medical toxicology integration into personalized …...source and cohabitant symptoms heckerling ps,...

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

2

“ 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

13

Substance Categories with the Greatest Rate of More

Serious Exposure Increase

14

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

67

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

68

No

Underlying

Toxicologic

Syndrome

All events biologically implausable

All heavy metal analysis were normal

30% see alternative medicine advice

30% seek litigation

69

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

74

“…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

jleikin@northshore.org

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