’ systems biology methods to accelerate the testing of the vast backlog of more than 80,000 chemicals humans are exposed to which have unknown potential toxicity and to provide test results that more accurately predict human toxicity than current methods. [6]
There are recent attempts to establish methods for human health risk assessment from combined exposure to multiple chemicals. [7] However, most regulatory and legislation decisions are still made based solely on toxicological evaluation of single substances under artificial laboratory conditions, [8] including little or no data on which chemicals do occur together in the real world as well as the health consequences of their co-exposure in susceptible humans and animals. Modernizing regulatory policies for safe drugs, safe foods, environmental protection and green chemistry during manufacturing to include systems toxicology approaches would provide more accurate, meaningful and useful descriptions of real-world exposures to potential environmental toxicants and their impact on health.
Where Do They Come From?
There is a large range of internal or external environmental factors that can modify the biological activity of single environmental toxicants. External factors include other chemicals in the mixture, exposure to heat and/or ultraviolet light, storage time, and other concurrent dietary choices, lifestyle habits, or circumstances (e.g. socioeconomic factors). Internal factors include genetics and epigenetics, health of the organs, especially the organs of elimination such as liver, gut, kidneys, skin, and lungs, functioning of organelles such as the mitochondria, overwhelming or persistent psychological stress, altered gut microbiota, and individual differences in age, sex/ gender and body mass composition.
How They Affect You
A systems science approach to toxicology can increase our understanding of the totality of the numerous factors influencing environmental health. For example, the potential harm caused by single environmental toxicants can be magnified with simultaneous exposure to external environment factors including heat, ultraviolet light and air pollution. Concurrent exposure to internal stressors such as persistent or overwhelming psychological stress, poor socioeconomic status, obesity and dysbiosis also can exacerbate the harm caused by individual pollutants.
Heat and Ultraviolet Light
Bisphenol A or phthalates leach from plastic containers into seawater [9] or into bottled water [10] at higher concentrations when there is exposure to heat or ultraviolet light. Similarly, the amount of BPA that migrates from food and beverage containers into the products they contain depends on temperature, manufacturing processes, the length of storage, repeated use as well as on the type of food and packaging. [11] [12] Similarly, more potentially toxic substances such as formaldehyde, acetaldehyde and antimony are released from polyethylene terephthalate (PET) bottles into water when it is stored at higher temperatures (40, 50 or 60C) [13] or exposed to increasing lengths of natural sunlight (2, 6, 10 days). [14] The amount of antimony leached from PET bottles was higher depending on the beverage it contained with the highest amount in carbonated and protein-rich beverages. [15]
Microplastics are environmental pollutants recently identified as a major global threat for environment, food safety and human health. [16] When tested under laboratory conditions of normal temperature and single use, the amount of microplastics released from bottled water and food packaging is considered as probably safe for human consumption. However prolonged storage time, repeated use and exposure to higher temperatures increases the quantity detected in food and drink and therefore, the potential harm. [17] For example, tea bags from numerous manufacturers are now constructed using material containing microplastics, and other chemicals, that increase their migration into the tea beverage when higher temperature (>90-95C) water is used. [18]
Air Pollution
Multiple factors increase the health risks of air pollution. For example, there may be combined health risks, including accelerated aging, cardiovascular and neurological disease, in people simultaneously exposed to the air pollutants and noise associated with heavy urban traffic. [19] Risk of negative health effects to small particulate matter (e.g. PM 2.5s) in air pollution also is higher in hotter climates during sunny periods. A recent study showed significantly increased mortality during co-exposure to extremes of heat and particulate air pollution, [20] suggesting that current levels of air pollution combined with the increasing number and intensity of heat waves associated with climate change could be a deadly combination. [21] Also, increased air pollution may decrease levels of physical activity; likewise, increased levels of physical inactivity may increase the negative effects of air pollution [22] And reduced sleep quality also may increase the negative health effects of air pollution. [23]
Air pollution, especially exposure to PM 2.5s, has been recognized as a key silent driver of cognitive dysfunction such as dementia. [24] The risk of dementia from long term exposure to PM 2.5s is even higher if other factors such as socioeconomic status, presence of the APOE allele, psychological stress, body mass index (BMI), age and female sex/ gender are present. [25] Numerous other common environmental toxicants may contribute collectively to an increased risk of cognitive dysfunction and dementia. [26]
Psychosocial Stress
Negative effects of different environmental toxicants can be modified, usually exacerbated, in persons who are also experiencing high amounts of psychosocial stress. For example, indicators of poor cardiovascular health, including hypertension and altered blood lipids, are elevated in persons exposed to the combination of higher amounts of psychosocial stress, PM 2.5s and ozone from air pollution. [27] [28] Children in high stress households have significantly reduced lung function parameters following exposure to air pollution than children from low stress households. [29]
Persistent or overwhelming psychosocial stress can increase the negative impact of environmental chemicals in different ways including affecting the gastrointestinal tract in different ways (e.g. causing dysbiosis, increasing intestinal permeability (i.e. leaky gut), altering motility), [30] interfering with detoxification pathways and triggering a low level of inflammation not only in the brain (i.e. neuroinflammation) but also the rest of the body. [31]
Socioeconomic Status
Lower socioeconomic status also can be an effect-modifier, increasing the negative effects of air pollution especially in vulnerable populations such as in children. [32] Current evidence suggests that child health outcomes are negatively influenced if pregnant women experience both non-chemical stressors including poverty, depression, discrimination and stressful life events and chemical stressors (e.g. pesticides, phthalates, polychlorinated biphenyls) simultaneously. [33] Socioeconomic characteristics, coexisting diseases and pollutant co-exposures also combine with air pollution to increase the risk Type 2 diabetes mellitus (T2DM). [34]
Obesity
The relationship between obesity and environmental toxicants is complex and bidirectional. Adipose tissue stores environmental toxicants, produces adipokines and other hormone-like signals that promote inflammation, interfere with metabolism and increase risk of diseases such as T2DM. [35] Environmental toxicants, including persistent organic pollutants, [36] microplastics and their additives such as phthalates, bisphenols and organotins, [37] work collectively as obesity promoting agents termed ‘obesogens’. [38] Moreover, many of these types of endocrine disrupting chemicals are found in mixtures in the environment, with insufficient or absent knowledge of their combined effects. [39]
Metabolism and the Gut
Multiple environmental pollutants profoundly affect metabolism including interfering with different parts of biochemical pathways regulating insulin-mediated glucose uptake into cells and tissues, [40] lipid metabolism in the liver, [41] as well as energy production and other functions of mitochondria. [42] Co-exposure to more than one toxicant, either simultaneously or throughout one’s lifetime, has combined effects that compounds risk of metabolic disease.
A complex bidirectional relationship exists between environmental pollutants and human gut microbiota. [43] The metabolism, absorption, pharmacodynamics and potency of many ingested substances including environmental toxicants, pharmaceutical drugs and natural health products is affected by the numbers and types of microbes in the gut. [44] [45] [46] Similarly, the health of gut microbiota can be negatively influenced by numerous factors including diet and lifestyle choices, [47] use of antibiotics and many non-antibiotic pharmaceutical drugs, [48] microplastics, [49] as well as inflammation. [50] The health of the gut microbiome is usually not considered in regulatory decisions on environmental pollutants; however, it could have a profound effect on the safety and efficacy of most ingested substances.
Age of Exposure
Age of exposure also influences the relative risk of harm from environmental toxicants. For example, multiple environmental chemicals can harm a developing fetus. [51] Reducing exposure to these agents, when by themselves or often in mixtures, can prevent disease in infants as well as help establish a foundation of good health throughout their lifetime. Negative health risks of air pollution are also higher if the person exposed is psychologically stressed or has other comorbidities but also is in a vulnerable age (e.g. very young or very old). [52] Elderly individuals also are at increased risk to the negative health effects of environmental toxicants. [53] [54] Most experiments guiding regulatory decisions for potentially toxic chemicals are performed in adults. Extrapolating this data to children or seniors could underestimate their potential harm.
How To Protect Yourself
Maintaining a healthy lifestyle and working on the health of your physical organs, especially the organs of elimination such as the gastrointestinal tract, liver, kidney, skin and lungs assists in protecting oneself from the myriad of dynamic mixtures of environmental toxicants one is exposed to daily. A prudent approach to prevention may include:
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reduce the burden of toxicants on body organs through regular general detoxification, at least once a year in otherwise healthy people.
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support healthy gut microbiota through diet, probiotics and other means, as gut microbiota metabolize ingested compounds, including various toxicants.
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ensure healthy sleep habits, as sleep plays a role in removal of potential toxic waste products from the brain and nervous system, [55] and prevents harm from environmental toxicants.
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support mental health, as prolonged or overwhelming psychological stress adds to the risk of harm from exposure to environmental toxicants.
Ideally, use plastic free containers such as glass, stainless steel or ceramic for storing water or beverages. However, if it is necessary to buy water or other beverages in plastic bottles one can reduce exposures to potentially harmful chemicals by reading labels for expiry dates before buying, and avoiding buying products that have been stored too long in the warehouse or in the shop; storing products in a cold, dark place away from heat and sunlight for the shortest time possible before use and avoiding reusing them, especially washing them with harsh detergents.
In general, the storage of acidic canned foods (e.g. vegetables) should be limited as they cause the most migration of BPA. BPA-lined food cans also should be stored for the shortest amount of time possible away from direct heat.
Avoid using tea bags that contain plastic. Use either unbleached paper tea bags or loose-leaf tea poured into glass, metal or ceramic strainers.
Work with a naturopathic doctor / naturopath to help you assess for environmental pollutants and to understand how they may be affecting your health. The information on this website is a guide for ways to protect you and your family from environmental pollutants. It is not meant to replace advice from a healthcare professional.
3 Essentials
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The impact of environmental chemicals is extraordinarily complex and involves numerous contributing factors including presence in mixtures, other influences from the external or internal environment and the age, sex and comorbidities of the individual as well as the health of their organs and organelles.
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The commonly used research methodology to set policies on acceptable levels of environmental pollutants provides only a general, and somewhat artificial estimate that does not accurately reflect real-world potential impacts on health. Even though an environmental toxicant may be regulated as safe when tested by itself in an artificial laboratory setting, once placed in a mixture or in an environment that more accurately reflects the real world, there may be synergistic or additive effects that trigger a tipping point towards disease.
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Systems toxicology is a 21st century systems biology approach to toxicology which aims to establish guidelines for research in toxicology and policy making that more accurately reflects the authentic/ genuine impact of environmental influence on human health and disease. Systems toxicology provides an additional foundational step in personalized medicine, providing more accurate estimates of environmental risks to guide more meaningful prevention and treatment plans.
Additional Key Recommendations
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It is important to be aware of the currently identified chemical and non-chemical stressors that could combine to negatively impact health. Enhancing awareness of individual environmental toxicants and their potential harm, helps avoid exposure to one or more toxicants found in mixtures of different household items, common foods, or drink. Building a solid foundation of healthy lifestyle habits including regular exercise, healthy sleep habits and regular activities that strengthen mental health reduces the potential for environmental pollutants to cause harm.
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