1. Detoxification
A Systems Medicine Approach
Keith Berndtson, MD

2. Definitions
• Toxin: a substance with harmful effects on living systems.
Includes heavy metals, biotoxins, and many industrial chemicals.
• Detoxification: to remove or neutralize the toxic quality of toxins.
• Xenobiotic: a chemical substance present within, but not made
within a living thing - a substance that is “a stranger to life.”
• Persistent Organic Pollutants (POPs): hazardous xenobiotics that
resist degradation within living systems.
• Toxic load: the sum total of toxins within a given living system.

3. How Toxicity Challenges
Our Natural Detoxification Systems
Truth
Ubiquitous
Too many to count
Complex interactions
Consequences
Altered brain function
Gut disturbances
Reproductive effects
Hormone disruption
Nutrient depletion
Inflammation
Cancer
Diabetes
Autoimmune disease
Degenerative disease
Cardiovascular disease
and more...

4. Lipophilic Toxins
Low molecular weight, non-polar, fat-soluble toxins easily move into
or through phospholipid membranes and into cells. They distribute
widely and can accumulate to hazardous levels. High molecular
weight lipophilic toxins are especially difficult to eliminate.
Common, Hazardous Lipophilic Toxins
volatile organics polyaromatic hydrocarbons mold toxins
polyvinyl chlorides industrial solvents ciguatera toxin
pesticides combustion products microcystin
phlalates perfluoro-octanoic acid dioxins
bisphenols tetrachloroethylene PCBs
flame retardants dinoflagellate toxins organohalides

5. Attention Please!
Doctors Needed to Engage this Problem
Growing awareness of the connection between toxicity and chronic disease.

6. Glutathione (GSH)
A molecule of primordial importance
Free radical and Phase 1 anions are
anion binding sites: stabilized and
COOH = carboxyl polarized, made
NH = amino ready for active
SH = sulfhydryl membrane transport
1. GSH maintains intracellular redox balance by mopping up
oxidative stress.
2. Glutathione-S-transferases conjugate GSH to phase 1 drugs,
toxins, and xenobiotics, preparing them for transport out.
3. GSH-dependent membrane transporters and efflux pumps
play key roles in toxin elimination.

7. The Biotransformation of Lipophilic Toxins
Phase 1 reactions add a functional group to a fat soluble toxin so the new
structure can be conjugated (joined to) a phase 2 substrate.
Phase 2 reactions continue the biotransformation process to create a water
soluble compound suitable for elimination into bile or blood for transport
and elimination by the bowel or kidneys.
Phase 1 Phase 2
Fat soluble Water soluble
Oxidation Sulfate conjugation
Reduction Glucuronide conjugation
Hydrolysis Glutathione conjugation
Acetylation Amino acid conjugation

8. Key Phase 1 and 2 Pathway Sites
The liver handles 70% of the
biotransformation work in the
body. Other active sites for these
pathways include:
1. kidneys
2. lungs
3. skin
4. intestinal cells
5. endothelial cells of the blood-
brain barrier
What these locations have in
common:
1. organs of detoxification
2. key tissue barriers

10. Phase 3: Membrane Transporters
antigens from inflamed gut
and hepatic artery are
processed by Kupffer cells
membrane transporters pump
phase 2-processed toxins
from liver cells into the
biliary collection system
toxins from inflamed gut
enter liver from the
membrane transporters pump portal vein
phase 2-processed toxins
into sinusoids for lymph and
blood transport to kidneys

11. Membrane Transporters and Efflux Pumps
ATP binding cassette (ABC) transporters
modulate the absorption, distribution,
metabolism, secretion, and toxicity of
xenobiotics. Emerging evidence is
defining their role in tissue defense,
especially in the GI tract.
P-glycoprotein is an ATP-dependent
efflux pump whose role is to detoxify
cells. It actively pumps toxins out of
intestinal epithelial cells and helps resist
invasion by enteric pathogens.
MRP2 is an organic anion transporter
found in liver, intestinal, and kidney cells.
Mercado-Lubo R, McCormick BA.
Gut Microbes 2010;1(5):301.
It’s expression increases in the presence of
intestinal inflammation, decreases in the
presence of chronic toxicity.

12. Mercury Species as
Transporter Disrupters
Animal evidence shows that conjugates of methyl-mercury and inorganic mercury
are transportable substrates of MRP2.
Bridges CC, Joshee L, Zalups RK. MRP2 and the handling of mercuric ions in rats exposed
acutely to inorganic and organic species of mercury. Toxicol Appl Pharmacol 2011:251(1):50.
Mercury anions interact with MRP1 and MRP2 either alone or as a mercury-
glutathione complex.
Wortelboer HM, et al. Glutathione-dependent interaction of heavy metal compounds with
multidrug resistance proteins MRP1 and MRP2. Environ Toxicol Pharmacol 2008:26(1):102.
HYPOTHESIS 1: MRP2 concentrates in the duodenum and upper jejunum.
Inorganic mercury leaching from amalgams into swallowed saliva, and
methylmercury produced within the gut microbiome, can interfere with transporter
binding, slowing phase 3 and phase 2, creating a phase 1/2 mismatch.
HYPOTHESIS 2: Un-conjugated methylmercury and inorganic mercury anions
interact with transporters, causing malfunctions that would predict upper intestinal
inflammation and slowed detoxification pathways.

13. Mercury Dynamics
Species, Routes of Passage, and Analysis
Mercury Speciation Testing
Used to gauge methylmercury and inorganic
mercury dynamics by comparing hair and
urine levels to blood levels.

14. Mercury Sources
Methyl-mercury: seafood and gut-space conversions
Inorganic mercury: dental amalgams and industry
Methylmercury distribution in seafood

15. Mercury Toxicity
Effects on the Brain and Nervous System
Mechanisms
Carvalho CM, et al. Inhibition of
the human thioredoxin system: a
molecular mechanism of mercury
toxicity. J Biological Chemistry
2008;283(18):11913-23.
Type of Brain Pathology Witnessed Mercury Autism
Microtubule degeneration Yes Yes Overall, mercury inhibition
Neuroinflammation Yes Yes was selective toward the
thioredoxin system. In
Oxidative stress and lipid peroxidation Yes Yes particular, the remarkable
Microglial/astrocytic activation Yes Yes potency of the mercury
Reduced glutathione level Yes Yes compounds to bind the
selenol-thiol group in the
Mitochondrial dysfunction Yes Yes active site of the TrxR*
Vascular endothelial cell dysfunction Yes Yes should be a major molecular
Increased amyloid precursor protein Yes Yes mechanism of mercury
toxicity.
Impaired methylation Yes Yes
Higher pro-inflammatory cytokine levels Yes Yes *TrxR = thiodoxin reductase

16. Natural Detoxification Pathways
Slide courtesy of Chris Shade, PhD, of Quicksilver Scientific

17. Disrupting the Detoxification Chain
With compromise
of small intestinal
barrier integrity...
1. Small intestinal inflammation
overworks phase 3 transporters.
2. Phase 3 slowing down-regulates
phase 2 conjugation.
3. Phase 2 slowing results in a
backlog of un-conjugated toxins.
4. Free radical damage rises due to
the phase 1/phase 2 mismatch.
...comes systemic
damage caused by
chronic toxicity.

18. Leaky Gut
Precursor to Chronic Toxicity, Autoimmune Disease
“This new paradigm subverts traditional theories underlying the development of these
diseases and suggests that these processes can be arrested if the interplay between genes
and environmental triggers is prevented by re-establishing the zonulin-dependent
intestinal barrier function.”
Fasano A. Leaky gut and autoimmune disease. Clin Rev Allergy Immunol 2012;42(1):71-8.

19. Leaky Gut
Loss of Tight Junction Functional Integrity
Cascade Effects
•Maldigestion
Fasano A. Physiol Rev 2011;91:151 •Gluten sensitivity
•Delayed food sensitivities
•Dysbiosis
•Nutrient malabsorption
•Bacterial overgrowth
•Yeast overgrowth
•Bacterial translocation
•Metabolic endotoxemia
•Systemic inflammation
•Neuro-inflammation
•Autoimmune disorders
•Chronic toxicity

20. Leaky Gut
Celiac Permissive and Non-Celiac Gluten Sensitivity
Type 1: Celiac Permissive
•3 celiac permissive genes:
DQ 2.5, DQ 2.2, DQ8.
•Celiac panel predicts likelihood of
celiac disease, not gluten sensitivity.
•Both malabsorption and leaky gut can
appear with this form.
•Gluten-free trial warranted.
Type 2: Non-Celiac
•No HLA genotype predictors thus far.
•No testing helpful at present.
•Malabsorption only with this form?
•Gluten-free trial warranted.

21. Leaky Gut
Bacterial Lipopolysaccharide (LPS) Translocation
as a cause of Metabolic Syndrome
Recurrent LPS translocation causes metabolic endotoxemia.
LPS is an inflammatory component of the cell-wall of gram negative bacteria. Intestinal immune cells are
largely responsible for the maintenance of intestinal homeostasis and must elicit robust responses to
pathogens yet still tolerate the commensal microbiota. Leaky gut invites metabolic endotoxemia - an
LPS-driven immune cascade that leads to obesity, diabetes, cancer, and cardiovascular disease.
Burcelin R, Garidou L, Pomie C. Immuno-microbiota crosstalk: the new paradigm for metabolic diseases. Seminars in Immunology 2012;24:67-74.

22. Systemic Inflammation
Pathways Involved in Neuroinflammation
Gut- and peripherally-derived
neuroimmune processes produce
neuropsychiatric and
neurocognitive consequences.
Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological
implications. Pharmacology and Therapeutics 2011;130(2):226-238.
Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous
system in normal gastrointestinal function and disease. Gastroneterology 2009;136(6):2003-14.

23. The Sluggish
Bowel
Traffic jams
in the gut space
invite trouble.

24. Biotoxin Illness
Chronic Inflammatory Response Syndrome
High cytokine levels in the capillaries attract white
The Biotoxin Pathway Capillaries
blood cells, leading to restricted blood flow, and lower
oxygen levels. HIF stimulates VEGF and TGF B-1.
In genetically susceptible people, biotoxins bind to pattern receptors, HIF Reduced VEGF leads to fatigue, muscle cramps, and
causing continuing, unregulated production of cytokines. shortness of breath (may be over-ridden by
replacement with erythropoietin). TGF B-1 changes
Surface cell type and interacts with Treg cells.
Receptors Dendritic
Biotoxin (Toll; Cells Immune System Symptoms
tible) C-type Increased Cytokines
(HLA suscep lectin;
Patients with certain HLA genotypes
HLA-DR (immune response genes) may develop
mannose inappropriate immunity. Most common
& others) are antibodies to:
Fat cells then -Gliadin (affects digestion)
produce more -Cardiolipins (affects blood clotting)
leptin, leading to Treg cells: Pathogenic T cells
obesity (which
doesn’t respond to Split Products of
exercise and diet). Complement Activation
Excessive cytokine Leptin C4a: capillary hypoperfusion
levels can damage receptor
Bioto
C3a: bacterial membranes
leptin receptors in Damaged leptin
the hypothalamus. Inflammation-related
receptors lead to
xin
Nerve cell/ Hypothalamus symptoms
reduced production
axon by the hypothalamus High levels of cytokines produce flu-like
VIP AVP of MSH, a hormone
MSH symptoms: Headaches, muscle aches, fatigue,
with many functions. unstable temperature, difficulty concentrating
Biotoxins have direct and more. High levels of cytokines also result in
!"#$%&'(( effects, including increased levels of several other immune-
)*$#(+,"( impairment of nerve response related substances, including TGF
-$./( cell function.
Reduced B-1, MMP-9, IL-1B, and PAI-1. MMP-9 delivers
MSH inflammatory elements from blood to brain,
In most people, Sleep Disturbance nerve, muscle, lungs, and joints. It combines
biotoxins are
Production of melatonin with PAI-1 in increasing clot formation and
either removed
is reduced, leading to arterial blockage.
from the blood
by the liver or chronic, non-restorative Resistant Coag-negative
attached by the sleep.
Staph Bacteria
immune system, Chronic Pain
broken down, Colonies of MARCoNS with resistance to multiple
and excreted Endorphin production is antibiotics may develop in biofilm or mucus membranes.
harmlessly. In suppressed. This can lead The bacteria produce substances that aggravate both
people who to chronic, sometimes the high cytokine levels and low MSH levels.
don’t have the unusual, pain.
Reduced ADH
right immune Gastrointestinal
response genes, Changes in Cortisol Reduced MSH can cause the pituitary to
Problems Prolonged Illness
however, and ACTH levels produce lower levels of anti-diuretic
biotoxins can Lack of MSH can cause White blood cells lose The pituitary may produce
hormone (ADH), leading to thirst, frequent
remain in the regulation of cytokine urination, and susceptibility to shocks from
malabsorption in the gut, elevated levels of cortisol and
body indefinitely. response, so that recovery ACTH in early stages of illness, static electricity.
resulting in diarrhea. This is
sometimes called “leaky from other illnesses, then drop to excessively low
including infections levels later. (Patients should Reduced Androgens
gut” and resembles (but is
diseases, may be slowed. avoid steroids such as Reduced MSH can cause the pituitary to lower its
not) celiac disease. IBS is prednisone, which can lower
c R. Shoemaker, 2011 often present. production of sex hormones.
levels of ACTH)
Find this chart @ www.survivingmold.com

25. Stealth Infections
Tick-borne and various other bacteria, viruses,
and parasites can stress detoxification systems
Anaplasmosis Babesiosis Bartonella Ehrlichiosis
Borreliosis Mycoplasma Chlamydia Epstein-Barr
HHV-6 Cytomegalovirus Entamoeba Blastocystis

26. The main problem is not
exposure level, but toxicity retention caused
by slowed detoxification pathways.
• Sluggish and/or leaky bowel =
slowed elimination, overworked
transporters. Chronic toxicity is
• Slowed phase 3 activity = retained a detox traffic jam
toxicity as elimination doors close.
• Slowed phase 2 activity = phase 1/2
mismatch, more oxidative stress.
• Poor nutrition = added systemic
pathway malfunctions.
• Weak genes = susceptibilities to
slowed detox function at various
systemic pathway points.
• Higher environmental exposure =
greater risk of detox traffic jams.

27. Review: Basic Necessities for
High-Performance Detoxification
Functional glutathione-dependent pathways
Functional phase 1 and 2 detoxification pathways
Functional phase 3 transporter pathways
A non-inflamed, non-toxic gut.

28. Team Detox needs a PR campaign!
Insert tag line here.

29. Glutathione
Mammalian biology’s best friend.
Phase 1 Pathways
The ninjas warriors of biotransformation.
Phase 2 Pathways
The US Marshalls of cellular biology.
Phase 3 Pathways
The fast and reliable way to ship.

30. Toxicity creep: it gets worse
• 10 billion pounds of toxic waste produced annually in US alone.
• 47 million pounds of mercury dumped into US environment each year.
• Xenobiotics and POPs a growing problem: bisphenols, PCBs, flame
retardants, pesticides, combustion products, acrylamides, and more.
• Toxins disrupt bodily systems: reproductive, developmental,
circulatory, mental, neurological, hormonal, immune, digestive,
metabolic, and most ironically - detoxification systems.

31. Ruzzin J. BMC Public Health 2012;12:298
The time for
action is now!
“The general population is exposed
to sufficient POPs, in terms of
concentration and diversity, to
induce metabolic disorders. The
situation should attract the greatest What’s the
attention from the public health and
governmental authorities.” hangup?

32. Moral Man and Immoral Society
Reinhold Niebuhr (1892–1971) is credited with coining the first
circulated version of what’s now known as the Serenity Prayer. He
was, and remains, widely admired for his theological, moral, and
political insights, including the idea that humankind would always
struggle to make the world a better place if left to its own authority.

33. Moral Hazard
Niebuhr observed that groups
condone immorality more than
individuals because the moral
responsibility for harms caused
gets diffused within the group,
making it easier to deflect
accountability. Corporations and
bureaucracies provide ample
cover for greed, corruption, and
the temptation to play God.
We depend on social cooperation to achieve things we cannot accomplish on our own.
That corporate needs conflict with social needs defines the moral hazard of our time.
Niebuhr concluded that we cannot trust ourselves to find the path that leads to human
flourishing and that we must defer to a higher source of wisdom if we are to find a
road to health and sustainability.
- excerpted from Seek Wisdom: The Modern Quest for Health and Sustainability

34. And Where is Our Medical Profession
on the Issue of Chronic Toxicity?
The Prayer of Maimonides
(excerpted)
Almighty God, you have created the human body with infinite
wisdom. You have blessed the earth, the rivers and the
mountains with healing substances that enable your creatures
to alleviate their sufferings and heal their illnesses. You have
endowed man with the wisdom to relieve suffering and to
recognize disorders, to extract the healing substances, to
discover their powers, and to apply them to suit every ill.
Inspire me with love for my art, and let me be content with
everything except the great science of my profession. Never let
the thought arise that I have attained sufficient knowledge, for
the art of medicine is great and the mind of man is ever
expanding.
1135 -1204

35. Do we have a medical model to handle
the complexity of chronic toxicity?
•Medical toxicologists address
the more straightforward
problem of acute toxicity.
•The chronic toxicity issue
paralyzes doctors who lack the
time and tools needed to deal
with this level of complexity.
•A systems medicine model can
handle the clinical complexity of
chronic toxicity.
•What is this model and why is
outside the mainstream?

36. The Systems Medicine Model
Environmental Systems: World System:
Merge ecological science Coordinated efforts
with corporate stewardship. to reduce toxicity.
Most moral hazards Cultural Systems:
Encourage health
found here
and sustainability.
Political and
Economic Systems:
Develop policies that The Human Bodymind:
reward progress toward Maintain and restore
healthy and sustainable functional integrity
living systems. through wise self-care
and clinical methods that
reduce chronic toxicity.
Copyright Keith Berndtson, MD

37. Living Systems as Overlapping Networks
A modern systems medicine model
Text
Diagram from: De Keulenaer GW, Brutsaert DL. Circulation 2011;123:1996-2005

38. Living Systems as Overlapping Networks
An ancient systems medicine model

39. Factors underlying our different
responses to toxic exposures:
Species A
• Genetic susceptibilities
• Levels of exposure
• Quality of nutrition
• Organ reserves
Pollution A
• Hormone balance
Species B
• Tissue barrier integrity
• Detoxification strength
• Restorative strength
• Emotional/spiritual balance
Pollution B
How are the As and Bs different? How are they the same?

40. How to Repair and Amplify
Your Body’s Detoxification Systems
• Get professional help. Find a good
source of detoxification expertise.
• Repair the gut. Restrict reactive foods
and restore a healthy gut microbiome.
• Mercury speciation testing. Assess the
need for mercury detox support.
• Test for biotoxin susceptibility. As
warranted based on history.
• Test for stealth infection. As
warranted based on history.
• Get nutrition counseling. For help
with dietary changes, detox support.
• Try acupuncture. And other methods
for balancing energy flow.
• Healthy lifestyle change. Find the
structure and support you need. Warrior One Pose

41. Conclusions
1. Hordes of toxins are infiltrating the living systems of the world.
2. Natural detoxification pathways are overworked and undernourished.
3. Healthy barriers support healthy detoxification (including moral barriers).
4. The prognosis for any chronic disease relates to detoxification capacity.
5. To reduce the costs of chronic disease, reduce chronic toxicity.
6. Chronic toxicity is best addressed using the systems medicine model.
7. Up with the systems medicine model!

42. Your source for
professional detox support.
For advanced detoxification expertise and
a chance at feeling better no matter what
your chronic health condition,
call to schedule:
847-232-9800
or register online:
www.parkridgemultimed.com
15 N. Prospect Avenue, Park Ridge, IL 60068

43. Patient-centered
systems medicine.