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The catch with toxicological testing is that it would be illogical for an industry to conduct testing at environmentally relevant doses, because the regulatory framework means that observations of effects will preclude registration. Research now contradicts this view that toxicity becomes apparent at higher doses and is not detectable below a certain level, as non-monotonic dose response curves are well recognized to be usually associated with endocrine effects [ 96 ].
Indeed, the American Chemical Society, with extensive membership among the chemical industry, recognizes that low-dose, endocrine disrupting effects are scientifically undermining the toxicological testing that underpins current chemical regulation [ 97 ]. Another obvious shortcoming of regulatory animal toxicology is that humans are not rodents.
Human studies of toxicants are ethically intransigent, and thus necessarily subject to limitations of observational studies, but health researchers and professionals argue persuasively why and how epidemiology could and should be given greater weight in chemical assessment [ 98 ]. The Substitution Principle is in part a pragmatic response to the enormity of the numbers and diversity of anthropogenic chemicals, as well as the logistical impossibility of scientifically assessing all chemicals, let alone combinations [ 99 ].
In essence, the least-toxic, and most environmentally sustainable options for a particular product or application are the ones that are permitted. With rules laid out as to allowable uses and levels of toxicants, protection of public health falls into the purview of a variety of professionals, from environment, agriculture, natural resource, and health ministries to local public health.
Pollution and human exposure may be tracked on many levels, by governments monitoring and reporting toxicants from large scale industrial emissions; environmental levels in air, water, soil, and wildlife; individual exposures in foods, drinking water and consumer products; and levels in people themselves with population surveillance. Governments regularly publish online data such as daily air quality, and may announce product recalls e. A list of some helpful websites addressing chemical assessment and monitoring is provided in Table 1 many additional sites are available for individual countries.
Nongovernmental organizations also carry on myriad public education campaigns such as recommending foods with lower levels of pesticides [ ] or personal care products with lower levels of chemicals of concern [ ], or even identifying houses at risk for child lead exposures [ ]. Evolution of public health initiatives as risks are recognized may drive innovation; for instance, more stringent standards are possible as water and waste treatment technologies improve, and best practices for pest management change when the array of permitted chemicals is limited.
Medical practitioners themselves should be knowledgeable, and have the resources to educate and facilitate their patients making the best choices for their personal, family, patient and community health. On a broader scale, the voice of the medical community has excellent credibility in setting public policy to promote health. The reality of the contemporary world is that toxicants are ubiquitous and, while avoidance is central to any management strategy, toxicants are not entirely avoidable.
Emerging evidence, however, challenges this misconception. The contention that the body has an inherent ability to eliminate quickly all adverse chemical compounds is inaccurate, as many toxicants with long half-lives accrue in tissues or blood, thus maintaining long-term potential to inflict damage.
Metals such as lead and cadmium, and many halogenated compounds e. Unfolding research reveals ineluctable evidence that various interventions facilitate elimination of retained compounds [ 87 , ], with the objective of diminishing the risks associated with biologically stockpiled poisons. Although more extensive reviews of various modalities to eliminate toxicants can be found in other works [ ], we present an overview of potential approaches that can be employed to facilitate the removal of accrued toxicants. With a wide range of distinct chemical compounds, each with a unique chemical structure and a potentially distinct way of interfacing with human biochemistry, there is no single mechanism or pathway for the body to eliminate the whole spectrum of 21st century chemical toxicants.
Thus, when attempting to detoxify the human body, it is first important to explore the specific accrued toxicants comprising the total chemical burden, and to employ effective methods to facilitate excretion of various components. When a patient with evidence of potential toxicant-related health problems presents to a clinician trained in environmental health sciences, an attempt is generally made to identify which adverse chemicals are retained within the body, in order to employ specific interventions to address each of these compounds.
With the vast array of toxicants that individuals are exposed to, how does one comprehensively determine which toxicants are present and then assess the extent of the total body burden? As clinical laboratory methods to assess many toxicants are not extensively validated with meaningful reference ranges, there is limited ability at this time to investigate a broad range of specific chemicals.
Blood and urine are most commonly sampled to assess levels of retained toxicants. Apart from difficulties interpreting results in the absence of population-specific reference-limits, these measurements may be significantly flawed as indicators of bioaccumulation because many compounds sequester in tissues; they do not remain in blood and may not be readily excreted in urine. Thus testing of whole blood or serum generally does not adequately detect toxicants that are being stored primarily in organs, bone, muscle or adipose tissues [ 26 , 87 ].
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As well, levels of toxicant compounds in blood and urine can also fluctuate rapidly as a result of nutrient or pharmaceutical use, caloric restriction, hydration, underlying nutrient status, thermal changes, or exercise [ — ]. For clinical purposes therefore, blood or urine testing to determine the total body load of toxicants may underestimate the level of accrual for many toxicants. Testing of other tissues and bodily excretions has also been explored, including salivary testing, hair analysis, stool sampling, perspiration testing, breath analysis, provocation testing, as well as biopsies of fat tissue.
Recent evidence confirms, however, that there are limitations with each of these approaches. Hair samples, for example may only reflect selected toxicant levels in the blood stream for the last few weeks, while stool samples only assess what is being eliminated through the gastrointestinal tract. Fat biopsy research confirms that toxicants sequester differently within different fat compartments, with toxicant concentrations varying widely among adipose tissue sites [ ]. Although selected testing techniques for some toxicants can be helpful as an indication of toxicant bioaccumulation, attempts to accurately and comprehensively delineate the accrued level of each toxicant compound are impractical clinically and prohibitively expensive.
The results are imprecise at best, and are prone to false negatives in the sense that a low blood value, for instance, may simply not reflect high levels in the bone, or a vital organ such as the kidney or brain. Values in urine, hair and feces by definition reflect the ability to excrete rather than the body burden of a toxicant, and impaired excretion may result in greater accretion and potential adverse effects, leading to the paradoxical finding that body burden is apparently lower in a population whose health is in fact being affected by a toxin, as was seen in children with autism [ — ].
So what is a reasonable clinical approach to patients who appear to have been harmed by bioaccumulative toxicant exposures? With currently available knowledge and technologies, three fundamental clinical steps should be considered in the initial assessment and patient care planning for those with potential toxicant-related health problems: Rather than specialized treatments for each specific toxicant identified, in this paper, we present a general approach to detoxification.
This is an ongoing area of research, and other works are available that provide further particulars in the management of specific toxicant categories and individual chemical exposures [ 87 , 88 , ]. The clinical approach to human elimination of accrued compounds generally involves three successive stages: This is fundamental to any successful strategy to diminish the toxicant burden of individuals and populations.
From a clinical perspective, it is useful for the health provider to perform a detailed inventory of potential exposures. By means of a meticulous environmental health questionnaire [ ], most common exposures can be identified. An inventory of the six routes of possible sources of exposure should be undertaken: By identifying exposures and apprising individual patients regarding where and how they are being contaminated, patients are empowered to avoid further chemical contamination.
With ongoing exposures minimized, the human organism is able to devote resources and energies of detoxification physiology to metabolizing and excreting retained compounds, with less devoted to ongoing exposures. The human body has enormous potential to detoxify foreign compounds through various physiological mechanisms. Endogenous detoxification of metabolic waste products as well as foreign toxicants is a primary physiological function, that requires considerable energy.
Major organs of detoxification include the liver, kidney, skin, and lungs. When toxicants are identified by physiological processes within the body, pathways of excretion are mobilized to diminish toxicity and to eliminate the xenobiotic compounds. The particular pathways used to excrete specific substances will depend on the chemical properties of the particular agent in question. Potential pathways include metabolism or conjugation to form water-soluble compounds for renal excretion, metabolism to less toxic forms e.
The ability to eliminate undesired compounds, however, depends completely on the physiological functioning and biochemical status of the individual. Anything that impairs full functioning of detoxification biochemistry, such as nutritional deficiencies, will preclude proper elimination of toxic substances. Accordingly, it is imperative that health providers understand the fundamentals of detoxification physiology and biochemistry to secure functioning of the organs of elimination [ 26 ].
Clinical history and physical examination can provide clues to the status of physiological function and potential causes for impairment. A history of substance use, for example alcohol or medications known to be hepatotoxic, can be helpful in assessing liver function. Nutritional biochemistry testing, urinary organic acid testing, and biochemical markers for function of organs such as liver and kidney, can be employed to assess physiological status and function.
Any impediment to proper physiological functioning should be addressed.
Remediation of disordered nutritional biochemistry is a fundamental component of patient care. For example, the protein molecule glutathione is a prerequisite component of cellular detoxification as well as an essential pillar in hepatic conjugation biochemistry.
Individuals with ongoing exposures or toxicant bioaccumulation often have diminished stores of glutathione, and thus require ongoing repletion. Optimal nutrition through dietary instruction, correction of disordered biochemistry and physiology, and use of directed supplementation as dictated by laboratory testing is required for efficient physiological functioning of elimination pathways. It has also been observed that despite biochemical competency, the human organism is not able to excrete some chemical toxicants effectively. A major reason for the failure of some compounds to be eradicated effectively is because of recycling within the body through reabsorption in the enterohepatic circulation [ ] or reuptake in kidney tubules [ ].
Accordingly, some toxicants are conjugated and released from tissues into the bloodstream for excretion, but are then reabsorbed back into the body. Additionally, some retained compounds deposit in specific tissues such as bone, fat, and muscle, where they will bioaccumulate and alter physiological functioning within these tissues.
Some compounds will also remain in blood to some degree, frequently bound to plasma proteins [ 88 ]. Interventions to enhance excretion of retained compounds can be invaluable in diminishing morbidity associated with toxicant accrual. Environmental determinants such as toxicant bioaccumulation in some situations may interfere with normal physiological function and thus necessitate intervention. For example, vitamin D an essential biochemical that regulates genetic expression, and facilitates absorption of calcium from the gut may potentiate absorption of toxic elements such as lead, aluminum, and cadmium, that in turn may impair metabolism of vitamin D [ ].
Mercury contamination may alter gastrointestinal absorption of required nutrients resulting in deficiencies and thus precluding normal physiology. Some persistent organic pollutants released from adipose tissue during weight loss, caloric restriction or exercise may suppress thyroid function [ 77 ]. Adverse effects from toxicant bioaccumulation may cascade within the body—some toxicants, for example, may alter immune function, which may in turn spawn autoimmunity [ ] and thus engender abnormal physiological functioning.
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In difficult cases, consultation with experienced environmental health specialists may be required. Empirical research has shown that various strategies can be employed to assist with the effective removal of some accrued toxicants. Research into such strategies, however, remains at an early stage in the continuum of clinical science as the problem of widespread toxicant bioaccumulation is a newly recognized phenomenon for clinical medicine. A few strategies and a general approach to clinical detoxification are highlighted here for consideration.
A more detailed discussion of commonly employed strategies to facilitate detoxification can be found elsewhere [ ]. The skin is a major organ of detoxification, and a vast array of toxicants are able to be excreted to differing degrees via perspiration [ 87 , , ]. Various researchers and clinicians have endeavoured to take advantage of this dermal mechanism to facilitate excretion of accrued compounds and toxicological biomonitoring has confirmed that body burdens of many toxicants diminish with therapy to induce sweating [ , , ].
Some chemical agents such as perfluorinated compounds, however, do not seem to be readily excreted [ 88 ]. Despite much attention given to saunas with heaters emitting at specific electromagnetic frequencies, research to date suggests that there is no difference in toxicant excretion rates between perspiration that occurs through infrared sauna, dry or wet regular saunas, or exercise [ 87 , ].
These perform a useful role in facilitating the elimination of some compounds. For example, judicious use of chelators, or agents which strongly bind to some toxic elements have been demonstrated to assist in the removal of such toxicants [ , ]. Chelating agents such as dimercaptosuccinic acid DMSA are generally safe and effectively bind to metals such as lead and mercury to enhance excretion rates and to prevent enterohepatic reabsorption of these compounds [ ].
Marked clinical improvement has been noted in metal contaminated patients who have been treated with use of such medications [ ]. The use of concomitant strategies, such as foods and supplements to increase glutathione, to enhance mobilization of toxicants from tissue storage sites may significantly increase the rate of elimination from the body when used along with chelators. Bile acid sequestrants such as cholestyramine have recently garnered increasing attention as compounds that bind to some persistent compounds in the gastrointestinal tract to prevent enterohepatic reabsorption [ 88 ].
These agents may be useful with such persistent agents as perfluorinated compounds [ 88 ] and have been clinically effective in patients with mycotoxin accrual after mold exposure [ ]. As medical interventions to enhance elimination of toxicants is a newer area of clinical research, much remains to be studied in order to develop evidence-based medication protocols for the removal of some toxic compounds. Direct evidence of specific benefits in humans of diet and dietary supplements is often of limited applicability beyond the subject population, because of interactions with factors such as regional environment e.
Some medical evidence exists, however, that nutritional status e.
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Research questions are often much more amenable to animal and tissue culture research, and this body of evidence has confirmed traditions that some foods and supplemental nutrients are enormously valuable in facilitating excretion and reducing biochemical toxicities of toxicants. Although by no means an exhaustive list, some supplements include curcumin in the spice turmeric [ ], alliums [ ], plant flavonoids such as quercetin [ ], selenium [ ], algal products Parachlorella [ , ] and Chlorella [ , ], naturally occurring organic acids [ ], folate requisite minerals, and dietary fibre [ ] as well as mixed antioxidants [ ] appear to be of great value to reduce the damage associated with toxicant exposure.
The mechanisms of action may include preventing absorption of toxicants, facilitating elimination of accrued toxic compounds, hindering enterohepatic recycling of some persistent compounds, and diminishing toxicity through protective mechanisms. Insoluble carbohydrate and other fibre consumed in the diet, for example, appears to act like a sponge and increases the removal of adverse agents such as mycotoxins and POPs, perhaps by diminishing reabsorption through the enterohepatic circulation, and thus increasing elimination.
One example is a supplemental product called Chlorella , an algae from the sea, that has recently garnered much research attention for its unique properties in facilitating detoxification and preventing absorption of adverse compounds [ — ]. Recent research papers reported animal results where Chlorella appears to induce the excretion of mercury [ ] and lead [ ]. Ongoing study continues to elucidate the range of compounds that are bound and removed with Chlorella as well as with other assorted foods and supplemental nutrients.
A caution, however, is that supplements may potentially contain toxicants that accrued as they grew, such as Chlorella and other biosorbents that are also noted for their ability to sequester toxic elements from their environment [ ], fish oil that may contain POPs [ ], or other products that may be contaminated for other reasons [ ].
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Unfortunately, there is limited research on many of the programs and therapies that are commonly used and scientific evidence is often lacking to support the audacious claims frequently made to vulnerable, sick people. Using data available to date, a basic approach that can be used clinically, that incorporates the three successive steps for detoxification avoidance, support of endogenous detoxification, and directed interventions is presented for consideration. Health care professionals in government ministries, public health, research, and the clinic will only be successful against the onslaught of chronic, debilitating diseases once environmental contributors are recognized, researched and addressed.
Clinical intervention to preclude further exposure and to detoxify the body of toxicants can be life changing for afflicted individuals [ ]. In an epoch marred by the unleashing of numerous untested chemical toxicants, basic knowledge of environmental medicine should be provided in the training of all health care workers. History repeatedly demonstrates, however, that the translation of emerging scientific information with adoption of required clinical skills is usually not expeditious [ , ].
Hopefully, in our modern era of rapid information transfer, the process of widespread problem recognition and solution implementation will be expedited to stem the tide of chronic disease that is said to be poised to bankrupt healthcare systems. Parts of this work arose from a toxic metals scoping review for which M. The authors thank participants at a Toronto meeting on toxic metals February for inspiration regarding general, pragmatic clinical approaches. There is no conflict of interests. Journal of Environmental and Public Health.
Indexed in Web of Science. Subscribe to Table of Contents Alerts. Table of Contents Alerts. Abstract The World Health Organization warns that chronic, noncommunicable diseases are rapidly becoming epidemic worldwide. Introduction Common chronic conditions include cardiovascular and cerebrovascular disease, cancer, diabetes, metabolic syndrome, and obesity, neurocognitive disorders, and immune dysfunction such as autoimmune disease.
Environmental Contributors to Chronic Disease In a recent, extensive review of associations between early exposures to various chemicals and chronic disease throughout life, Cooper et al. Toxic Elements These elements such as arsenic [ 22 ], cadmium [ 23 ], lead [ 24 ], and mercury [ 25 ] are typically found in drinking water, foods, dust, fish, dental amalgams, consumer products, and old pesticides.
Naturally Occurring Substances These include molds and their volatile metabolites, as well as animal, plant, and food allergens. Persistent Organic Pollutants POPs These are a large group of diverse chemicals defined by their longevity in the environment and in the body. Volatile Organic Compounds VOCs These are another large group of chemicals, defined by their lower molecular weight and volatility [ 46 ]. Plastics These are manufactured from monomers, that are chemically strung together to form polymers.
Mechanisms of Toxicity in Chronic Diseases The web of effects and interactions with diverse toxicants affecting multiple metabolic and physiological pathways may seem to defy reductionist approaches to single-chemical toxicities and causation of conditions. Oxidative Stress This features in development and exacerbation of many chronic conditions [ 29 , 51 , 52 ], such as allergy and autoimmunity [ 53 , 54 ], cancer [ 55 ], cardiovascular disease [ 56 — 58 ], diabetes [ 59 ], neurological compromise [ 60 ], lung disease, and sensitization and pain syndromes [ 28 , 61 ].
Endocrine Disruption This is apparent in altered puberty and sexual development as well as energy utilization, glucose sensitivity, and neurological development. Genotoxicity This has been studied extensively for single chemicals but is now recognized as only one aspect of development of clinically relevant cancers. Enzyme Inhibition This is a direct effect of pesticides designed to bind with receptors, or of toxic metals that bind with protein sulfhydryl groups, thereby inactivating a wide range of enzymes, with diverse adverse effects.
Dysbiosis Dysbiosis or disruption of the human microbiome has become an area of intense research and clinical interest with the recently initiated Human Microbiome Project by the US National Institutes of Health http: Major Chronic Diseases 3. Vascular Disease This manifests in cardiac, renal, cerebral and peripheral disorders.
Cancer This is an extensively studied endpoint, with many carcinogens identified in occupational settings. Neurocognitive Impairment This, including reduced IQ and aberrant behaviour, is linked to early life exposure to a wide range of environmental toxicants, including heavy metals, various POPs and pesticides [ 80 ].
Multi-System Complaints Patients significantly disabled with multisystem complaints are increasingly commonly presenting themselves to clinicians. Timing and Vulnerabilities The exquisite vulnerability of the young and unborn was tragically clear when mothers in Minimata, Japan, who were coping with relatively mild symptoms from methylmercury in the fish they ate, gave birth to children with severe neurological damage [ 81 ].
Responses to Toxicants 6. Recognition A potential risk must be recognized before any response is possible. Chemical Assessment Numerous, diverse environmental exposures merit scrutiny for health effects, including factors affecting chronic disease.