Medical Toxicology Integration into Personalized
Medicine: Environmental, Toxicogenomic &
Forensic Perspectives
Presented by:
Jerrold B. Leikin MD, FACP, FACEP, FACMT, FAACT, FACOEM
Director of Medical Toxicology
NorthShore University HealthSystem-OMEGA
Clinical Professor of Medicine
Pritzker School of Medicine-University of Chicago
Professor of Medicine and Pharmacology
Rush Medical College
Senior Editor- Disease-a-Month Journal
Elsevier
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EDUCATION
CHEMISTRY
INORGANIC ORGANIC
BIOCHEMISTRY
BIOLOGY
PHARMACOLOGY
PHYSIOLOGY
TOXICOLOGY
PATHOLOGY
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“ Hot” Medical Terminology
of the 21st Century
Telemedicine
Translational Medicine
Personalized Medicine
(Precision Medicine)
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4
Ref: Tomanek L. J Proteomics.2014; 104:92-106
Paracelcus’ (1493-1541)
Principle of Toxicology
“Everything is a poison, there is nothing
which is not. Only the dose differentiates a
poison from a remedy.”
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2nd Principle of Toxicology
Toxidrome
Group or pattern of signs and
symptoms associated with a
particular class of substances.
Ref: Mofenson HC, Greensher J. The nontoxic ingestion. Ped Clin North
Am 1970. 17(3): 583-590 6
Ref: www.sketchymedicine.com 7
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POISON CONTROL CENTERS
The original “telemedicine”
First Poison Center established in
1953 (Chicago)
AAPCC established in 1959
About 3 million poison calls
nationally (252 calls in Illinois daily)
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2013 AAPCC DATA
57 Regional Poison
Centers
2,188,013 human
exposures (6.8 per
100,000 population)
59,496 animal
exposures (90% dogs
& 8% cats)
806,347 information
calls
Ref: Mowry JB, et al: 2013 Annual Report of the American Association of Poison
Control Centers’ National Poison Data System (NPDS). 31st
Annual report. Clin Tox 2014: 52:1032-1283 11
Top Six Human Exposures (overall)
1. Analgesics* 11.5%
2. Cosmetics 7.7%
3. Household Cleaning substances 7.6%
4. Sedatives/antipsychotics/hypnotics 5.9%
5. Antidepressants 4.2%
6. Foreign bodies/toys 4.0%
* Greatest increase over the past 12 years (8,780 calls /year) 12
Change in Encounters by Outcome from 2000
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Substance Categories with the Greatest Rate of More
Serious Exposure Increase
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Case
46 year old Type 1 diabetic
(poorly controlled)
Developed intense
numbness, neuropathic
pain, itching
Had barracuda soup in
South America
Mild gastrointestinal
symptoms for 24 hours
after meal
Heat/cold reversal of
symptoms
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Ciguatera Food Poisoning
Caused by fish ingestion of
dinoflagellates
Toxin is odorless, tasteless,
lipid soluble, heat/gastric acid
stable
Accumulates in larger predator
fish (over 2 kg)
Toxin modulates sodium ion
entry in neuronal tissue
50,000 reported cases
worldwide per year. In Florida,
incidence is 5.6/100,000
Treat as neuropathy (lasts 2-3
months)
Ref: Calvert GM, Hryhorczuk DO, Leikin JB. J Toxicol Clin Toxicol. 1987; 25(5):423-8
Radke EC, Reich A, Morris Jr JG. Am J Trop Med Hyg. 2015; 93:425-32
Anticardiolipin Antibody & Cocaine
20 of 44 cocaine abusers
were positive
43 of 203 healthy volunteers
were positive
Patients who used cocaine
intravenously were more likely
to be positive then those who
“snorted” (p < 0.05)
Of 7 cocaine patients with
seizures or thromboembolic
disorders, 5 were antibody
positive
Ref: Fritsma GA, Leikin JB, Maturen AJ, et al. J Emerg Med. 1991; 9:37-43 17
Case
40 year old appliance repairman with
cough at work
Traditional work-up negative
RAST serology positive for isocyanates
(HDI, MDI)
Ref: Leikin JB, Paloucek FP. Poisoning and Toxicology Handbook, 4th ed. CRC Press. 2008 18
Other environmental examples
Low level CO poisoning identified in ED: alternative heating
source and cohabitant symptoms
Heckerling PS, Leikin JB, Maturen A, Perkins A. Ann Intern Med. 1987;
107(2): 174-77
CO2 narcosis in a car from dry ice
Leikin JB, Mitton JF, Freedom T. Ann Intern Med. 2009; 150: 361-2
Metal-on-Metal hip implant toxicity (Cobalt)
Leikin JB, Karides HC, Whitely PM. Clin Toxicol. 2013; 51:230-6
Topical pyrethrin exposure resulting in stuttering in a toddler
Hammond K, Leikin JB. Am J Ther. 2008; 15:323-4
Facial nerve neuritis from UV-B radiation from a 1000 watt light
bulb
Bryant SM, Cumpston KL, Leikin JB, et al. Vet Hum Toxicol. 2003; 45:217-8
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Other environmental examples
(continued) Leukemoid response in ethylene glycol poisoning
Mycyk M, Drendel A, Sigg T, Leikin JB. Vet Hum Toxicol. 2002;
44(5): 304-6
Topical use of DEET causing severe encephalopathy
Oker E, Leikin JB. Acad Emerg Med. 1999; 12(6): 1295-7
Ephedra causing eosinophilic myocarditis and CHF in a 32 year
old male.
Zaacks SM, Klein L, Tan DC, et al. J Toxicol Clin Toxicol. 1999;
37(4):485-9
Association of Peyronie’s disease with petrochemical exposure
Leikin JB, Carlson A, Rubin R, et al. JCOEM. 2002; 44(2): 105-6
Toluene neurotoxicity in paint thinners presenting as multiple
sclerosis in painters.
(see above)
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Proposition
An environmental toxin can silently cause
disease processes usually through inhalation,
which can result in disabling symptoms
(usually neurologic) without objective signs.
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Variants
Dose Relationship
Ultra-Sensitivity
No anatomical pattern to complaints
Models- Lead, Carbon Monoxide
No toxidrome
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Outgassing
The emission of chemicals (usually volatile
organic chemicals or VOC) from building
materials.
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Formaldehyde Emissions
Sealants
Motor
Caulking
Paints
Woods
Plastics
Vinyl Products
Foams
Insulation
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Total VOC over 3mg per m3
Headache
Drowsiness
Fatigue
Confusion
Decline in FEV
Dryness
Burning eyes
Upper airway irritation
Note that during refueling, TVOC ranges from 50
to 150mg/m3
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Carpet: 4 phenylcyclohexane (4-PC)
From rubber latex binding
at back of carpet
Source of new carpet odor
Odor runs from 30ppb to 1ppb after
installation
Odor threshold is 5ppb
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Symptoms of 4-PC at 2ppb
Headache (67%)
Throat soreness (52%)
Upper airway irritation (48%)
Nausea (48%)
Ocular irritation (38%)
Skin irritation (24%)
Can be reduced by steam cleaning
carpet and improved ventilation
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Example of pesticide interaction, xenobiotic
enzymes/genetic variant and Parkinsonism
Diazinon, chlorpyrifos, parathion exposure in
351 cases in rural California (2001-2008); 363
controls
DNA samples provided
Carriers of variant MM PONI-55 genotype
exposed to diazinon and chlorpyrifors
exhibited > 2 fold increase in Parkinson
disease risk
No increase in risk with parathion
Ref: Manthripragada AD, et al. Epidemiology. 2010; 21(1):87-94 32
Environmental
“Cancer-Causing” Proposition
Carcinogen implies carcinogenicity in any species at a common site (bioassy concordance between rats and mice is only 70%)
Asymptomatic (no “toxidrome”)
Dose-effect relationship impossible to quanitate -- “Threshold” (dose of dinitropyrenes contained in an 8 ounce serving of cooked chicken exceeds one year exposure of diesel exhaust in a tunnel)
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Environmental
“Cancer-Causing” Proposition
Confounders
Ignores beneficial effects
Data primarily extrapolated from occupational medicine (healthy workers-170 hr month exposures)
Data also directly extrapolated from rodents to humans (teratogen model)
Latency
Guarantees -- emotional impact
No biomarkers
Risk assessment is difficult
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Risk Assessment Example
22 year old exposed to ethylene oxide
for one year at a maximum air
concentration of 10 ppm (8 hour OSHA
time weighted average is 1 ppm).
What is her risk for developing lymphatic
or hematopoietic cancer?
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Risk Assessment Example
Exposure of EtO at 1ppm for 45 years, a
rate ratio of 1.2 was published (IARC:
Monograph - 1994 - pg 73-159)
EPA provisional inhalation unit cancer
risk estimate is 1 x 10 -4 (ug/m3)-1
Increased cancer risk of 1.5/10,000
Baseline cancer rate is about
3,000/10,000
Her rate would be 3001.5/10,000 38
Environmental causes of
Childhood Leukemia
Radiation (radon)
Chemotherapy (AML)
Benzene (AML)
Pesticides (?)
Arsenic/chromium/trichloroethylene in
groundwater (Woburn, MA)
Home paint exposure (ALL)
Near industrial sites (glass fibers, metals)
Source: www.cancer.org (ACS) 1. Durant JL, et al. Environ Health Persp. 1995; 103:93-8 3. Garcia-Perez J, et al. Environ Res. 2015; 140: 542-53
2. Bailey HD, et al. Cancer causes control. 2015; 26(9): 1257-70 39
CNS Tumors & Baseball
9 MLB personnel with primary
CNS tumors (careers
spanned 1961 to 2004). Rate
of 2.5 tumors per 1500
personnel per decade
All personnel had at least 2
years exposure to outdoor
first generation artificial turf
CBTRUS registry – 6.5 to
20.6 primary CNS tumors per
100,000 individuals per
decade
Fisher exact test < 0.05
Ref: Nelson ME, Lank PM, Leikin SM, et al. Chicago Medicine. 2014; 117(12):22-23 40
Asbestos Case
A group of water-
meter readers are
concerned about
asbestos exposure
when entering old
homes. How do you
counsel them?
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Home Involvement
20% of all US buildings have some
asbestos-containing materials.
Only a health hazard if it is friable
(released into air): sprayed on decorative
coatings or insulation.
Not usually friable: thermal insulation,
floor tiles (9 inch), or wallboard.
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Drinking Water & Food (processed)
A contaminant not felt to pose any
health risk.
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Home Risk Assessment
School levels 0.0004 to 0.0010
fibers/cubic centimeter
100 to 200 times lower than OSHA PEL
5,000 times lower than heavy industrial
exposure prior to 1970
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Bronchogenic Carcinoma
Asbestos accounts for about 5% of cases
annually (cigarette smoking accounts for 85%)
Asbestosis is a risk factor (scar cancer?)
Usually located in peripheral lower lobe
lesions
Latency: 15 to 35 years
Threshold is probably about 5 fiber-years (50
year exposure at OSHA-PEL level of 0.1f/cm3)
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Mesothelioma
Deaths will peak in 2020 and may
account for 1% of deaths for men born in
the 1940’s
Multiplicative relative risk of 1.9 for each
fiber year /ml of exposure
No increase risk for mesothelioma in
very low-dose asbestos exposures
(occupants of buildings) Ref: Metintas, S et al: Chest 2002: 122:2224-9
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Hormesis
A dose-response relationship in which
there is a stimulatory effect (positive
response/tumor inhibition) at low doses,
but an inhibiting effect (negative
response/tumor induction) at high doses
--- The “U” shaped curve as opposed to
the linear dose-response curve (as
adopted by a conservative public health
approach).
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Another definition of Poisons:
A lower threshold of toxicity than other
substances
Ruldolf Arndt (psychiatrist)
Hugo Schulz (pharmacologist)
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Key Principle of Hormesis
Homeostasis: the tendency of an
organism to keep itself on an even keel
Immune system “gears up” to cope with
foreign invaders and the organism
becomes resistant to the disease
Hormesis usually occurs at doses five
times lower than the toxic threshold
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Radon and Hormesis
Cytodynamic 2-stage (CD2) cancer
model
Females over 40 years old in 2,821
counties dying of lung cancer in 1950-
1954 (VA exluded)
Long term US EPA data
Ref: Bogen KT: Belle newsletter 1998: 7: (2) 9-14.
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Arsenic and Hormesis
Utah/Taiwan Reanalysis
Hormetic effect at 25 to 75 ppb
Raising EPA level back to 50ppb would
prevent 1,000 cancer deaths daily
nationwide
Ref: Hively, W: Discover, December 2002, p80
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IMMUNOTHERAPY
Ref: Leikin JB, Leikin RE, Evans MA, Wiener S, Hryhorczok DO. J Toxicol Clin Toxicol.
1991; 29: 59-70 60
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Postmortem Pharmacogenomics
(Molecular Autopsy)
Milwaukee County Medical Examiner
25 Fentanyl Deaths
Mean blood Fentanyl level – 19.9 ng/ml
CYP3A5 is involved in fentanyl metabolism and homozygous
CYP3A5*3 can result in impaired fentanyl metabolism to norfentanyl (homozygous variant)
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Molecular Autopsy
Milwaukee County Medical Examiner
Oxycodone deaths
Genotyping by DNA extraction from WBC
of CYP2D6(poor metabolizers-
homzygous) provided more definitive
interpretation of oxycodone toxicity due to
metabolic differences in four of 15 cases.
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Clinical Aspects
Paroxonase 1 (PON-1) gene
correlated with Ache and
clinical organophosphate
toxicity
CYP2D6 deficiency resulting in
prolonged TCA toxicity
Ref: 1) Matthews AR, Sutter ME, Rentz DE. J Med Toxicol 2011: 7: 243-247
2) Smith JC, Curry SC. J Med Toxicol 2011: 7: 220-223 64
Cocaine and fatalities
Cocaine fatality does not correlate with with blood cocaine
levels
Butyrylcholinesterase (BChE) is primarily cocaine hydrolase
producing non-toxic metabolite ecgonine methyl ester.
A reduction of BChE can result in an increase in hepatic
carboxylesterase to produce norcocaine (as a toxic
byproduct)
58 known mutations of BChE gene-atypical variant (ASP 70
Gly) exhibits ten-fold reduced activity toward cocaine.
K variant is most common variant resulting in 33% lower
plasma BChE activity.
Ref: Duysen EG, Lockridge O. Drug Metabolism and Disposition. 2001;39(8):1321-1323 65
Codeine- ultra rapid metabolizer
CYP2D6 functional gene
duplication (CYP2D6 um)
Occurs in 1 to 10 % of
individuals of European
descent and up to 30% of
North African descent
Significantly greater production
(50 to 75% ) of morphine from
parent drug
Correlated with toddler deaths
at appropriate codeine dosage
(maximum 6 mg/kg daily)
Ref: Kelly LE, Rieder M, Van den Anker J, et al. Pediatrics. 2012; 129 (5): e1343-e1347 66
No
Underlying
Toxicologic
Syndrome
20 patients
mean age 41 years
No previous psychiatric disorder
Not on any psychotropic medications
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Ref: Leikin JB, Mycyk MB, Bryant S, et al. Journal of Clinical Toxicology. 2004; 42(5):
pp 643-648
No
Underlying
Toxicologic
Syndrome
50% male
All describe single toxic trigger
None describe multiple chemical sensitivity
5% - Ongoing Exposure
45% currently employed
90% by inhalation exposure
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No
Underlying
Toxicologic
Syndrome
All events biologically implausable
All heavy metal analysis were normal
30% see alternative medicine advice
30% seek litigation
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No
Underlying
Toxicologic
Syndrome
Multiple Chemical Sensitivity Syndrome
(Idiopathic Environmental Illness)
Panic Disorder
Post Traumatic Stress Disorder
Somatization Disorder
A cross between
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Prospective German Study
117 patients with “Environmental Illness”
vs. 59 workers in semiconductor
industry.
Workers had fewer physical complaints,
fewer psychiatric diseases and more
toxicological lab abnormalities.
Psychotherapy was most helpful:
Somatization disorder and symptom
projection which approaches paranoia.
Zilker, Th. Clin Tox 2002: 40: 296-297 .
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“Damage by distraction: regulating low
hypothetical risks. Putting huge amounts
of money into minuscule hypothetical risks
damages public health by diverting
resources and distracting the public from
major risks.”
Ref: Ames, B.N. and Gold, L.S. Paracelsus to Parascience:The Environmental
Cancer Distraction. Mutation Research 447, 3-13 (2000)
Conclusions (NUTS)
Odor Toxicity
Silent neurotoxicity
in adults is unlikely
to occur.
Fatigue alone is not
a toxic symptom.
Irritant effects will
dominate
Biological
implausible toxic
effects are just that
Do not confuse
regulatory toxicology
with medical
toxicology
Media reports of a
toxic exposure can
be more toxic than
the exposure 73
Conclusions
Knowing the environment (domestic, occupational)
is essential in the total care of the patient
Risk assessment must integrate environmental
metrics
Medical Toxicology (aka External Medicine) should
be incorporated into “ Personalized Medicine”
Medical Toxicology has been utilizing the concepts
of telemedicine, translational and personalized
medicine for decades
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“…the prevailing focus on an individual’s genes and
biology insufficiently incorporates the important role of
environmental factors in disease etiology and health”
“…a better understanding of the relationship between
environmental exposure and the epigenome might
lead to more efficient preventive measures”
“… embracing the impact of the environment on health
will require a new framework to guide both research
and its application, and to steer public investment and
research efforts”
Ref: Carlsten C, Brauer M, Brinkman F, et al. EMBO Rep. 2014 Jul; 15(7): 736–739. 75
Ref: The Journal of Irreproducible Results. June 2014; 52(3): 29 76
THANK YOU
JERROLD B LEIKIN M.D.
DIRECTOR of MEDICAL TOXICOLOGY
NorthShore University HealthSystem - OMEGA
(847) 657-1700
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