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Upcoming ACS Webinars
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Thursday, May 19, 2016

Design of Deliverable Macrocycles
Session 5 of the 2016 Drug Design and Delivery Symposium

Scott Lokey, Professor of Chemistry & Biochemistry, UC Santa Cruz

Nicholas Meanwell, Executive Director, Bristol-Myers Squibb

Thursday, June 9, 2016

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Rich Hartel, Professor of Food Engineering, University of Wisconsin-Madison
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Forensic Toxicology: Cracking the Case with Chemistry

Dr. Jason E. Schaff Darren Griffin

Forensic Chemist,
Professor of Genetics,
U.S. Government
University of Kent, UK

Slides available now! Recordings will be available to ACS members after one week
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Contact ACS Webinars at acswebinars@acs.org 11

UNCLASSIFIED

FORENSIC TOXICOLOGY:
CRACKING THE CASE WITH CHEMISTRY

Dr. Jason E. Schaff

Forensic Chemist

12 UNCLASSIFIED 05/12/2016

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UNCLASSIFIED

DISCLAIMER

All opinions expressed or implied herein

are those of the speaker. None of them
represent, in any way, official positions of
the of the United States Government or
any agency thereof.

13 UNCLASSIFIED 05/12/2016

UNCLASSIFIED

OUTLINE
• What is forensic toxicology?

• Pharmacokinetics / pharmacodynamics

• Analytical methods

• Interpretation of results

• Common drug classes

• Closing thoughts

• Questions

14 UNCLASSIFIED 05/12/2016

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UNCLASSIFIED

WHAT IS TOXICOLOGY?
• From dictionary.com:
• the science dealing with the effects … of poisons

• “Poison is in everything, and no thing is without poison.

The dosage makes it either a poison or a remedy.”
– Paracelsus

• Interface of pharmacology and analytical chemistry

15 UNCLASSIFIED 05/12/2016

UNCLASSIFIED

COMPLIANCE TESTING
SPECIMENS
• Most often urine
• Sometimes blood, sweat, CHALLENGES
hair, or oral fluid • Fast, cheap testing required
• Setting cutoff levels
• Variable urine density
WHAT IS THE QUESTION? – creatinine normalization
• Using something forbidden? • Conflicting regulations
• Not using something required? • People “beating the test”

16 UNCLASSIFIED 05/12/2016

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Audience Survey Question

ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT

Which specimen can be used to PROVE that a person is

intoxicated?

• Urine
• Hair
• Breath
• Blood
• All of the above

17

UNCLASSIFIED

DRIVING UNDER THE INFLUENCE

SPECIMENS
• Blood!!
– only way to prove intoxication CHALLENGES
• Breath (presumptive alcohol) • Accurate quantitation critical
• Urine (exposure only) • Specimen handling / storage
– especially for ethanol

WHAT IS THE QUESTION? • Interpretation absent per se

• Was a per se law violated? • Many specialized attorneys
• Potential impairment from
intoxication?

18 UNCLASSIFIED 05/12/2016

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UNCLASSIFIED

DRUG-FACILITATED ASSAULT

SPECIMENS
• Blood ideal, but often CHALLENGES
collected too late
•Extremely low LODs required
• Urine most common
•Huge (& weird) analyte list
• Hair increasingly useful
•Complex pharmacological
interpretation
WHAT IS THE QUESTION? •Educating contributors
• Was a person chemically
incapacitated?
• Possible chemical impairment of
short-term memory?

19 UNCLASSIFIED 05/12/2016

UNCLASSIFIED

POST-MORTEM TOXICOLOGY
SPECIMENS
• Everything but the kitchen sink!
CHALLENGES
• Blood, urine, bile, vitreous
• Huge target analyte list
humour, liver, brain, etc
• Huge range of concentrations
• Putrefaction
• Post-mortem redistribution
WHAT IS THE QUESTION?
• Pharmacological meaning
• Was there a chemical cause
of, or contribution to, death?
• Could insurance claims or
criminal charges be affected?

20 UNCLASSIFIED 05/12/2016

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UNCLASSIFIED

PHARMACOKINETICS (PK)
• What does the biological system do to the toxicant?

1st Order Kinetics

CONCENTRATION
– Adsorption Zero Order Kinetics

2 Compartment Model
(How does it get in?)
– Distribution
(Where does it go?) TIME

– Metabolism
(How does the system try to detoxify it?)
– Excretion
(How does the system get rid of it?)

21 UNCLASSIFIED 05/12/2016

UNCLASSIFIED

PHARMACODYNAMICS (PD)
• What does the toxicant do to the biological system?

• Desired Effects
– Treat disease or symptom
– Antidote to another toxicant
– Change in mental state

• Undesired Effects
– Damage to healthy tissue
– Functional impairment
– Change in mental state

22 UNCLASSIFIED 05/12/2016

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UNCLASSIFIED

PHARMACOGENOMICS
• How does an individual’s genetic profile affect PK and PD?

• e.g. metabolism of ethyl alcohol

– Ethanol + ADH  Acetaldehyde (toxic)
– Acetaldehyde + ALDH  Acetate (fuel)
– ALDH underproduction = “Asian flush” response to alcohol

23 UNCLASSIFIED 05/12/2016

Audience Survey Question

ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT

Which of the following analytical techniques is considered

a “rising star” in forensic toxicology?

• Immunoassay
• Gas Chromatography
• Liquid Chromatography
• Gas Chromatography Mass Spectrometry
• Liquid Chromatography Mass Spectrometry

24

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UNCLASSIFIED

ANALYTICAL TECHNIQUES
• IMMUNOASSAY
• Antibody binding test with colorometric detection
• Fast, cheap, simple, but very little specificity

GAS CHROMATOGRAPHY LIQUID CHROMATOGRAPHY

•Robust, mature technology
•Very high peak capacity
•Limited by analyte thermal
stability and volatility
•GC-MS is a “Gold Standard” in
forensic toxicology.
•Works for almost all polar compounds
•Tolerant of “dirty” samples
•Problems with very non-polar
compounds
•LC-MS is a “Rising Star” in forensic
toxicology.

25 UNCLASSIFIED 05/12/2016

UNCLASSIFIED

MASS SPECTROMETRY
• Only common detection technique providing unambiguous
identification

• Not a “magic bullet”; know the limitations

– Libraries suggest; standards confirm
– No identification without fragmentation
– Uniform procedures for data interpretation
– Similar spectra within compound classes
– At least two dimensions of overall data required
– High resolution ≠ accurate mass

26 UNCLASSIFIED 05/12/2016

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UNCLASSIFIED

INTERPRETATION
• What is the question?

• What is the scenario?

• Presence / Absence?
– Absence is usually definitive.
– Mere presence less so.

• Concentration
– Per se limits
– Therapeutic vs. toxic vs. fatal
– Measurement uncertainty

• Does the answer make sense?

27 UNCLASSIFIED 05/12/2016

UNCLASSIFIED

TOLERANCE
• Pharmacokinetic
– Increased enzyme activity due to toxicant exposure
– Higher dose needed to obtain a given concentration

• Pharmacodynamic
– Altered receptor / messenger activity due to exposure
– Higher concentration needed to obtain a given effect

• Dependence
– Special case of pharmacodynamic tolerance
– Toxicity or impairment from too low a level

28 UNCLASSIFIED 05/12/2016

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UNCLASSIFIED

DRUG-DRUG INTERACTION
• Pharmacokinetic
– Toxicant competition for available enzymes
– Increased enzyme activity from toxicant exposure
– Effects on renal clearance

• Pharmacodynamic
– (de)Sensitization of receptor systems
– Different receptor systems with the same gross effect
– Additive vs. synergistic vs. antagonistic

• Drug-Food Interactions
– e.g. grapefruit juice

29 UNCLASSIFIED 05/12/2016

UNCLASSIFIED

POST-MORTEM REDISTRIBUTION
• Chemical Potential Gradient
– Biological “pumping” stops

• Gravimetric Gradient
– Fluid redistribution

• Trauma
– Leakage from rupture of the diaphragm, bladder, or GI tract

• Effect Very Compound-Dependant

• Resistant Specimens
– Especially vitreous humour

• Great Care Interpreting Concentrations

30 UNCLASSIFIED 05/12/2016

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Audience Survey Question

ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT

Which of the following is considered the most common

illicit toxicant of forensic interest today?

• Ethanol like alcohol

• THC like marijuana
• Opioids like morphine
• Hypnotic-Sedatives like benzodiazepines
• Stimulants like cocaine

31

UNCLASSIFIED

ETHANOL
• Most Common Toxicant of Forensic Interest

• CNS Depressant
– No single neurotransmitter target
– Depresses higher functions before lower
– Euphoria / excitation at lower doses
– MANY drug-drug interactions

• Per Se Laws
– Based on studies of “average” population
– Back-extrapolation for determination of violation

• Determination of Impairment and Toxicity

– Complicated by very strong tolerance effects

32 UNCLASSIFIED 05/12/2016

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UNCLASSIFIED

THC
• Most Common Illicit Toxicant of Forensic Interest

• Extremely Lippophillic; Long Detection Half-Life

• Pharmacodynamics difficult to classify

– Cannabinoid-specific receptor systems (CNS and peripheral)
– Dosing rate and route of administration matter
– Hysteresis between effect and blood concentration

• “Synthetic Cannabinoids”

33 UNCLASSIFIED 05/12/2016

UNCLASSIFIED

OPIOIDS
• Clinically as Analgesics, Antitussives, Anesthetic
Aids

• Morphine and Derivatives

– From opium poppies; used for thousands of years
– Complex PK and PD; extensive interconversion
– Severe tolerance and dependence effects

• Synthetic Opioid Agonists

– Fentanyl, tramadol, methadone, etc.

• Opioid Antagonists
– e.g. naloxone; antidote for heroin overdose

34 UNCLASSIFIED 05/12/2016

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UNCLASSIFIED

HYPNOTIC-SEDATIVES
• CNS Depressants
– Sleep aids, antidepressants, anti-seizure, anesthetic aids

• Barbiturates (direct)
– No longer common (overdose risk and dependence)

• Benzodiazepines (indirect)
– Extremely common prescription drugs
– Complex metabolism and wide range of effects

• Common in Drug-Facilitated Assault

35 UNCLASSIFIED 05/12/2016

UNCLASSIFIED

STIMULANTS
• Cocaine
– Both enzymatic and non-enzymatic metabolism
– Strong tolerance effects

• Phenethylamines
– Wide range of chemical structures and additional effects
• Pure (almost) stimulant (methamphetamine)
• Decongestant (pseudoephedrine)
• ADHD treatment (methylphenidate)
• Halucinogens (MDMA / “ecstasy”, cathinones / “bath salts”)

36 UNCLASSIFIED 05/12/2016

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UNCLASSIFIED

CLOSING THOUGHTS
• Forensic toxicology operates at the interface of
pharmacology, and analytical chemistry.

• There are many subfields of forensic toxicology, each

with its own focus and requirements.

• The analytical tests must be tailored to answer the

relevant questions.

• Excellent analytical chemistry is no good if the results

aren’t interpreted carefully.

37 UNCLASSIFIED 05/12/2016

Forensic Toxicology: Cracking the Case with Chemistry

Dr. Jason E. Schaff Darren Griffin

Forensic Chemist,
Professor of Genetics,
U.S. Government
University of Kent, UK

Slides available now! Recordings will be available to ACS members after one week
www.acs.org/acswebinars
Contact ACS Webinars at acswebinars@acs.org 38

•19
 •5/11/2016

®
Upcoming ACS Webinars
www.acs.org/acswebinars

Thursday, May 19, 2016

Design of Deliverable Macrocycles
Session 5 of the 2016 Drug Design and Delivery Symposium

Scott Lokey, Professor of Chemistry & Biochemistry, UC Santa Cruz

Nicholas Meanwell, Executive Director, Bristol-Myers Squibb

Thursday, June 9, 2016

Ice Cream Chemistry
Rich Hartel, Professor of Food Engineering, University of Wisconsin-Madison
Maya Warren, Food Scientist, Cold Stone Creamery

39
Contact ACS Webinars ® at acswebinars@acs.org

Forensic Toxicology: Cracking the Case with Chemistry

Dr. Jason E. Schaff Darren Griffin

Forensic Chemist,
Professor of Genetics,
U.S. Government
University of Kent, UK

Slides available now! Recordings will be available to ACS members after one week
www.acs.org/acswebinars
Contact ACS Webinars at acswebinars@acs.org 40

•20
 •5/11/2016

®
How has ACS Webinars
benefited you?

“ACS Webinars provide great tangible

examples to share with my students. I am so
excited to have this applied case to describe
so that pKa can have real meaning for them,
great timing and great presentation.”
Quote in reference to: http://bit.ly/ChemDeath

Amy Naylor, N.D.

Biology & Chemistry Instructor
Mitchell Community College

41
Be a featured fan on an upcoming webinar! Write to us @ acswebinars@acs.org

facebook.com/acswebinars
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Benefits of ACS Membership

Chemical & Engineering News (C&EN)

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NEW! Free Access to ACS Presentations on Demand®

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recordings from recent ACS meetings and select events.

NEW! ACS Career Navigator

Your source for leadership development, professional
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43
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ACS Webinars does not endorse any products or
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not necessarily reflect the views or policies of the
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Contact ACS Webinars ® at acswebinars@acs.org 44

•22
 •5/11/2016

®
Upcoming ACS Webinars
www.acs.org/acswebinars

Thursday, May 19, 2016

Design of Deliverable Macrocycles
Session 5 of the 2016 Drug Design and Delivery Symposium

Scott Lokey, Professor of Chemistry & Biochemistry, UC Santa Cruz

Nicholas Meanwell, Executive Director, Bristol-Myers Squibb

Thursday, June 9, 2016

Ice Cream Chemistry
Rich Hartel, Professor of Food Engineering, University of Wisconsin-Madison
Maya Warren, Food Scientist, Cold Stone Creamery

45
Contact ACS Webinars ® at acswebinars@acs.org

•23