Download Read the complete Detox Module

Clinical Nutrition Series
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Detoxification Module
Scientific Review, Interpretation and
Clinical Considerations 2016
Subject Matter Leads: Romilly Hodges, MS, CNS;
Kara N. Fitzgerald, ND
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Table of Contents
Background ................................................................................................................................................... 3
Definition of Toxins and Detoxification ...................................................................................................... 3
The Landscape of Toxins .......................................................................................................................... 4
Toxic Elements .......................................................................................................................................... 5
Chemical Pollutants .................................................................................................................................. 7
Additional Categorizations of Toxins ....................................................................................................... 10
Talking with Clients/Patients about Toxins ............................................................................................. 11
Endogenous Biotransformation Mechanisms ......................................................................................... 11
Interactions with detoxification enzyme systems .................................................................................... 14
Assessment ................................................................................................................................................. 17
Potential Indicators of Excess Toxic Burden ........................................................................................... 17
Health and Exposure History .................................................................................................................. 18
Physical Examination .............................................................................................................................. 19
Laboratory Assessment .......................................................................................................................... 20
Intervention, Education, Management ........................................................................................................ 26
Reducing Exposure ................................................................................................................................. 27
Gastrointestinal (GI) Support .................................................................................................................. 28
Nutrient Requirements and Support ....................................................................................................... 29
Additional Considerations for Heavy Metals ........................................................................................... 33
Lifestyle Interventions ............................................................................................................................. 35
Controversies and Contraindications ...................................................................................................... 36
Monitoring and Evaluation........................................................................................................................... 38
Resources and Further Reading ................................................................................................................. 39
Resources ............................................................................................................................................... 39
Further Reading ...................................................................................................................................... 39
Addendum: Tables with Full References .................................................................................................... 40
References .................................................................................................................................................. 42
About the Board for Certification of Nutrition Specialists ............................................................................ 60
About the Authors ....................................................................................................................................... 60
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Background
Definition of Toxins and Detoxification
Toxins can be broadly defined as any biochemical input that has a negative impact on health. This includes
environmental inputs, such as heavy metals, chemicals, and pathogenic microbes. Toxic inputs may also be
endogenous such as metabolic waste products, hormones, and gut-derived microbial metabolites. Each of
these competes for processing by the enzymes of biotransformation and elimination, the body’s detoxification
mechanisms.
This Detoxification Module will limit its scope of toxic inputs to heavy metals and the major problematic
chemical toxicants, especially those that have been introduced into, or increased in, the environment as a
result of human activity. In particular the metals arsenic, mercury, lead and cadmium, and the chemical
organotoxins. However, it is helpful for the practitioner to recognize the broader context of toxicant exposure,
and certainly the intervention options described herein will support biotransformation and elimination of all
categories of toxins.
Key definitions for detoxification:
Detoxification: The transformation of a toxin into a less harmful form, and excretion from the body.
Exposome: The combination of simultaneous exogenous and endogenous exposures that a person may
experience at any one time.
NO(A)EL: No Observable (Adverse) Effect Level, the highest dose or exposure level that produces no
noticeable toxic effects. This means of evaluation may be problematic because it only observes over short time
periods, it assumes we all have the same capability to detoxify, and it doesn’t consider either cumulative or
compound effects when combined with other toxins, nor subtle epigenetic and multi-generational effects. It also
fails to account for periods of vulnerability such as preconception, pregnancy, or the presence of comorbidity.
Subclinical toxicity: Effects that are not severe enough to cause overt and acute disease, but can cause
subtle disturbances that lead to chronic health issues.
Toxin/Toxicant: A substance that is capable of causing injury, especially chemical.
Total toxic load: The total body burden of toxic exogenous and endogenous compounds, which includes
past exposures and body stores of toxins.
Xenobiotic: A chemical compound, such as drugs or pesticides, that is foreign to a living organism.
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The Landscape of Toxins
We are all exposed to toxins. More than 80,000 synthetic chemicals have been introduced into our
environment, and an additional 2,000 are registered each year for use in agriculture, foods, personal care
products, household cleaners and lawn care products (NIH, 2015). Before the Toxic Substances Control Act
(TSCA) was established in 1976, the US government had virtually no records of chemicals introduced into the
environment, and no way to regulate them (Phillips, 2006). Even with the TSCA in place, however, only 7% of
chemicals have completed basic level testing (which does not include long-term human studies), and 43%
have not been tested at all (Environmental Protection Agency (EPA), 2004). Chemical manufacturers are not
required to prove safety, rather it is up to the EPA to prove potential for harm (Phillips, 2006). It is important to
note that safety testing does not study the potential outcomes of simultaneous or compounded exposures, their
effects on vulnerable population groups or individuals with comorbidities, nor their long-term effects. What has
also not been widely appreciated is that total body burden can increase over time above ‘safe’ levels and that
there is a significant variation in individual sensitivity to toxin exposure.
We now know that exposure to
environmental chemical toxins is inevitable,
“We’ve been very careless in simply presuming that chemicals
even before we are born. 287 synthetic
are innocent until proven guilty.”
chemicals were detected in the umbilical
cord blood of 10 randomly-selected
Dr. Philip Landrigan, Mt Sinai School of Medicine
newborns whose mothers had participated in
the 2004 national cord blood collection
program, demonstrating that our exposure begins in utero (Environmental Working Group (EWG), 2005). Of
those chemicals, 180 were known carcinogens, 217 were neurotoxins and 208 were those known to cause
birth defects or abnormal development (EWG, 2005). In a study lead by Mount Sinai School of Medicine in
New York, 167 chemicals, pollutants and pesticides were found in adult Americans, none of whom worked
directly with chemicals as part of their employment (Thornton, McCally, & Houlihan, 2002).
While most research attention has focused on the toxic effects of individual acute, high-dose exposures, there
is accumulating evidence that low dose, cumulative exposures such as those uncovered in the studies above,
may lead to subclinical impairments and chronic disease (Grandjean & Landrigan, 2006; Lim et al., 2009;
Thornton et al., 2002). Multiple toxic exposures may also act synergistically to produce greater effects
(Uversky, Li, Bower, & Fink, 2002).
Acceptance of the harms of environmental toxins has had a turbulent history, and has frequently been met with
denial and/or active rebuttal. Unless the exposure is extreme, such as in occupational exposure cases,
symptoms can be vague, attributed to other issues, or dismissed. However, the accumulation of data, as
reviewed below, arguably provides compelling scientific evidence of the far-reaching impacts that can be
attributed to environmental toxins. The most common biochemical mechanisms of harm attributable to
environmental toxins include increased oxidative stress, endocrine disruption, DNA damage, enzyme inhibition,
dysbiosis and increased inflammation.
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Toxic Elements
Lead
Lead is a known neurotoxin and exposure, including past exposure, has been associated with
cognitive impairment, age-related cognitive decline, Alzheimer’s Disease, Parkinson’s Disease,
schizophrenia, and Attention Deficit Hyperactivity Disorder (ADHD) (Goodlad, Marcus, & Fulton,
2013; Sanders, Liu, Buchner, & Tchounwou, 2009; Stewart & Schwartz, 2007). Prenatal and early-life
exposure can lead to impaired cognitive development and IQ in offspring (Sanders et al., 2009).
Research also suggests that lead exposure can increase the permeability of the blood brain barrier
(Song et al., 2014). The Centers for Disease Control and Prevention (CDC) has been continually
reducing its guidelines for the maximum safe levels of lead in blood for children, and now advises a
limit of 5 mcg/dL (CDC, 2014), although it admits that no safe level of lead in blood has been
identified. 95% of lead is stored in bones and teeth (CDC, 2014), which have adverse implications
especially for post-menopausal women who may increase their circulating lead levels during bone
demineralization. Lead exposure may most frequently arise from lead-based paint (used in houses
prior to 1978), soil contamination, lead-glazed ceramic pottery, pewter utensils and drinking vessels,
older plumbing systems using leaded pipes, children’s trinkets or toys, some folk remedies and
cosmetics, and hobbies such as shooting (CDC, 2009).
Nutrient interactions for lead (Goyer, 1997): Low dietary calcium may increase lead absorption and
deposition in the brain and other critical organs. It has been suggested that milk alone may not
effectively protect against this occurrence since lactose and fat enhance lead absorption. Iron
deficiency also increases lead absorption from the gut, and lead can impair heme biosynthesis.
Similarly, zinc deficiency may enhance lead absorption and also lead may increase zinc excretion.
The content of lead and copper in human milk are inversely related.
Mercury
Mercury is also especially toxic to the nervous system, and can associate with memory impairment,
mood changes, sleep disturbance, headaches, tremors, visual/auditory deficits, as well as immune
disturbances (hyper- and hypo-reactivity), and impaired renal, cardiovascular and reproductive
function (ATSDR, 2015a; K.-H. Kim, Kabir, & Jahan, 2015). Serum levels of mercury have been
shown to be significantly higher in autistic children than in healthy controls (P<0.001) (Mostafa,
Bjørklund, Urbina, & Al-Ayadhi, 2016). Sources of mercury exposure include food (e.g. fish),
occupational and household uses, dental amalgams, multi-dose flu vaccines, and air pollution
particularly from coal burning (K.-H. Kim et al., 2015; “Thimerosol in Vaccines,” 2015). While studies
on the effects of dental amalgams have been contradictory, it has been shown that having more than
one amalgam filling significantly correlates with higher levels of urinary mercury in children (P<0.001)
(Baek et al., 2016). It is estimated that each amalgam-filled tooth surface releases 0.2 – 0.4 mcg/d,
and each amalgam-filled tooth 0.5 – 1.0 mcg/d, suggesting that individuals with multiple amalgam
fillings may exceed the EPA’s reference exposure level of 0.3 mcg/m(3) (Richardson et al., 2011).
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Nutrient interactions for mercury: Selenium protects against mercury toxicity through its antioxidant
activity, and by directly binding mercury for excretion (Cuvin-Aralar & Furness, 1991).
Cadmium
Cadmium exposure is associated with increased risk of osteoporosis and bone fracture, cancer,
impaired kidney function, cardiovascular disease and stroke (Åkesson et al., 2014; Ferraro, Costanzi,
Naticchia, Sturniolo, & Gambaro, 2010; J. L. Peters, Perlstein, Perry, McNeely, & Weuve, 2010).
Exposure to cadmium is primarily through tobacco smoke and through diet, especially leafy
vegetables, potatoes, grains, peanuts, soybeans, and sunflower seeds due to bioaccumulation from
soil (ATSDR, 2015c). The uptake of cadmium from the soil by plants may be increased by the use of
synthetic phosphate fertilizers that contain cadmium (Roberts, 2014).
Nutrient interactions for cadmium: Cadmium interferes with renal calcium and vitamin D metabolism,
leading to hypercalciuria and depletion from bone. Cadmium displaces zinc binding to
metallothionein. Iron deficiency increases cadmium absorption from the gut (Goyer, 1997).
Arsenic
Arsenic is #1 on the Agency for Toxic Substances and Disease Registry’s (ATSDR, a division of the
CDC) 2015 Substance Priority List (ATSDR, 2015b). Exposure, even at common levels, is associated
with cancer, neurotoxicity, diabetes, and cardiovascular disease (Escudero-Lourdes, 2016; Kuo et al.,
2015; Moon et al., 2013). Risks of arsenic-associated metabolic disease appear to be enhanced by in
utero exposure to this metal (Barrett, 2016). Arsenic exposure can occur through soil, CCA-treated
wood, tobacco smoke, water, and also diet, especially seafood, rice, mushrooms and poultry. These
food sources are generally thought to contain the less harmful organic arsenic forms (ATSDR, 2007),
however some research indicates that their content of harmful inorganic arsenic may exceed
recommended guidelines for water (there are currently no guidelines for arsenic in foods), and can be
concentrated in products such as brown rice syrup, infant formula and cereal bars, even if they are
organic (Jackson, Taylor, Karagas, Punshon, & Cottingham, 2012). Some seaweeds may also
contain the more harmful inorganic forms (ATSDR, 2007).
Nutritient interactions for arsenic: Arsenic is partially biotransformed via methylation (Lord & Bralley,
2012), so increased exposure may drain endogenous methyl donors and methylation-associated
nutrients such as folate and vitamin B12.
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Chemical Pollutants
Herbicides
Over 800 million pounds of herbicides are used in the US per year, consisting predominantly of
glyphosate, chlorophenoxy acids, chloroacetanilides and atrazine (EPA, 2011; Myers et al., 2016).
Humans are exposed via direct contact during residential, commercial, forestry or agricultural
applications, as well as via residues on food and contamination of drinking water. Atrazine is a potent
endocrine disrupting chemical that induces aromatase expression, feminization and chemical castration in
male animals; it is associated with increased weight gain and insulin resistance, even at low chronic
exposures, and is suspected to be neurotoxic and carcinogenic (Hayes et al., 2010; LaVerda, Goldsmith,
Alavanja, & Hunting, 2015; Li, He, Ma, Wu, & Li, 2015; Lim et al., 2009). Glyphosate is also considered a
probable human carcinogen. Glyphosate may have cellular toxicity effects, may alter gut bacteria, may
inhibit cytochrome P450 enzymes, and has been shown to induce intestinal permeability in vitro
(Mesnage, Bernay, & Séralini, 2013; Myers et al., 2016; Samsel & Seneff, 2013; Vasiluk, Pinto, &
Moore, 2005).
Pesticides
Carbamate insecticides are commonly used on residential and commercial lawns, ornamentals, in
nurseries and on golf courses (CDC, 2009), and have been shown in animal studies to induce
inflammation and oxidative stress in the liver, as well as immunosuppressive effects (El-Bini Dhouib,
Lasram, Annabi, Gharbi, & El-Fazaa, 2015). Organophosphorus pesticides have mostly been phased
out for residential use, but are still used on food crops and for public health applications such as
mosquito control. Organophosphate pesticides are developmental neurotoxicants and can also
induce long-lasting metabolic dysfunction and insulin dysregulation (Adigun, Wrench, Seidler, &
Slotkin, 2010). An older class of pesticides, organochlorines, including aldrin, dieldrein, and
dichlorodiphenyltrichloroethanes (DDTs), are no longer widely used in the US (CDC, 2009). However,
they are persistent in the environment, their use continues in other countries, and they are regularly
detected in human serum from North America and around the world (Kang & Chang, 2011).
Organochlorine pesticide exposure associates with neurotoxicity including behavioral alterations,
seizures, autism, and Parkinson’s Disease (Saeedi Saravi & Dehpour, 2015), as well as endocrine
disruptive activity associated with breast fibroids, endometriosis, miscarriage, preterm delivery and
reduced fetal growth (United Nations Environment Programme and World Health Organization, 2013).
Perfluorochemicals (PFCs)
Man-made chemicals, not naturally occurring in the environment, PFCs are used in waterproofing and
protective coatings and breathable membranes for clothing, furniture and other products, as well as in
household products (including non-stick cookware), adhesives, flame retardant foams and electrical
wire insulation. They are persistent in the environment (Kovarova & Svobodova, 2008), and leach into
water supplies, soils, and food products (Domingo, 2012). They bioaccumulate in humans since they
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are not metabolized and are recirculated via enterohepatic circulation. PFCs have multi-year half
lives, so continued low level exposures can add up to a high body burden (EPA, 2009). Data from the
National Health and Nutrition Examination Survey (NHANES) indicate that PFCs are detectable in
over 98% of the US population (Calafat, Wong, Kuklenyik, Reidy, & Needham, 2007), and it has been
argued that low-level contamination of drinking water over time can cause adverse health effects
(Post, Cohn, & Cooper, 2012). PFCs studies in animals have identified effects including
hepatotoxicity, developmental toxicity, immunotoxocity, endocrine disruption and carcinogenic
potential (Fromme, Tittlemier, Völkel, Wilhelm, & Twardella, 2009). While human data has so far been
contradictory, there are associations between low level exposures and altered lipid levels, fetal
growth, and childhood neurological function (Bach et al., 2015; Geiger et al., 2014; Vuong et al.,
2016; Zeng et al., 2015).
Bisphenol A (BPA)
BPA is a chemical component of certain plastics used to make CDs, automobile parts, food can
linings, baby bottles, plastic dinnerware and food-storage containers, eyeglass lenses, dental
sealants and composites, thermal paper receipts, and toys. It was originally manufactured as a
potential synthetic estrogen for pharmaceutical use. Urinary BPA concentrations in the general
population average 2.6 mcg/L, according to NHANES data, although exposures in some individuals
may reach four times that (CDC, 2009). Accumulating literature in vivo and in vitro indicates that low
doses of BPA have endocrine disrupting effects and induce epigenetic alterations (Acconcia,
Pallottini, & Marino, 2015), which may explain associations between BPA and metabolic disease,
reproductive disorders and certain cancers (Paulose, Speroni, Sonnenschein, & Soto, 2015;
Rochester, 2013). Driven by consumer demand, BPA is being removed from many consumer items,
although the effects of its replacement, BPS, are poorly understood and also have the potential for
harm (Eladak et al., 2015).
Phthalates
Used in plastics for flexibility and resilience, and also as solubilizing and stabilizing agents in
adhesives, detergents, pharmaceuticals, solvents, and personal care products including soap,
shampoo, lotions, fragrances, hair spray and nail polish. Phthalates are easily released from products
during use or disposal since they are not chemically bound to the plastics (CDC, 2009). According to
a recent meta-analysis, higher phthalate exposure is associated with reduced sperm function and
morphology (Cai et al., 2015). Phthalates are also considered endocrine disruptors, associated with
increased risk for estrogen-related cancers, early puberty in girls, and increased body mass index (T.H. Hsieh et al., 2012; Oktar et al., 2015; Poursafa, Ataei, & Kelishadi, 2015).
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Polybrominated Diphenyl Ethers (PBDEs)
PBDEs are organohalogen flame-retardants found in foam padding, textiles, or plastics. These may
be used in upholstered or padded furniture, carpeting, children’s car seats, mattress pads and nursing
pillows (EWG, n.d.). They are lipophilic and bioaccumulative in humans (Erkin-Cakmak et al., 2015).
They appear to have endocrine disrupting effects, such as alterations in TSH, TT4, FT4, FT3 levels
and the T4/T3 ratio in humans (Jonathan Chevrier et al., 2010; Lin et al., 2011; Vuong et al., 2015). In
animals, PBDEs have been shown to be directly thyrotoxic, thyroid hormone disruptive, and
neurotoxic during development (He et al., 2011; Szabo et al., 2009). Human blood concentrations of
PBDEs are associated with increased BMI (Erkin-Cakmak et al., 2015). PBDEs have also been
shown to stimulate the release of arachidonic acid which can increase pro-inflammatory signaling
molecules (Kodavanti & Derr-Yellin, 2002).
Polychlorinated Biphenyls (PCBs)
PCBs are chlorinated aromatic hydrocarbons that are highly persistent in the environment. Human
exposure is primarily through food (especially higher-fat animal foods including dairy products and
fish), since PCBs contaminate animal feeds, and also through human milk (CDC, 2009). PCBs
interact with estrogen and thyroid receptors, and with thyroid transport proteins. Altered thyroid levels
have been associated with PCB exposures in humans (CDC, 2009; Duntas & Stathatos, 2016; Giera,
Bansal, Ortiz-Toro, Taub, & Zoeller, 2011). They display tumor-promoting properties (Umannová et
al., 2008) and multiple data suggest exposure to PCBs increases the risk for cardiovascular disease,
hypertension, diabetes and impaired cognitive function (Carpenter, 2015). Similarly to PDBEs, PCBs
induce arachidonic acid release with increased biosynthesis of inflammatory prostaglandins such as
PGE2 (Kodavanti & Derr-Yellin, 2002; Umannová et al., 2008). Higher serum PCBs, specifically, have
been associated with lower 25(OH)D3 concentrations in pregnant women, and may contribute to
vitamin D deficiency (Morales et al., 2013). In animal studies, PCBs deplete liver stores of retinoic
acid (Esteban et al., 2014). Higher serum PCBs are associated with reduced white blood cell count,
indicative of reduced immune function (Serdar, LeBlanc, Norris, & Dickinson, 2014).
Polycyclic Aromatic Hydrocarbons (PAHs)
PAHs are produced by the incomplete combustion of organic materials such as coal, oil, gas, wood,
garbage and tobacco. Major sources of exposure for humans include motor vehicle exhaust,
residential and industrial heating sources, coal-fired power stations, petroleum processing, roofing tar
and asphalt application, waste incineration and tobacco smoke (CDC, 2009). PAHs are also formed
in foods that are smoked, grilled or broiled. PAHs display properties including genotoxicity,
immunotoxicity, and developmental toxicity (Guo, Wu, Huo, & Xu, 2011). NHANES data indicates that
increased PAH exposure is associated with increased need for emotional support (Shiue, 2015).
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Volatile Organic Compounds (VOCs)
VOCs are volatile chemicals such as benzene, ethylbenzene, styrene, toluene and xylene. These are
found in gasoline and vehicle emissions, aviation fuel and emissions, paints, paint thinners,
adhesives, cleaning solutions, aerosolized insecticide sprays, tobacco and polystyrene products
(CDC, 2009). They typically become airborne easily and are well absorbed by inhalation, dermal or
oral routes. Xylene exposure has been found to impair glucose metabolism, increase lipid
peroxidation, DNA damage and protein oxidation in organs including the liver, heart, kidney and
reproductive organs, as well as promote carcinogenesis (Bahadar et al., 2015; Nakai et al., 2003;
Rana & Verma, 2005).
Additional Categorizations of Toxins
Persistent Organic Pollutants (POPs)
Many of the chemicals discussed above are highly persistent in the environment, and bioaccumulate
in tissues and up the food chain (Lim et al., 2009). Therefore human exposure can continue even
after a substance is banned from use. Examples of hazardous POPs are atrazine, organochlorine
pesticides, PFCs, PCBs, and PBDEs. One of the major problems with POPs is that they can be toxic
even at low levels of chronic exposure (Duk-Hee Lee & Jacobs, 2015).
Obesogens
This specific term has been defined in the scientific literature to include endocrine-disrupting toxins
that have been shown to promote weight gain. Known or suspected obesogens include atrazine,
organochlorines, BPA, phthalates, PFCs, DDE (from DDT), PCBs, and PBDEs (Janesick & Blumberg,
2016).
Xenoestrogens
Endocrine disrupting chemicals demonstrate specific pro-estrogenic activity by binding to, and
activating, estrogen receptors. Many environmental toxins are xenoestrogens including DDT, BPA,
phthalates, PCBs, PFCs, and atrazine (United Nations Environment Programme and World Health
Organization, 2013).
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Talking with Clients/Patients about Toxins
A common response to learning about the landscape of environmental toxins and the inevitability of
exposure is understandable concern and fear. For this reason, it is important to maintain a positive
attitude when discussing toxins with clients/patients. There is much we can do to limit exposure
where it is within our control, and to support our bodies’ ability to detoxify.
Endogenous Biotransformation Mechanisms
The body has the capability to biotransform a number of environmental toxins so that they can be
excreted from the body. The effectiveness of this system is dependent on factors such as gene
variants affecting detoxification enzymes, nutrient cofactor availability, available antioxidant level, total
toxic load, and competitive enzyme inhibition by endogenous substrates such as steroid hormones,
phytonutrients, and drugs, which are also metabolized through detoxification pathways. Detoxification
activity occurs mostly in the liver, but also in gut enterocytes, kidney, lungs and at the blood brain
barrier via Phase I and Phase II enzymes.
Phase I detoxification enzymes
Phase I detoxification is conducted via the cytochrome P450 superfamily of enzymes, and involves
the addition of a reactive group via oxidation, peroxidation and reduction reactions to the xenobiotic.
These reactions create metabolites that are more reactive than their precursors and are ‘primed’ for
phase II reactions, but they also have the potential to generate oxidative damage. Therefore
excessive Phase I with inadequate antioxidant or Phase II activity can enhance the harmful effects of
toxins. Phase I activity is induced by exposure to toxicants and substrates such as caffeine (Kot &
Daniel, 2008).
Cytochrome enzymes are categorized into the subfamilies CYP1, CYP2, CYP3, and CYP4. The
CYP1A family substrates include PAHs, PCBs, estrogen metabolites, caffeine and many others.
CYP2C and CYP2D and CYP3A4 are important metabolizers of many drugs. CYP2E1 is known to
metabolize ethanol and VOCs, and generates oxidative stress regardless of substrate (H. R. Pohl &
Scinicariello, 2011). CYP2E1-related oxidative stress has been shown to suppress GLUT4
expression and impair insulin action (Armoni, Harel, Ramdas, & Karnieli, 2014).
Phase II detoxification enzymes
Phase II enzymes perform conjugation reactions, joining the ‘primed’ Phase I xenobiotic metabolites
with conjugates that render them less harmful, water-soluble and ready for transport and excretion in
bile, urine or sweat.
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There are various categories of Phase II enzymes, including:
UPD-glucuronysyltransferases (UGTs): One of the most important Phase II pathways with
substrates that include insecticides, herbicides, heterocyclic amines, BPA and phthalates. UGTs
conjugate these substrates with D-glucaric acid, a process referred to as glucuronidation.
Sulfotransferases (SULTs): SULT enzymes transfer a sulfuryl group from 3’-phosphoadenosine-5’phosphosulfate (PAPS) onto their xenobiotic substrate. They detoxify many environmental chemicals,
protect against endocrine imbalance and disruption and metabolize many polyphenols. Although
commonly described as sulfation, this process is actually more accurately termed sulfonation or
sulfurylation.
Glutathione S-transferases (GSTs): GSTs attach a glutathione group to Phase I intermediates or
heavy metals.
Amino acid transferases: Conjugate amino acids and organic acids of various types, including
taurine, glycine, glutamine, arginine and ornithine to reactive molecules for excretion.
N-acetyl transferases (NATs): NATs transfer acetyl groups onto substrates such as aromatic
amines or hydrazines.
Methyltransferases: Methylation groups are transferred from methyl donors such as S-adenosyl-Lmethionine (SAMe), by N- and O-methyltransferases. Catechol O-methyltransferase is one such
enzyme that utilizes SAMe and has gained attention for its role in estrogen and catecholamine
metabolism and degradation.
The transcription factor, Nrf-2 (nuclear factor erythroid 2 (NF-E2) p45-related factor 2) upregulates the
transcription of over 500 genes, most of which have cytoprotective functions, including genes
associated with phase II detoxification and antioxidant enzymes. Upregulation of genes with
cytoprotective functions leads to increased biotransformation and excretion of xenobiotics and toxic
metals (Pall & Levine, 2015). As we shall review below, many diet and lifestyle factors influence the
induction of Nrf-2 signaling and Phase II detoxification and antioxidant enzymes, and play an
important role in detoxification support.
Figure 1 provides an overview of detoxification pathways, including reactions and associated
nutrients and antioxidants. Detoxification processes utilize many nutrients which are reviewed in more
depth below.
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Figure 1: Liver Detoxification Pathways and Supportive Nutrients (Cline, 2015)
(Figure used with the permission of the author & the Institute of Functional Medicine).
Phase III detoxification
Although not as well defined as Phase I and II detoxification systems, it has been proposed that there
is a Phase III detoxification system involving cross-membrane transport proteins (Chodorowski, Sein
Anand, Rybakowska, Klimek, & Kaletha, 2007; Liska, 1998). These transport proteins are energydependent antiporter proteins (ABCB1 or p-glycoproteins) that pump xenobiotics out of a cell.
Interest in ABCB1 transporters has primarily focused on their effects on the pharmacokinetics of
pharmaceuticals, since they play an important role in their first pass metabolism of these compounds
in intestinal enterocytes. For this reason, genes encoding for these transport proteins have been
termed multi-drug resistance (MDR) or multidrug resistance-associated protein (MRP) genes.
However, their activity likely has implications beyond drug delivery; polymorphisms in ABCB1 genes
may potentiate the effects of xenobiotic exposure and may increase susceptibility to disease. There is
research demonstrating that pesticide-exposed fruit workers with homozygous MDR1 polymorphisms
had the greatest DNA damage in peripheral blood (C.-C. Chen et al., 2014). Organochlorine and
organophosphorus pesticide exposure appears to increase risk of Parkinson’s Disease in a manner
related to ABCB1 genotype (Narayan et al., 2015). Other research indicates a potential link between
such polymorphisms and increased susceptibility to childhood acute lymphoblastic leukemia related
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to household chemical exposure (especially paints and indoor insecticides) (Chokkalingam et al.,
2012).
Compounds from environmental xenobiotics, as well as hormone modulators and food-derived
compounds are being investigated for their effects on ABCB1 activity. Certain pesticides, for example,
may inhibit ABCB1 (Lacher, Skagen, Veit, Dalton, & Woodahl, 2015; Mazur, Marchitti, & Zastre,
2014). Conversely, estrogenic activity induced by genistein may increase ABCB1 activity (Arias et al.,
2014). Some food-derived compounds, such as the citrus flavonoid tangeretin, are being investigated
for their ability to inhibit ABCB1 for the purpose of enhancing drug effectiveness (Feng et al., 2016),
though the implications for general xenobiotic detoxification still need to be elucidated.
Interactions with detoxification enzyme systems
Phase I and Phase II detoxification enzymes metabolize a variety of compounds, not just xenobiotics,
including vitamins (such as retinoic acid), fatty acids and steroid hormones, therefore these
compounds have the capability to competitively inhibit enzyme availability. A number of food-derived
components and botanicals may also modulate detoxification enzyme activity via similar inhibition of
enzyme function, or increased expression resulting in increased activity.
Although data in this field are still emerging, it may be conceivable that such understanding could be
used to counteract potential negative effects of known genetic polymorphisms in detoxification
enzymes. It also behooves the nutrition practitioner to be aware of potential interactions especially
when using supraphysiological doses of nutraceutical compounds (Hodges & Minich, 2015).
Table 1: Potential inducers and inhibitors of detoxification enzyme systems (data from Hodges
& Minich, 2015)
Enzyme
Foods and bioactives
that may INDUCE activity
Foods and bioactives
that may INHIBIT activity
CYP1A1
Cruciferous vegetables,
resveratrol, green tea,
black tea, curcumin,
soybean, garlic, fish oil,
rosemary, astaxanthin
Black raspberry, blueberry,
ellagic acid, black
soybean, black tea,
turmeric
CYP1A2
Cruciferous vegetables,
green tea, black tea,
chicory root, astaxanthin
Apiaceous vegetables,
quercetin, daidzein,
grapefruit, kale, garlic,
chamomile, peppermint,
dandelion, turmeric
CYP1B1
Curcumin, cruciferous
vegetables
(none identified)
CYP2A
Chicory root
(none identified)
15
CYP2A6
Quercetin, broccoli
(none identified)
CYP2B
(none identified)
Ellagic acid, green tea,
cruciferous vegetables
CYP2B1
Rosemary, garlic
Turmeric
CYP2B2
Rosemary
(none identified)
CYP2C
(none identified)
Green tea, black tea,
ellagic acid
CYP2C6
(none identified)
Ellagic acid
CYP2C9
(none identified)
Resveratrol, myricetin
CYP2C19
(none identified)
Kale
CYP2D6
(none identified)
Resveratrol, garden cress,
kale
CYP2E1
Fish oil, chicory root
Watercress, garlic, Nacetyl cysteine, ellagic
acid, green tea, black tea,
dandelion, chrysin,
medium-chain triglycerides
CYP3A
Rooibos tea
Green tea, black tea,
quercetin
CYP3A1
Garlic, fish oil
(none identified)
CYP3A2
Garlic, cruciferous
vegetables
Cruciferous vegetables
CYP3A4
Curcumin
Grapefruit, resveratrol,
garden cress, soybean,
kale, myricetin
CYP4A1
Green tea
(none identified)
CYP4B1
Caffeic acid
(none identified)
UGT
Cruciferous vegetables,
resveratrol, citrus,
dandelion, rooibos tea,
honeybush tea, rosemary,
soy, ellagic acid, ferulic
acid, curcumin,
(none identified)
16
astaxanthin
SULT
Caffeine, retinoic acid
(none identified)
GST
Cruciferous, allium,
resveratrol, citrus, garlic,
fish oil, black soybean,
purple sweet potato,
curcumin, rooibos tea,
honeybush tea, ellagic
acid, rosemary, ghee,
genistein
Apiaceous vegetables,
quercetin, genistein
For further information, the reader is referred to the full text article.
17
Assessment
The impact of chronic or cumulative toxin exposure on the body varies significantly from individual to
individual. Beyond the level of ongoing or cumulative exposure, these differences may be explained
by deficiencies in nutrient intake and status, genetic differences in the effectiveness of detoxification
enzymes, as well as factors that may place additional physiological stress on the body and compete
for endogenous antioxidant and detoxification resources such as emotional stress or trauma, proinflammatory diets (e.g. high sugar, processed foods), intestinal dysbiosis or bacterial overgrowth,
and other sources of uncontrolled inflammation and oxidative stress including obesity, autoimmune
disease, and blood sugar dysregulation.
Various indicators and tools may assist the practitioner in evaluating an individual’s toxic burden. It is
important to note, however, that there is no single assessment tool that can accurately reflect the
complexity of the interaction of toxins in the body, nor their clinical effects. Practitioners should be
mindful of this context in their interpretation and application of their findings, and interpret the results
in light of clinically relevant symptoms and concerns.
Potential Indicators of Excess Toxic Burden
A number of complaints and conditions can be associated with increased toxicity and need for detox
support (Table 2; references provided in an Addendum to this document). Their presence does not
automatically indicate an excess toxic burden or impaired detoxification capacity, but can be part of a
clinical picture that, if not otherwise well-explained, should prompt a practitioner towards further
investigation.
Table 2: Potential Indicators of Excess Toxic Burden
Neurological
Hormonal
Cognitive or memory difficulties
Mood and behavior disorders
Tremors
Peripheral neuropathy
Chronic headaches
Insomnia
Chronic neurological conditions such as
autism, ADHD, depression, anxiety,
Parkinson’s disease, Alzheimer’s disease
Unexplained weight gain or loss
Blood sugar dysregulation, insulin
resistance
Thyroid dysfunction
Adrenal dysfunction
Premature puberty
PMS
Polycystic ovarian syndrome
Endometriosis
Fibroids
Sperm dysfunction
Hypoandrogenism
Infertility
Immune
Mitochondrial and Metabolic
Asthma
Allergies
Fatigue
Fibromyalgia
18
Chemical sensitivities
Autoimmune conditions
Recurrent infection
Food sensitivities
Leukopenia
Unexplained inflammation
Osteoporosis
Cardiovascular disease
Gastrointestinal
Genotoxic
Constipation (poor clearance of toxins)
Dehydration (poor clearance of toxins)
Gut dysfunction
Loss of appetite
Metallic taste
Cancer
Spontaneous abortion
Birth defects
Developmental disorders
Questionnaires, such as the Institute for Functional Medicine’s Master Symptoms Questionnaire
(MSQ) and Toxin Exposure Questionnaire (TEQ), the Quick Environmental Exposure and Sensitivity
Inventory (QEESI), and others, may also be useful for assessing excessive toxic burden. If an excess
toxic burden is suspected, the practitioner may decide to conduct deeper investigation and
assessment. There are a number of options including a detailed health and exposure history,
anthropometrics, a physical exam, and laboratory testing.
Health and Exposure History
A detailed health and exposure history provides an assessment of possible sources of exposure or
impaired detoxification capability. Table 3 provides a list of potential areas to probe which are relevant
from both a current and historical perspective (table references are provided in an Addendum to this
document. Some of these areas are specific to certain toxins, such as dental amalgams and mercury,
or hobby shooting and lead, and can therefore provide more specific information for decisions about
further testing or interventions.
Table 3: Potential Indicators of Exposure or Impaired Detoxification Capability
Medical History
Dental amalgams, potentially exacerbated with high electromagnetic frequency (EMF)
exposure
Periods of bone loss, e.g. menopause (resorption can release toxins such as lead
from bone)
Known maternal exposure
Disorders of the liver, kidney, bowel or thyroid
Polypharmacy (increased burden on detoxification enzymes)
History of reactions to medications (suggestive of phase I/II single nucleotide
polymorphisms (SNPs))
19
Dietary History
Regular fish eater (especially high mercury fish and farmed fish)
High consumption of high fructose corn syrup
Processed foods
Canned foods
Non-organic foods
Alcohol use
Plastic-packaged foods
Low intake of detoxification-related foods and nutrients
Lifestyle History
Smoking or second-hand smoke
Use of recreational drugs
High air travel frequency
Physical activity
Ability to work up a sweat
Poor sleep
Personal care products
Living in a city
Living in a farming area
Living in homes built before 1978 (lead-based paint)
Living near areas of heavy industry
Hobbies such as model airplanes (paint fumes), shooting (lead), golfing (herbicides,
pesticides)
Home use of pesticides and herbicides
Home renovation
Use of some traditional medicine supplements
Physical Examination
Physical exam findings can help inform the assessment of toxic burden and detoxification status.
Anthropometry: According to NHANES data, percentage body fat (especially abdominal adiposity)
are associated with increased burden of POPs (Zong, Grandjean, Wu, & Sun, 2015). Weight, body
mass index, percentage body fat, waist circumference and waist-hip ratio may therefore be relevant
indicators of assessment. Any weight loss program should prompt consideration for detoxification
support since, stored fat-soluble toxins can be released into circulation (J Chevrier et al., 2000;
Dirinck et al., 2015).
Intracellular Water: Clinically, it has been observed using bioelectrical impedance analysis (BIA) that
the ratio of intracellular to extracellular water can be an indicator of toxin retention. The lipid
membrane is a common site for toxin damage (Apostoli et al., 1988; Selhi & White, 1975), therefore
higher extracellular fluid is traditionally interpreted to suggest damage to that membrane, which may
be of toxic origin.
20
Nutrition Physical Exam: Although a detailed review of physical exam findings that relate to nutrient
status is beyond the scope of this Module, nutrient status is an essential component to detoxification
and, as such, a Nutrition Physical Exam is relevant to the assessment of detoxification capacity.
Assessment of taste may be relevant for both assessment of toxic burden (associated with metallic
taste or dysgeusia), as well as reduced intake of detoxification-supportive foods in sensitive bitter
tasters. Specific nutrient requirements for detoxification appear in Figure 1 above, and are reviewed
in the section Intervention, Education, Management.
Additional Physical Findings: If not already identified, a physical examination can reveal the
presence of toxicity-relevant findings such as dental amalgams and peripheral neuropathy.
Laboratory Assessment
Both standard chemistry panels as well as specialized testing have been used in the assessment of
toxic burden and detoxification capability. These offer both opportunities as well as challenge in both
the decision to use expensive testing, understanding which tests to select, as well as the
interpretation of findings. There is, therefore, a lack of consensus among experts in this field as to
how to proceed with laboratory assessment. Despite this, laboratory assessment for evaluation of
toxic exposure and burden is widely used in Functional Medicine and, while frank abnormalities
prompt a practitioner to initiate further evaluation or intervention, clinicians may often be flagged when
they see values approaching abnormal.
Standard Laboratory Tests
Tests such as standard chemistry profiles, complete blood counts (CBC), and other common (usually
insurance-covered) tests can be relatively inexpensive and easy to obtain. While they cannot provide
specific information about the exact toxins present, or rule out other potential influencing factors,
alterations in detoxification capability and status can be reflected in their results. These tests also
provide an important means for the assessment of detoxification capability before a detoxification
program is begun; deficits may be indicative of a contraindication for a detoxification program or need
for additional support and corrective action before additional detoxification protocols are initiated.
CBC findings: A white blood cell count that dips below normal can be indicative of toxin effects on
bone marrow if other possible pathologies such as hepatitis C or medications are ruled out. In
particular, benzene, arsenic, strontium and hexavalent chromium are known to damage bone marrow
tissue and reduce white cell production (Agency for Toxic Substances and Disease Registry
(ATSDR), 2004; Kuang & Liang, 2005; OSHA, 2012; Xu et al., 2008).
Liver function and status: Impaired liver function can indicate toxin damage, or indicate the reduced
ability to process and eliminate xenobiotics. Serum bilirubin, ALT, AST, ALP, GGT, lactate
dehydrogenase and albumin can be used to assess liver function and status. ALT is almost
exclusively found in liver and is therefore more specific for liver conditions including fatty liver (YkiJärvinen, 2016). AST, ALP and lactate dehydrogenase are found in liver but also in other tissues.
21
Increased indirect (unconjugated) bilirubin may indicate compromised liver conjugation. Increased
direct (conjugated) bilirubin may indicate obstructed bile flow. Albumin, one of the many proteins
produced in the liver, may also fall with impaired liver function.
Glutathione utilization: Although most often considered a measure of liver status, GGT is also a
marker for glutathione utilization. An elevation of GGT may indicate the upregulation of the
glutathione utilization pathway in response to a stressor such as drugs, alcohol, obesity, POPs, heavy
metals and other toxins (Colacino, Arthur, Ferguson, & Rozek, 2014; D-H Lee, Steffes, & Jacobs,
2008; Duk-Hee Lee & Jacobs, 2009; Duk-Hee Lee, Lim, Song, Boo, & Jacobs, 2006; Tinkov et al.,
2014).
Kidney function: Creatinine levels are used to assess kidney function, which is relevant to
detoxification capability. Certain toxins, especially Cadmium, are highly damaging to renal tubules
(Ferraro et al., 2010).
Iron status: Since heme is needed for the biosynthesis of cytochrome enzymes, iron status can have
an impact on detoxification capacity.
Whole blood metals: Many insurances and mainstream labs offer testing for specific metals in whole
blood and urine. Whole blood metal testing is preferred over urine metals since reference ranges from
mainstream laboratories are not considered sensitive enough. Whole blood metals are generally
reflective of current (acute) exposure. Past exposures and total body stores need to be evaluated
through challenge testing (see Specialty Testing below).
Methylation status: Indicators of methylation status including serum homocysteine and erythrocyte
folate levels can provide information about endogenous methylation capability.
Inflammation biomarkers: Ferritin, CRP, ESR and other acute-phase reactants that are commonly
used as biomarkers of inflammation may sometimes be elevated with increased toxicity (B. A. Peters
et al., 2015).
Uric acid: Hyperuricemia is positively correlated with higher levels of POPs in serum that correlate
with background exposure rather than acute, high exposures (Y.-M. Lee, Bae, Lee, Jacobs, & Lee,
2013).
Specialty Testing
Specialty laboratory testing is available that may help with further identification of specific toxins and
total toxin burden, as well as detoxification capability. These tests may not be covered by insurance,
but may be useful when faced with difficult cases, conditions with unidentifiable etiologies, to aid with
patient/client compliance or to track progress over time.
Definitive assessment of toxic burden and clinical correlations is challenging, as reflected in the
considerable disagreement among experts as to the best way to assess toxicity. The reality is that
there is no perfect test. It is important for practitioners to differentiate between acute exposure
(generally represented as blood levels) and total body load (generally requiring challenge testing
before measuring blood or urine levels).
22
In addition, a positive test result is indicative of the presence of a substance, not necessarily toxicity.
Population studies tell us that we are all exposed to toxic substances at varying levels (CDC, 2009),
but not everyone experiences toxic effects. Beyond exposure level, toxic effects are determined by
our capability to detoxify, which is in turn dependent on genetics, nutrient status and other
environmental inputs.
Table 4: Assessment of toxin exposure, burden and effects:
Category
Measures
Comment
Toxin exposure
Blood levels of volatile
solvents, POPs,
glyphosate
Blood levels of toxins reflect ongoing
or very recent exposure (within the
past 4-5 weeks). They also reflect
gradual release from body stores such
as bone, and may therefore fluctuate
according to bone resorption rates
(e.g. higher for females during and
post menopause)
Organic acids: 2methylhippurate, 3methylhippurate,
glucarate, alphahydroxybutyrate,
pyroglutamate
2-methylhippurate and 3methylhippurate are markers specific
for xylene exposure. 3,4
dimethylhippurate is indicative of
trimethylbenzene exposure.
Madelate and phenylglyoxylate
indicate styrene exposure.
Monoethyl phthalate, phthalic acid,
and quinolinate are present with
phthalate exposure.
Para-hydroxybenzoate is a marker for
paraben exposure.
Glucarate is a marker for phase I
detoxification activity.
Alpha-hydroxybutyrate is a marker for
glutathione biosynthesis.
Pyroglutamate (also referred to as 5oxoproline) is a marker for poor
glutathione recovery.
Urinary BPA, phthalates,
parabens, VOCs,
organophosphates.
Urinary levels of toxins such as heavy
metals may be useful for screening for
environmental or non-occupational
exposures (NHANES, 2008).
23
Toxic elements
Urine testing combined
with oral or IV chelating
agent such as DMSA or
DMPS.
Provoked urine assessments are likely
the most reflective of total mobilizable
body stores (Hoet et al., 2006).
However, there is a lack of long-term
studies to validate reference ranges
so practitioners must use clinical
judgment to evaluate relevance.
Selectivity for chelating agents is
warranted since they have different
element binding affinities (BlaurockBusch & Busch, 2014).
Ideally use before-and-after measures
for comparison with baseline.
Toxicant effects
Markers of oxidative
stress such as lipid
peroxides and 8hydroxy-2’deoxyguanosine
(8OHdG)
Can be useful for assessing the
clinical impact of toxins as well as
tracking progress over time. Higher
levels of oxidative stress from other
sources can also make us more
vulnerable to the effects of toxins.
Indirect and nonspecific.
Porphyrin profiling
Various enzymes of the porphyrin
pathway are sensitive to inhibition by
toxins including PCBs, chlorinated
organics, lead, mercury and arsenic
(Cantoni, Rizzardini, Graziani,
Carugo, & Garattini, 1987; Franklin,
Phillips, & Kushner, 2005; Lord &
Bralley, 2012).
Indirect and nonspecific.
Table 5: Assessment of detoxification and elimination capability:
Category
Measures
Comments
Nutrient status
Erythrocyte levels of
nutrients that are
relevant to detoxification
(e.g. zinc, selenium)
Identifies potential deficits in
substrates or cofactors that can impair
detoxification ability.
Urine organic acids that
relate to detoxification
nutrient status and
Similarly identifies potential deficits in
substrates or cofactors that can impair
24
Elimination and
barrier control
utilization:
Formiminoglutamic acid
(FIGLU), methylmalonic
acid (MMA), sulfate,
pyroglutamate.
detoxification ability.
Plasma amino acids
(e.g. homocysteine,
methionine,
cystathionine, taurine,
glycine).
Provides indicators of the status of
amino acids that are relevant for
detoxification.
Erythrocyte glutathione
A low level of glutathione is indicative
of a need for support.
Erythrocyte or plasma
essential fatty acids
Healthy levels of essential fatty acids
can improve resistance to the effects
of toxins. However, caution with
excessive levels of polyunsaturated
fats since they can also be vulnerable
to oxidative stress.
S-adenosyl
homocysteine (SAH),
SAMe:SAH ratio
Elevated SAH may indicate a
blockage in the metabolism of
homocysteine via methylation or
transulfuration (Ingrosso et al., 2003).
The SAMe:SAH ratio is commonly
considered a indicator of methylation
potential.
Beta-glucuronidase
(stool)
Beta-glucuronidase is an enzyme
produced by certain microbial species
in the gut that cleaves conjugated
molecules such as toxins allowing
them to be reabsorbed and
recirculated. Excessive levels may
indicate high enterohepatic circulation
of toxins.
Lactulose/Mannitol Test
for Intestinal
Permeability
Increased intestinal permeability
allows dietary toxins in the gut lumen
increased access to endogenous
tissues.
SIBO breath test, stool
testing for dysbiosis
Unhealthy gut flora in either the small
or large intestine can contribute to
increased intestinal permeability.
Conversely, healthy gut flora can
25
promote healthy barrier function.
Indicators of potential SIBO include
abdominal discomfort and gas after
eating, improvement with low
FODMAPs diet.
Genetic profiling
Single nucleotide
polymorphisms (SNPs)
Genetic testing can identify SNPs in
Phase I and Phase II detoxification
enzymes and enzymes related to the
status of detoxification-relevant
nutrients. Phase II SNPs may create
an imbalance between Phase I and
Phase II detoxification activity,
creating excessive amounts of
reactive intermediates that are not
efficiently conjugated. This is
sometimes referred to as a
‘pathological detoxifier’ state.
Since research into the field of
nutrigenetics and nutrigenomics is still
in its infancy, the vast majority of
known SNPs are understood from a
qualitative rather than quantitative
perspective. In addition, the combined
effects of multiple SNPs is largely
unknown.
However, genetic profiling can prove
useful if SNPs correlate with clinical
signs and improvements are seen
when specific nutritional and lifestyle
interventions are adopted.
26
Table 6: Environmental Assessments:
Category
Measures
Comments
Water
Heavy metals, inorganic and Drinking water can be a
organic chemicals, VOCs,
significant source of exposure to
pesticides, herbicides, PCBs. toxins.
Soil
Heavy metal contaminants in
soil.
Vegetables and fruits grown in
contaminated home soils can be a
source of exposure. Children are
also at higher risk for exposure to
soil-based toxins during outdoor
activities.
Testing services are often
available through regional
governmental facilities and
universities.
Home
Lead and other heavy metals
via home-use test kits or
commercial testing services
using XRF analyzers.
Home evaluations for lead and
other heavy metal contaminants
may be advisable, especially in
houses built prior to 1978.
Hair analysis: A caution. Hair has been used for assessment of heavy metal status, however there
are a number of drawbacks to this sample source. The presence of a substance in hair can indicate
both internal or external exposure and does not indicate the source of the exposure (Harkins &
Susten, 2003). In addition, there is significant variability of hair growth and excretion rates with age,
gender, and ethnicity, and useful reference ranges have not yet been established.
Intervention, Education, Management
Detoxification is an ongoing, daily physiological process. There are many valid ways to support
detoxification and opportunities to personalize the approach according to the needs of the individual
patient/client and the skills of the practitioner. Interventions may range from daily, gentle detoxification
support through reduced exposures, nutrient repletion, detoxification-specific foods, and lifestyle
adjustments, to time-defined nutraceutical or other clinical programs that provide a more intense
detoxification regime.
27
Reducing Exposure
Organic diets
Many toxins are encountered through diet. Organic diets are shown to significantly lower exposure to
chemical toxins such as organophosphorus pesticides and insecticides (Bradman et al., 2015; Curl et
al., 2015; Curl, Fenske, & Elgethun, 2003; Lu et al., 2006). Organic produce may also confer other
benefits relevant to detoxification such as increased nutrient quantity and phenolic compounds
(Asami, Hong, Barrett, & Mitchell, 2003). If a complete organic diet is impractical, resources such as
the Environmental Working Group’s Clean Fifteen and Dirty Dozen guide can advise consumers as to
the foods with the highest pesticide residues and thus the most important to buy organic. Washing
conventional produce is also important to help reduce surface toxins (Guardia-Rubio, Ayora-Cañada,
& Ruiz-Medina, 2007; Lozowicka, Jankowska, Hrynko, & Kaczynski, 2016).
Non-GMO foods
While organic foods cannot contain GMO ingredients by law, conventional foods may contain GMO
ingredients without consumer notification. GMO foods that are specifically bred to withstand herbicide
and pesticide applications may contain higher levels of chemical toxins (Bøhn et al., 2014).
Patients/clients may also be guided to look for voluntary labeling such as Non-GMO Project verified.
Whole foods, minimally processed and packaged
Minimizing consumption of synthetic additives as found in processed foods can help reduce the load
on detoxification systems. In addition, unprocessed or minimally processed foods are richer in natural
vitamins, minerals and phytonutrients that aid detoxification. Avoiding canned foods can substantially
reduce circulating BPA and phthalates by two thirds, even after just a few days (Rudel et al., 2011).
Minimizing plastic packaging, cellophane, and aluminum foil, especially with hot or acidic foods
respectively, may be advisable. Glass and stainless steel may be preferable.
Food preparation
Avoidance of Teflon cooking surfaces and high/dry heat cooking can reduce exposure to
perfluorochemicals and advanced glycation end products. Food preparation techniques that maximize
nutrient availability are advantageous, such as steaming, slow cooking, soaking and sprouting.
28
Environmental changes
As deemed appropriate and possible, environmental changes may be advisable to minimize ongoing
exposures. Relatively straightforward changes include using a carbon block water filtration system,
HEPA air filters. More extensive home and lifestyle changes may be warranted in certain situations.
A thorough review of the Background section of this report as well as Further Reading may be useful
for identifying other possible sources of exposure to act upon.
Gastrointestinal (GI) Support
The gastrointestinal tract performs important roles in blocking the absorption of toxic molecules,
eliminating unwanted wastes, as well as regulating the uptake of nutrients.
Bowel elimination
It is essential that the pathways of elimination are functioning well and that the enzymes of
biotransformation have the nutrient substrates and cofactors necessary for proper processing of
toxins. If these are lacking, any intervention to ‘pull’ toxins from body stores can lead to an increase in
circulating toxins, increased enterohepatic recirculation and the potential for a worsening of
symptoms.
Basic nutritional steps to ensure adequate hydration and fiber intake can support proper elimination of
toxins through stool. Proper hydration will also have the benefit of improving toxin clearance via the
kidneys (Sears, 2013). By improving stool bulk, fiber also minimizes the direct contact between toxic
molecules and the surface of the intestinal mucosa. Soluble fiber is found in foods such as legumes,
oat bran, berries, banana, plums, pears, apples, broccoli, squash, and Jerusalem artichoke. Insoluble
fiber is found in whole grains, green beans, cauliflower, celery, peppers, leeks, greens, onion,
cabbage, banana, cherries, melon, avocado, nuts, flaxseeds, and legumes. Average fiber intake in
the U.S. is 18 and 15g/day for adult males and females respectively (Hoy & Goldman, 2014), which
falls far short of the recommended daily intakes of 30.8 and 25.2g/day for 31-50 year olds according
to the 2015-2020 Dietary Guidelines for Americans (USDHHS & USDA, 2015).
Bile flow
Toxins processed in the liver are released into the intestines through bile. Botanicals such as
artichoke leaf and bitters as well as lipotropic factors (choline, vitamin B6, folate and vitamin B12)
have been used to improve bile synthesis and flow (Gabuzda, 1958).
Assimilation
Digestion and absorption are important for optimizing the assimilation of detox-related nutrients.
Support for digestion, as required, may be warranted including betaine HCl, digestive enzymes, and
29
bitters. Gastric acid is required for the release of nutrients such as vitamin B12, and for the
metabolism of phytonutrients such as indole-3-carbinol (I3C) which is converted to its more active
form, diindolylmethane (DIM), in the stomach (Bradlow & Zeligs). In addition, a healthy gut barrier can
assist with the proper uptake of nutrients as well as prevent entry to toxins.
Microbiota
Commensal bacteria in the gut play an important role in the provision of short chain fatty acids to
meet the energy needs of colonocytes for cellular activity including detoxification. Microbial species
also facilitate the metabolism of many dietary detoxification-supportive polyphenols into their more
active forms such as isoflavones, indole-3-carbinol and lignans (Johanna W Lampe, 2003). Dietary
fibers including resistant starches also provide beneficial support for healthy gut microbes. Not least,
certain beneficial bacterial strains reduce the activity of beta glucuronidase, including Lactobacillus
rhamnosus GG, Lactobacillus acidophilus and Bifidobacterium bifidum (D. K. Lee et al., 2011; Verma
& Shukla, 2013), especially in conjunction with increased dietary fiber, indicating that a healthy gut
microbiota is supportive of detoxification.
Nutrient Requirements and Support
Detoxification is a nutrient dense process. The nutrient connections to detoxification can be far
reaching, and nutrient needs for ‘behind the scenes’ pathways that support detoxification, such as
heme biosynthesis and transulfuration of homocysteine, should also be considered. Minerals such as
iron can also block absorption of toxic heavy metals such as lead and cadmium in the intestine by
competitive inhibition for DMT transporters, illustrating the value of optimizing intake (Allen, Prentice,
& Caballero, 2013; Berglund, Akesson, Nermell, & Vahter, 1994).
It can be argued that nutrient needs should be met through food sources wherever possible since
foods contain the rich complexity of nutrients plus phytochemicals, many of which are beneficial for
detoxification. In addition, there is evidence to suggest that supraphysiological doses of specific
nutrients and bioactive compounds can have unexpected, often opposite, effects to those seen at
normal dietary levels (Hodges & Minich, 2015). For example, EGCG, milk thistle, saw palmetto, and
cranberry are metabolized via UGT enzymes (Mohamed & Frye, 2011), leading to competitive
inhibition at higher doses. Therefore caution may be warranted when using doses beyond that
normally obtained through diet alone.
A varied, whole foods diet can provide an abundance of detoxification nutrients, though it is prudent
to evaluate intake through periodic dietary analysis since it can take some practice on the part of the
patient/client to adopt a nutritionally replete eating pattern. Since the process of detoxification utilizes
certain nutrients irreversibly (such as selenium as it binds mercury), nutrient requirements may
increase during periods of heavy detoxification.
30
Phase I Nutrient Support
B vitamins including riboflavin, niacin, pyridoxine, folate and vitamin B12 are needed for cytochrome
enzyme function. Adequate amino acid availability for protein synthesis is needed as well as iron and
zinc for heme and cytochrome biosynthesis.
Modulation of Phase I enzymes appears possible through food, although caution is warranted since
Phase I activity in excess of antioxidant capacity or Phase II detoxification can be harmful. Foods that
support Phase I and upregulate Phase II may be of greatest benefit, such as cruciferous vegetables,
green tea, curcumin, garlic, berries, pomegranate and rosemary (Hodges & Minich, 2015). Some
bioactive constituents such as catechins from green tea may also attenuate excessive Phase I activity
and oxidative stress induced by toxicants (P. Sharma & Goyal, 2015).
Early data on the ability to induce defined cytochrome families using specific foods is available, such
as using cruciferous vegetables to induce CYP1A2 enzymes (Hakooz & Hamdan, 2007; Peterson et
al., 2009). Conversely, other foods such as berries (via their constituent polyphenol ellagic acid) may
attenuate CYP1A1 overactivity (Aiyer & Gupta, 2010). The CYP2E1 enzyme is known as a major
driver of oxidative stress induced by, among other chemicals, alcohol and VOCs (Pohl & Scinicariello,
2011), and excessive enzyme activity can suppress GLUT4 expression and increase risk for heart
disease and gastric cancer (Hodges & Minich). Attentuation of CYP2E1 may therefore confer benefits
in some cases, as appears possible with watercress and garlic (Hodges & Minich, 2015).
Antioxidants are important to protect against the reactive intermediate products of Phase I activity.
Important dietary antioxidants and antioxidant nutrients include carotenoids, ascorbic acid, vitamin E,
selenium, copper, zinc, iron, manganese, coenzyme Q10, lipoic acid, glutathione, sulfur-containing
foods (including sulfur amino acids, eggs, onions, garlic, cruciferous vegetables, chives), and
flavonoids.
Phase II Nutrient Support
Glucuronidation
The substrate for glucuronidation via UGT enzymes is D-glucaric acid, which is found in fruits and
vegetables including oranges, spinach, apples, carrots, alfalfa sprouts, cabbage, Brussels sprouts,
cauliflower, broccoli, grapefruit, grapes, peaches, plums, lemons, apricots, sweet cherries, corn,
cucumber, lettuce, celery, green pepper, tomato and potatoes, as well as mung beans and adzuki
beans (Dwivedi, Heck, Downie, Larroya, & Webb, 1990; Zółtaszek, Hanausek, Kiliańska, & Walaszek,
2008). Human studies have shown induction of UGT enzymes by cruciferous vegetables, resveratrol
and olive oil (Hodges & Minich, 2015; Mateos et al., 2013). Adequate magnesium status is also
required for glucuronidation (Brown & Bidlack, 1991).
Beta-glucuronidase inhibition in the intestinal lumen is also supportive of glucuronidation status and
elimination of conjugated toxins. Calcium D-glucarate, dietary fiber, berry polyphenols, milk thistle
(silibum marianum), and reishi (ganoderma lucidum) are inhibitors of beta-glucuronidase, (Dwivedi et
31
al., 1990; Fotschki et al., 2016; D. H. Kim, Jin, Park, & Kobashi, 1994; D. H. Kim, Shim, Kim, & Jang,
1999). As noted above, Lactobacillus rhamnosus GG, Lactobacillus acidophilus and Bifidobacterium
bifidum also reduce beta-glucuronidase activity (D. K. Lee et al., 2011; Verma & Shukla, 2013).
Sulfation
Sulfur containing compounds are essential for a steady supply of the PAPS cofactor for sulfonation;
foods that can provide sulfur include meats, fish, shellfish, eggs, cheese, legumes, barley, oatmeal,
cruciferous vegetables, Brazil nuts, mustard and ginger (Masters & McCance, 1939).
Methylsulfonylmethane is another beneficial sulfur compound found in foods such as asparagus,
Swiss chard, tomatoes, alfalfa, beets, cabbage, corn, cucumber, apples, raspberries, coffee and tea
(Pearson, Dawson, & Lackey).
SULT enzymes may be induced by caffeine, glucosinolates (found in cruciferous vegetables) and
retinoic acid (Abdull Razis, Mohd Noor, & Konsue, 2014; Maiti, Chen, & Chen, 2005; Zhou, Chen,
Huang, & Chen, 2012). Support for transulfuration activity and production of PAPs is also heavily
reliant on vitamin B6 (Lord & Bralley, 2012).
Glutathione conjugation
Consumption of cruciferous and allium vegetables, both containing bioactive components that are
GST substrates, has been shown to increase GST expression in humans (Hoensch et al., 2002; J W
Lampe et al., 2000; Navarro et al., 2009). Apple polyphenols, curcumin, pomegranate and butyrate
also induce GSTs (Biswas, McClure, Jimenez, Megson, & Rahman, 2005; Kaur, Jabbar, Athar, &
Alam, 2006; Petermann et al., 2009; Scharlau et al., 2009). Butyrate is a short chain fatty acid
produced by commensal gut bacteria, which can further justify attention towards restoring a healthy
microbiota through probiotics and prebiotics. Ghee is also rich in butyric acid (Muehlhoff, Bennett, &
McMahon, 2013) and may act as a direct source.
Since glutathione is a direct cofactor for GST activity, and also performs important antioxidant
functions, supporting glutathione (GSH) levels can be considered a cornerstone of detoxification.
Foods that increase GSH include undenatured whey protein, asparagus, broccoli (and other
cruciferous), avocado, spinach, garlic and onion. Alpha lipoic acid, milk thistle and curcumin have
also been shown to increase GSH levels (Durgaprasad, Pai, Vasanthkumar, Alvres, & Namitha, 2005;
Georgakouli et al., 2013; Nencini, Giorgi, & Micheli, 2007) Oral supplementation with N-acetylcysteine
(NAC) has been widely used, since the availability of cysteine in the blood is the rate-limiting
substrate for glutathione biosynthesis (Kerksick & Willoughby, 2005) and has been shown to increase
intracellular GSH in humans (Gamage, Lee, & Gan, 2014; Kasperczyk, Dobrakowski, Kasperczyk,
Ostałowska, & Birkner, 2013). Vitamin C and vitamin D may also play a role in supporting intracellular
GSH pools (Garcion, Sindji, Leblondel, Brachet, & Darcy, 1999; Johnston, Meyer, & Srilakshmi,
1993). Although the predominant thinking on oral glutathione supplementation is that its effectiveness
is limited by poor absorption, recent study findings indicate that it can effectively increase intracellular
GSH (Richie et al., 2015).
32
Methylation
A number of nutrients are known to be essential for production of methyl donors, especially Sadenosylmethionine (SAMe), including folate, vitamin B6, vitamin B12, betaine, zinc and methionine
(Lord & Bralley, 2012). These nutrients serve as direct cofactors and required inputs in the conversion
of homocysteine to methionine via methionine synthase and betaine-homocysteine
methyltransferase, as well as the formation of SAMe from methionine. Choline may also be
considered useful since it can be converted to betaine in the body (Anderson, Sant, & Dolinoy, 2012).
Good food sources of folate include dark leafy greens, cruciferous vegetables, legumes and liver
(USDA, 2015). Vitamin B6 is quite widely distributed and is in herbs, spices, seeds, liver, fish, leeks
and shiitake mushrooms, among other foods (USDA, 2015). Vitamin B12 is found in animal products
especially shellfish and liver (USDA, 2015). Food sources of betaine include beets, spinach, quinoa,
liver and sunflower seeds (USDA, 2015). Egg yolk and liver are especially rich in choline (Patterson,
Bhagwat, Williams, Howe, & Holden, 2008).
Support for methylation may also consist of the attenuation of other pathways that can utilize methyl
donors to excess. Catecholamines activated by the stress response, histamine activated by an
immune response, and estrogen metabolites, all utilize SAMe-dependent methylation in their
metabolism and may therefore deplete methyl donor pools when in active or excess states. Oxidative
stress, regardless of source, can increase transulfuration activity at the expense of methylation status
(Lord & Bralley, 2012). The nutrients selenium, phosphatidylethanolamine and niacin are metabolized
via methylation, again suggesting that food based sources or physiological dosing may be better than
high dose supplementation. Conversely, increased intake of phosphatidylcholine or creatinine may
spare methyl donors since they both utilize SAMe in their biosynthesis.
Amino acid conjugation
High quality protein sources provide amino and organic acid substrates for this detoxification enzyme
group. Amino and organic acids used in phase II conjugation include glycine, taurine, glutamine,
ornithine and arginine. Taurine is synthesized in the body from cysteine (Lord & Bralley, 2012).
Ornithine is synthesized via the urea cycle, using arginine and magnesium (Hodges & Minich, 2015).
Rich dietary sources include meats, fish, shellfish and eggs, although plant foods such as nuts,
seeds, legumes and grains can also be good sources (USDA, 2015). Conjugated minerals may be a
useful way to administer these nutrients where supplementation is deemed useful, such as
magnesium glycinate or taurate. As a supplement, glycine’s sweetness can make it palatable,
especially for children.
33
Acetylation
Acetylation reactions, requiring the transfer of an acetyl group from acetyl CoA, benefits from
adequate vitamin B1, vitamin B2, vitamin B3, pantothenic acid and lipoic acid, which are the cofactors
required for the synthesis of acetyl CoA from pyruvate.
Nrf-2 activation
Nrf-2 is activated by many phenolic compounds such as from blueberry, pomegranate, rosemary,
purple sweet potato, ellagic acid, and resveratrol (Hodges & Minich, 2015). Other activators of Nrf-2
signaling include gamma- and delta-tocopherols and tocotrienols, DHA and EPA, alpha-lipoic acid,
carotenoids (especially lycopene), curcumin, xanthumol, cruciferous vegetables, sulfur compounds
form allium vegetables and terpenoids (L. Das & Vinayak, 2015; Dietz et al., 2013; Pall & Levine,
2015; Shay, Moreau, Smith, Smith, & Hagen, 2009).
Additional Considerations for Heavy Metals
A finding of clinically-relevant elevated heavy metals is followed by a need to determine the best
intervention approach. The intensity of intervention that is appropriate may be determined by factors
such as clinical symptoms, laboratory findings of dysregulation, comorbidities, and life stage. In some
cases, simple reduction of exposure and basic support for daily detoxification through nutrient
repletion and food-based phytonutrients may be sufficient, but in other cases further interventions
may be justified.
A number of food-derived components, such as polyphenols and minerals, have shown ability to
chelate heavy metals, as well as provide antioxidant protection.
Quercetin demonstrates lead-reducing properties, even specifically within the hippocampal region, in
animals (P. Hu et al., 2008). It appears to prevent arsenic deposition in tissues and reduce arsenicrelated tissue damage (Jahan et al., 2015), as well as enhance the effectiveness of the oral chelator
MiADMSA in removing arsenic from target organs (Mishra & Flora, 2008). Quercetin also appears to
ameliorate pathological changes associated with cadmium nephrotoxicity (Renugadevi & Prabu,
2010). Quercetin is found in many fruits and vegetables and is especially high in apples, onions,
parsley, citrus, olive oil, grapes, cherries and berries (UMMC, 2015).
Anthocyanins from blueberry also demonstrate an ability to chelate with cadmium to reduce the body
burden, as well as protect from cadmium-related nephrotoxicity (Gong et al., 2014). Ferulic acid has
been studied for its protective effects on neurodevelopmental lead toxicity (Yu, Zhao, & Niu, 2015). It
is found in many plant foods and is particularly concentrated in beets, grapefruit, orange, whole grain
rice, oats, wheat and corn (N. Kumar & Pruthi, 2014). Chinese parsley, also known as coriander leaf
(Coriandrum sativum), may decrease lead deposits and attenuate lead toxicity (Aga et al., 2001).
34
Selenium has the ability to bind mercury in the body to inactivate it (Khan & Wang, 2009). The
selenium used in this process cannot be recycled, so an increased supply of selenium may be
required for mercury detoxification. Brazil nuts are especially rich in selenium, and halibut, cod,
sardine, shrimp and salmon are also good sources. Selenomethonine may be an ideal choice for
supplementation, if required, since it will also support methylation detox activity.
Alpha lipoic acid, glutathione and curcumin also have the ability to chelate metal ions, in addition to
their multiple other roles in detoxification (García-Niño & Pedraza-Chaverrí, 2014; Gorąca et al.,
2011; Jozefczak, Remans, Vangronsveld, & Cuypers, 2012; Sandbichler & Höckner, 2016). Lipoic
acid can cross and stabilize the blood brain barrier (Schreibelt et al., 2006). Curcumin has specifically
been shown to reduce tissue concentrations of mercury (Agarwal, Goel, & Behari, 2010) and may
also act within the brain (Benammi, El Hiba, & Gamrani, 2016). Andrographic paniculata reduces
arsenic deposition in liver (S. Das, Pradhan, Das, Nath, & Das Saha, 2015).
Additional agents that appear to be protective against tissue damage caused by heavy metals include
garlic, carotenoids, EGCG, milk thistle, and vitamin C (Hsueh et al., 1998; Shalan, Mostafa,
Hassouna, El-Nabi, & El-Refaie, 2005; S. Sharma & Litonjua, 2014).
Metallothionein is a cysteine-rich protein, which may also be an important consideration for heavy
metal detoxification since it can bind and sequester divalent cations including mercury, cadmium, lead
and arsenic (Hodges & Minich, 2015). Metallothionein can be upregulated at the gene transcription
level by zinc (Chu et al., 2015). Dietary phytonutrients from turmeric, hops, pomegranate, prune,
watercress and other cruciferous vegetables, as well as quercetin and Cordyceps sinesis, may also
enhance cellular concentrations of metallothionein (Agarwal et al., 2010; R. Hu et al., 2004; Lamb et
al.; Singh et al., 2013; Weng, Chen, Yeh, & Yen, 2011).
Chelating agents, whether conventional, nutraceutical or dietary, bind essential minerals as well as
toxic metals. The CDC recommends chelation when pediatric blood lead levels are greater than or
equal to 45mcg/dL. (Flora & Pachauri, 2010; Sears, 2013). Caution must be exercised since these
effective chelating agents can increase the circulation of heavy metals before their excretion, and
may cause redistribution, pro-oxidant effects, hepatotoxicity and nephrotoxicity. Cadmium is
especially toxic to kidneys. Coadministration of antioxidants such as alpha lipoic acid, NAC, and
melatonin as well as supplementation with essential minerals may improve conventional chelation
outcomes (Flora & Pachauri, 2010).
35
Lifestyle Interventions
Exercise
Exercise reduces the harmful effects of toxins. For example, aerobic exercise attenuates PCBinduced cardiovascular risk factors including oxidative stress, glucose intolerance and
hypercholesterolemia (Murphy et al., 2016). Exercise also appears to induce the Nrf-2 pathway and
increases reduced glutathione biosynthesis (Dieter & Vella, 2013). However, caution should be used
with overtraining, since the acute effects of exercise diminish antioxidant status including glutathione
(Laher et al., 2013).
Perspiration
Sweat is a conduit for toxin elimination, including some PCBs, phthalates, BPA and PFCs (S J
Genuis, Birkholz, Ralitsch, & Thibault, 2010; Stephen J Genuis, Beesoon, Birkholz, & Lobo, 2012;
Stephen J Genuis, Beesoon, & Birkholz, 2013; Stephen J Genuis, Beesoon, Lobo, & Birkholz, 2012).
Sweat can be induced via exercise, or higher temperatures such as through sauna therapy.
Sleep
Partial sleep deprivation and sleep apnea induce oxidative stress and deplete antioxidant reserves
(Alzoubi, Khabour, Rashid, Damaj, & Salah, 2012; Passali et al., 2015; Villafuerte et al., 2015), and
therefore reduce available antioxidants for detoxification needs. Detoxification enzymes are under
regulation by circadian rhythms, and can therefore be disturbed by jet-lag, shift work and clock gene
dysfunction (Zmrzljak & Rozman, 2012).
Stress
Glucocorticoids have been shown to suppress Nrf-2-dependent detoxification and antioxidant
responses (Kratschmar et al., 2012) indicating that activation of the stress response, especially in
chronic stress states, can impair detoxification capability.
36
Controversies and Contraindications
Fasting Versus Food-Based Detoxification
Various forms of modified, intermittent fasting, and juice fasting, have been used traditionally for
detoxification. In addition, caloric restriction has been shown to have significant health benefits
(Horne, Muhlestein, & Anderson, 2015; Hou et al., 2016). However, scientific evidence for a beneficial
connection between fasting and detoxification remains sparse.
As we have reviewed, many nutrients are required for detoxification, including amino acids. It would
therefore be assumed that detoxification activity would deplete endogenous nutrient reserves, unless
an adequate dietary or supplemental supply is provided. Given the research that has been presented
above, a balanced, varied, whole-foods, plant-based diet, with ample phytonutrients and adequate
amounts of high quality protein would seem to be of most importance for core detoxification. This
should be achieved without excess calories, by emphasizing nutrient density over caloric density as
appropriate.
Lifecycle Considerations
Fetal and early-life exposure to toxins is known and is of significant concern since this lifecycle stage
represents a window of vulnerability for epigenetic programming that can have effects later in life
(Vaiserman, 2014; Waring, Harris, & Mitchell, 2016).
Ideally, detoxification should be regular practice in preparation for pregnancy, allowing a 3-month
time-frame between the end of an intensive detoxification program and conception. Maternal
detoxification protocols that involve the mobilization of body toxin stores into circulation are
contraindicated during pregnancy and lactation, since they risk increasing the exposure of the fetus or
infant. However, modified and careful support for detoxification that relate to ongoing, background
xenobiotic exposures may be useful.
Food-based nutrient support for detoxification may be the safest approach, including phytonutrientrich plant foods, cruciferous vegetables, garlic, essential fatty acids, high quality protein, fiber and
hydration. Modified gut-restoration protocols and probiotics can be helpful. Pregnancy-appropriate
exercise, sleep and stress management are other safe interventions for this life stage (saunas,
however, would be contraindicated). Some detoxification-related supplements, such as N-acetyl
cysteine, carotenoids, garlic, turmeric, ginger, vitamin D and essential fatty acids, have been used
during pregnancy (Bone & Mills, 2013; NaturalMedicines, 2016), but practitioners should refer to
specialist references on other supplements that are safe for use during pregnancy and lactation.
Detoxification programs for children, arguably the most vulnerable population group, should also
focus on the safest forms of intervention centering on reducing exposure, food-based dietary changes
that maintain nutrient repletion, hydration, age-appropriate exercise and sleep. Careful chelation
protocols have been used by specialists in children, as deemed necessary (Centers for Disease
37
Control and Prevention, 2016b). N-acetylcysteine has been used in children and also has chelating
properties (Bloch et al., 2016; Wink et al., 2016). Alpha-lipoic acid, with similar chelating properties
has been used in adolescents (Hegazy, Tolba, Mostafa, Eid, & El-Afify, 2013). Caution is advisable in
implementing detoxification programs for other vulnerable populations such as the elderly or in
individuals with severe illness. Gentle detoxification strategies may be more appropriate than
intensive interventions.
Detox Symptoms
It is not uncommon for individuals who adopt detoxifying dietary habits or engage in specific
detoxification programs to experience so-called “detox symptoms” or “Herxheimer (Herx) reactions.”
These may include headache, sleep disturbance, diarrhea, constipation, fatigue, brain fog, mood
changes, and skin breakouts.
Although these symptoms are often argued to be a good sign—that detoxification is happening, it is
also an indication of detox systems that are overwhelmed, of increased oxidative stress, and
inflammation. A safer approach, that minimizes harmful effects of detoxification, is to adjust the
detoxification protocols to slow the pace of toxin mobilization and/or to increase nutraceutical support
for biotransformation and elimination.
38
Monitoring and Evaluation
1. Ongoing individual assessment and comparison against baseline measures, as
appropriate
a. Re-administration of questionnaires such as MSQ and QEESI
b. Anthropometrics: Weight, body mass index, percentage body fat, waist
circumference and waist-hip ratio
c. Ratio of intracellular to extracellular water
d. Nutrition physical exam
e. Standard laboratory testing: CBC, liver function, glutathione utilization, kidney
function, iron status, whole blood metals, methylation status, uric acid.
f. Specialty laboratory testing: toxins in blood and urine, organic acids, provoked urine
testing, markers of oxidative stress, porphyrin profiling.
g. Nutrient laboratory evaluation: Nutrient status, gut function, intestinal permeability,
SIBO
2. Ongoing behavior change
a. Monitoring behavior change and adherence to diet and lifestyle recommendations
i. Reducing exposure
ii. GI support
iii. Dietary changes
iv. Supplemental nutrients and botanicals
b. Identification and resolution of obstacles to patient/client success
c. Continued education and information
3. Review of progress towards patient/client goals
39
Resources and Further Reading
Resources
•
Handout: Example Detox Food Plan
•
Handout: Detoxification Supplement Dosing
•
Handout: Decreasing Harmful Metal and Chemical Exposure
•
Handout: Toxicity Assessment
Further Reading
•
2012, World Health Organization: State of the Science of Endocrine Disrupting Chemicals
•
Carson, R. Silent Spring
•
Environmental Working Group www.ewg.org, including their Clean Fifteen/Dirty Dozen report
and SkinDeep Cosmetics Database
•
Glyphosate Research by Dr. Stephanie Seneff, MIT
•
National Resources Defense Council www.nrdc.org - Mercury Levels in Fish
•
National Water Testing Laboratories
•
Pesticide Action Network www.panna.org
•
Schettler, T. and Solomon, G. Generations at Risk: Reproductive Health and the Environment
•
The Detox Project www.detoxproject.org
•
The Stockholm Convention (Persistant Organic Pollutants)
•
Toxicant Induced Loss of Tolerance www.drclaudiamiller.com
40
Addendum: Tables with Full References
Table 2: Potential Indicators of Excess Toxic Burden
Neurological
Hormonal
Cognitive or memory difficulties (Milioni et
al., 2016)
Mood and behavior disorders (Arbuckle,
Davis, Boylan, Fisher, & Fu, 2016)
Tremors (Ji et al., 2015)
Peripheral neuropathy (Mochizuki et al.,
2016)
Chronic headaches (Rastogi, Tripathi, &
Ravishanker, 2010; Trikunakornwongs et
al., 2009)
Insomnia (Hasanato & Almomen; Rastogi
et al., 2010)
Chronic neurological conditions such as
autism, ADHD, depression, anxiety,
Parkinson’s disease, Alzheimer’s disease
(Chin-Chan, Navarro-Yepes, & QuintanillaVega, 2015; Dufault et al., 2009;
Neugebauer et al., 2015; Weisskopf et al.,
2010; Yassa, 2014)
Unexplained weight gain or loss (Gattineni,
Weiser, Becker, & Baum, 2007; Heindel,
Newbold, & Schug, 2015)
Blood sugar dysregulation, insulin
resistance (Kuo et al., 2015)
Thyroid dysfunction (Su et al., 2015)
Adrenal dysfunction (Martinez-Arguelles &
Papadopoulos, 2015)
Premature puberty (Schoeters, Den Hond,
Dhooge, van Larebeke, & Leijs, 2008)
PMS (Shamberger, 2003)
Polycystic ovarian syndrome
(Gregoraszczuk & Ptak, 2013)
Endometriosis (Buck Louis et al., 2012;
Heilier, Donnez, & Lison, 2008)
Fibroids (Trabert et al., 2015)
Sperm dysfunction (Meeker & Hauser,
2010)
Hypoandrogenism (Meeker & Hauser,
2010; Schell et al., 2014)
Infertility (Gregoraszczuk & Ptak, 2013)
Immune
Mitochondrial and Metabolic
Asthma (K.-N. Kim, Bae, Park, Kwon, &
Hong, 2015; Meng et al., 2016)
Allergies (Jerschow et al., 2012; J. H. Kim,
Chang, Choi, Kim, & Kang, 2016)
Chemical sensitivities (Winder, 2002)
Autoimmune conditions (Mostafalou &
Abdollahi, 2013)
Recurrent infection (Dewailly et al., 2000;
Sunyer et al., 2010)
Food sensitivities (Menard et al., 2014;
Rowe, Brundage, Schafer, & Barnett, 2006)
Leukopenia (Xu et al., 2008)
Fatigue (Kern et al., 2014)
Fibromyalgia (Kern et al., 2014)
Unexplained inflammation (GiménezBastida, Surma, & Zieliński, 2015;
Mostafalou & Abdollahi, 2013)
Osteoporosis (Wallin et al., 2016)
Cardiovascular disease (K.-H. Kim et al.,
2015; Ljunggren et al., 2014)
Gastrointestinal
Genotoxic
Constipation (poor clearance of toxins)
Dehydration (poor clearance of toxins)
Gut dysfunction (Chan, 2011; Yalçın, Örün,
Yalçın, & Aykut, 2015)
Loss of appetite (Prasad, 1983)
Taste changes and metallic taste (Chan,
2011; Prasad, 1983)
Cancer (CDC, 2009)
Spontaneous abortion (S. Kumar, 2011)
Birth defects (Brender & Weyer, 2016)
Developmental disorders (R.-L. Hsieh et
al., 2014)
41
Table 3: Potential Indicators of Exposure or Impaired Detoxification Capability
Medical History
Dental amalgams, potentially exacerbated with high electromagnetic frequency (EMF)
exposure (Homme et al., 2014; Mortazavi et al., 2008, 2014)
Periods of bone loss, e.g. menopause (resorption can release toxins such as lead form
bone (B.-K. Lee & Kim, 2012))
Known maternal exposure (Z. Chen et al.)
Disorders of the liver, kidney, bowel or thyroid (impaired detoxification capability)
Polypharmacy (increased burden on detoxification enzymes)
History of reactions to medications (suggestive of phase I/II single nucleotide
polymorphisms (SNPs)) (J. Chen et al., 2014; Chung et al., 2014)
Dietary History
Regular fish eater (especially high mercury fish and farmed fish) (NRDC, n.d.;
Siedlikowski et al., 2016)
High consumption of high fructose corn syrup (Dufault et al., 2009)
Processed foods (more artificial ingredients, may use harmful processing techniques)
(Environmental Working Group, 2016a)
Canned foods (Environmental Working Group, 2007)
Non-organic foods (Curl et al., 2015; Environmental Working Group, 2016a)
Alcohol use (Seitz & Mueller, 2015)
Plastic-packaged foods (J. Lee, Pedersen, & Thomsen, 2014; Maqbool, Mostafalou,
Bahadar, & Abdollahi, 2016)
Low intake of detoxification-related foods and nutrients (Tutelyan et al., 2013)
Lifestyle History
Smoking or second-hand smoke (S. Y. Jung et al., 2015)
Use of recreational drugs (Schwingel et al., 2015)
High air travel frequency (de Graaf, Hageman, Gouders, & Mulder, 2014)
Physical activity (Dieter & Vella, 2013; Murphy et al., 2016)
Ability to work up a sweat (Stephen J Genuis, Beesoon, Lobo, et al., 2012)
Poor sleep (Alzoubi et al., 2012; Zmrzljak & Rozman, 2012)
Personal care products (Environmental Working Group, 2016b)
Living in a city (K. H. Jung et al., 2015; Rakyan et al., 2010)
Living in a farming area (Beseler & Stallones, 2009)
Living in homes built before 1978 (lead-based paint) (Centers for Disease Control and
Prevention, 2016a)
Living near areas of heavy industry (Peluso et al., 2013)
Hobbies such as model airplanes (paint fumes), shooting (lead), golfing (herbicides,
pesticides)
Home use of pesticides and herbicides
Home renovation (Herbarth & Matysik, 2010)
Use of some traditional medicine supplements (Karri, Saper, & Kales, 2008)
42
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About the Board for Certification of Nutrition Specialists
The Board for Certification of Nutrition Specialists (BCNS) is the certifying body for the Certified Nutrition
Specialist® (CNS®) and the Certified Nutrition Specialist-Scholar℠(CNS-S) credentials. The BCNS’ mission is
to foster human health through the science and practice of professional nutrition care.
Certified Nutrition Specialists are advanced clinical nutrition professionals who apply the latest nutrition science
to the complexity of human health and function. CNS’s perform advanced medical nutrition therapy—
individualizing nutrition assessment, evaluation, intervention, and monitoring—to prevent and improve health
conditions.
The CNS requires a master’s or doctoral degree in nutrition or a related field, a supervised experience of 1000
hours and a passing grade on a qualifying exam. In order to maintain the credential, CNSs must complete
continuing professional education requirements. The CNS program is accredited by the National Commission
on Certifying Agencies.
The BCNS is committed to the concept that nutrition is both a profession and a powerful tool, and has
encouraged a growing number of health professionals to obtain the necessary education and experience to
utilize nutrition in practice. Thus, in addition to clinical nutritionists, the CNS credential may be obtained by
advance-degreed health professionals who demonstrate the requisite knowledge and skills in clinical nutrition
to become nutrition specialists.
About the Authors
Romilly Hodges, MS, CNS
Romilly Hodges is an integrative clinical nutritionist. She is passionate about the ability of food to nourish and
heal the body, using a science-based approach. She has proven experience in the fields of nutritional
detoxification and immune health. Romilly is the staff nutritionist at the office of Kara Fitzgerald, ND, maintains
her own private practice, and engages in nutrition research and writing for publication. She regularly guides
patients and clients through detoxification programs and daily detoxification support strategies.
Romilly holds a Master’s Degree in Human Nutrition from the University of Bridgeport, Connecticut. Romilly is a
Certified Nutrition Specialist through the Board for Certification of Nutrition Specialists, and has completed
advanced training at the Institute for Functional Medicine.
Romilly has published in the Journal of Nutrition and Metabolism as lead author and researcher on the topic of
foods and food-derived components for detoxification. She has contributed to the textbook Nutritional and
Integrative Strategies in Cardiovascular Medicine (Sinatra & Houston eds.). She has also served as Teaching
Assistant to Dr. Deanna Minich, CNS for the Certified Food and Spirit Advanced Detoxification Module,
designed for professionals in the field of health and nutrition.
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Kara N. Fitzgerald, ND
Dr. Fitzgerald received her doctorate of naturopathic medicine from National College of Natural Medicine in
Portland, Oregon. She completed the first CNME-accredited post-doctorate position in nutritional biochemistry
and laboratory science at Metametrix (now Genova) Clinical Laboratory under the direction of Richard Lord,
Ph.D. Her residency was completed at Progressive Medical Center, a large, integrative medical practice in
Atlanta, Georgia.
Dr. Fitzgerald is lead author and editor of Case Studies in Integrative and Functional Medicine, a contributing
author to Laboratory Evaluations for Integrative and Functional Medicine and the Institute for Functional
Medicine’s updated Textbook for Functional Medicine. She has been published in numerous peer-reviewed
journals and has lectured extensively on the impact of toxins on health, as well as detoxification support.
Dr. Fitzgerald is on faculty at the Institute for Functional Medicine, and is an Institute for Functional Medicine
Certified Practitioner. She was formerly on faculty at University of Bridgeport in the School of Human Nutrition.
She is a clinician researcher for The Institute for Therapeutic Discovery. Dr. Fitzgerald regularly lectures
internationally for several organizations and is in private practice in Sandy Hook, Connecticut. Dr. Fitzgerald
regularly blogs for professionals at www.drkarafitzgerald.com.