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ChemIDP.org
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®
Contact ACS Webinars ® at acswebinars@acs.org
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
•5/11/2016
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www.acs.org/acswebinars www.acs.org/acswebinars Slides available now! Recordings will be available to ACS members after one week
Forensic Toxicology: Cracking the Case with Chemistry
Contact ACS Webinars at acswebinars@acs.org
Darren Griffin Professor of Genetics, University of Kent, UK
Dr. Jason E. Schaff Forensic Chemist, U.S. Government
UNCLASSIFIED
FORENSIC TOXICOLOGY: CRACKING THE CASE WITH CHEMISTRY
Dr. Jason E. Schaff Forensic Chemist
12
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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.
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OUTLINE
• What is forensic toxicology?
• Pharmacokinetics / pharmacodynamics
• Analytical methods
• Interpretation of results
• Common drug classes
• Closing thoughts
• Questions
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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
=
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COMPLIANCE TESTING
SPECIMENS
• Most often urine
• Sometimes blood, sweat,
hair, or oral fluid
WHAT IS THE QUESTION?
• Using something forbidden?
• Not using something required?
CHALLENGES
• Fast, cheap testing required
• Setting cutoff levels
• Variable urine density
– creatinine normalization
• Conflicting regulations
• People “beating the test”
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Audience Survey Question
Which specimen can be used to PROVE that a person is intoxicated?
ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
• Urine
• Hair
• Breath
• Blood
• All of the above
DRIVING UNDER THE INFLUENCE
SPECIMENS
• Blood!!
– only way to prove intoxication
• Breath (presumptive alcohol)
• Urine (exposure only)
WHAT IS THE QUESTION?
• Was a per se law violated?
• Potential impairment from
intoxication?
CHALLENGES
• Accurate quantitation critical
• Specimen handling / storage
– especially for ethanol
• Interpretation absent per se
• Many specialized attorneys
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DRUG-FACILITATED ASSAULT
SPECIMENS
• Blood ideal, but often
collected too late
• Urine most common
• Hair increasingly useful
WHAT IS THE QUESTION?
• Was a person chemically
incapacitated?
• Possible chemical impairment of
short-term memory?
CHALLENGES
•Extremely low LODs required
•Huge (& weird) analyte list
•Complex pharmacological
interpretation
•Educating contributors
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POST-MORTEM TOXICOLOGY
SPECIMENS
• Everything but the kitchen sink!
• Blood, urine, bile, vitreous
humour, liver, brain, etc
WHAT IS THE QUESTION?
• Was there a chemical cause
of, or contribution to, death?
• Could insurance claims or
criminal charges be affected?
CHALLENGES
• Huge target analyte list
• Huge range of concentrations
• Putrefaction
• Post-mortem redistribution
• Pharmacological meaning
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PHARMACOKINETICS (PK)
• What does the biological system do to the toxicant?
– Adsorption
(How does it get in?)
– Distribution
(Where does it go?)
– Metabolism
(How does the system try to detoxify it?)
– Excretion
(How does the system get rid of it?)
CO
NC
EN
TR
AT
ION
TIME
1st Order Kinetics
Zero Order Kinetics
2 Compartment Model
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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
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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
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Audience Survey Question
Which of the following analytical techniques is considered a “rising star” in forensic toxicology?
ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
• Immunoassay
• Gas Chromatography
• Liquid Chromatography
• Gas Chromatography Mass Spectrometry
• Liquid Chromatography Mass Spectrometry
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ANALYTICAL TECHNIQUES
• IMMUNOASSAY
• Antibody binding test with colorometric detection
• Fast, cheap, simple, but very little specificity
GAS CHROMATOGRAPHY
•Robust, mature technology
•Very high peak capacity
•Limited by analyte thermal
stability and volatility
•GC-MS is a “Gold Standard” in
forensic toxicology.
LIQUID CHROMATOGRAPHY
•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.
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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
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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?
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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
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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
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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
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Audience Survey Question
Which of the following is considered the most common illicit toxicant of forensic interest today?
ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
• Ethanol like alcohol
• THC like marijuana
• Opioids like morphine
• Hypnotic-Sedatives like benzodiazepines
• Stimulants like cocaine
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
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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”
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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
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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
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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”)
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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.
UNCLASSIFIED 37
UNCLASSIFIED
05/12/2016
38
www.acs.org/acswebinars www.acs.org/acswebinars Slides available now! Recordings will be available to ACS members after one week
Forensic Toxicology: Cracking the Case with Chemistry
Contact ACS Webinars at acswebinars@acs.org
Darren Griffin Professor of Genetics, University of Kent, UK
Dr. Jason E. Schaff Forensic Chemist, U.S. Government
•5/11/2016
•20
Upcoming ACS Webinars www.acs.org/acswebinars
39
®
Contact ACS Webinars ® at acswebinars@acs.org
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
40
www.acs.org/acswebinars www.acs.org/acswebinars Slides available now! Recordings will be available to ACS members after one week
Forensic Toxicology: Cracking the Case with Chemistry
Contact ACS Webinars at acswebinars@acs.org
Darren Griffin Professor of Genetics, University of Kent, UK
Dr. Jason E. Schaff Forensic Chemist, U.S. Government
•5/11/2016
•21
Be a featured fan on an upcoming webinar! Write to us @ acswebinars@acs.org
41
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.”
Amy Naylor, N.D.
Biology & Chemistry Instructor
Mitchell Community College
Quote in reference to: http://bit.ly/ChemDeath
42
facebook.com/acswebinars
@acswebinars
youtube.com/acswebinars
Search for “acswebinars” and connect!
•5/11/2016
•22
Benefits of ACS Membership
43
http://bit.ly/ACSjoin
Chemical & Engineering News (C&EN) The preeminent weekly news source.
NEW! Free Access to ACS Presentations on Demand® ACS Member only access to over 1,000 presentation recordings from recent ACS meetings and select events.
NEW! ACS Career Navigator Your source for leadership development, professional education, career services, and much more.
44
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presentation are those of the presenter and do
not necessarily reflect the views or policies of the
American Chemical Society.
®
Contact ACS Webinars ® at acswebinars@acs.org
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Upcoming ACS Webinars www.acs.org/acswebinars
45
®
Contact ACS Webinars ® at acswebinars@acs.org
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
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