the expert witness in forensic pharmacology and toxicology
DESCRIPTION
Two one hour undergraduate lectures on a BSc (hons) Forensic Science Course.TRANSCRIPT
The Expert Witness in Forensic Pharmacology /
Toxicology
Professor N. J. BirchAcademic Consultancy Services Ltd
Copyright 2012 N.J.Birch
Copyright 2012 N.J.Birch
Copyright 2012 N.J.Birch
Evidence
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Different lenses allow the investigation of different aspects of the evidence
Using this analogy we can see that we obtain different information from a handheld lens, from a dissecting lens and from the different forms of microscopy (e.g. transmitted light, polarised light, fluorescence, electron beam, EXAFS )
Each scientific specialism has its own “lenses” and this is equally true in Forensic Toxicology and Pharmacology. The “lenses” in this case are those of the relevant basic science, toxicology and pharmacology, PLUS extra skills based on forensic training and experience
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Copyright 2012 N.J.Birch
Copyright 2012 N.J.Birch
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Forensic Pharmacology
• Basic tenet of pharmacology:– that there is always an ordered relationship
between the concentration of a drug acting in the body and the magnitude of its effect
– There are always TWO sets of considerations:
–Pharmacodynamics–Pharmacokinetics
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Pharmacological issues in criminal cases• Those in which the drug is the main issue
• Illicit drugs, possession or dealing
• Those in which drug effects are related to the offence
• Driving offences:
• Behaviour alleged to be modified by presence of drug• Intent, memory, ability to comprehend, ability to perform
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• Behaviour triggered by drug:• Aggression, Confusion, Amnesia, Consent, Unconsciousness
• Alcohol by definition, Other drugs by implication
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Pharmacodynamics= response of the body to the presence of a drug
• The actions of a drug at a receptor or receptors
response is proportional to drug concentration at receptor
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Drug effects and toxicity
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Useful dose range Increasing toxicity
Ineffective
Drugtarget blood concentration
range
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Phenytoin marginal overdose
Drug response may be influenced by:
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naturally occurring substances present at receptor e.g. neurotransmitters, hormones
other drugs or xenobiotics present at receptor factors affecting number, structure or function of
receptors• disease, exercise, abnormal environment, starvation,
obesity dehydration, age, sex, previous drug or dietary history
genetic variability
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Pharmacokinetics movement of drug to and from the locality of the receptor
ADME controls the concentration of drug present at the receptor at any precise time
–EXCRETION
–METABOLISM
–DISTRIBUTION
ABSORPTION
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Drug distribution & kinetics• For many drugs :
– Blood concentration of drug (at equilibrium) is reasonably representative of whole body
– Volume of distribution is the volume apparently occupied by the drug at the same concentration as in blood.• characteristic of each drug
– Volume of distribution x blood concn. • = body load of drug • = dose administered – loss (metabolic & excretion)
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Drug distribution & kinetics
concentration vs time
exponential
Blood Lorazepam vs Time Approximation from urine analysis: minimum blood concentration compatible with
urinary detection limit of 1mg / litre.
t0.5 = 14.0 hr, Vd= 1.3 l/kg, Body weight 44.5 kg, Clearance = 1.1ml/min/kg*
-2
-1
0
1
2
3
4
5
6
-36 -24 -12 0 12 24 36 48 60 72
Time before (-) or after (+) urine sample (hours)
Pro
ject
ed B
lood
Lor
azep
am (
Cte
m)
(mg/
l)C(Lorazepam)
log C(Lorazepam)
* = pharmacokinetic data from Hardman et al (1995)
log10 concentration vs time
linear
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• characteristic range of values for each drug–long-acting drugs have long half-life
Copyright 2009 N.J.Birch Academic Consultancy Services Ltd
HALF LIFE Dose at time zero = 16
t0.5= 1 hours. Residual dose vs time
0
5
10
15
0.00 1.00 2.00 3.00 4.00 5.00
Time after dose (hours)
Re
sid
ua
l do
se
= t½
Half life is the time taken for the blood concentration to decline to one-half of its present value
Fluoxetine pharmacokineticsSingle dose. Half life = 72 hours
0
1
2
3
4
5
6
7
0 2 4 6 8 10 12 14 16 18 20
Days
Bloo
d flu
oxet
ine
conc
entra
tion
(arb
itary
uni
ts)
Multiple dosesFluoxetine:
Pharmacokinetic curve, 20mg / dayOnce daily dosing (Half-life = 72Hr)
0
5
10
15
20
25
30
35
0 2 4 6 8 10 12 14 16 18 20 22
days
Blo
od
co
ncen
trati
on
(a
rbit
rary
u
nit
s)
• Equilibrium occurs between four and five Half- Lives after first dose
Effect of single 60mg dose after equilibration with 20mg once daily dose
0
5
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15
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25
30
35
40
45
days
blo
od
co
nce
ntr
atio
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srb
itra
ry u
nit
s
Fluoxetine(20mg/day): effect of discontinuation for three days followed by a single 3 x dose (60mg)
0
5
10
15
20
25
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35
16 19 22 25 28 31
days
Blo
od fl
uoxe
tine
conc
entr
atio
n (a
rbitr
ary
units
)
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Fluoxetine pharmacokineticsFluoxetine Comparison of
pharmacokinetics of 20mg and 60mg daily doses
0102030405060708090
1000 3 6 9
12 15 18 21 24 27 30 33 36 39 42 45
days
bloo
d co
ncen
trat
ion
arbi
trar
y un
its
Drug doses• Three variables:
–Dose of drug(= weight of drug administered)
–Concentration in body fluids
–Volume of body fluid in which it is diluted
• If we can measure any TWO of these we can calculate the third
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Volume of distribution
Total water =
8.7 l 33.6 l 42 l
Weight =
14.5 kg (3yr) 56kg (20yr) 70 kg (20yr)
Total body water is approximately 60% of lean body mass
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Total Body Water• The part of the body which is NOT hard
tissues, cell membranes/structures or fat– Approximately 60% of LEAN BODY MASS
• Depends on sex, age, height, weight– Fat content is sex dependant – Fat content generally increases with age
• WATSON(1988) formula for MEN:TBW = 2.45 + (0.11 x Height) + (0.34 x Weight) - (0.095 x Age)
– Data determined from 700 subjects aged from 17 to 86 years
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Psychotropic drugs and crime• Drugs may be used in the performance of criminal acts:
e.g. murder, abduction
• Drugs may be themselves the main issue of the crime: e.g. drink driving, drug dealing
• Drugs may precipitate the criminal act: e.g. psychiatric patient who commits theft whilst confused or drug interaction leading to uncharacteristic disinhibition
• Drugs may cause failure of memory: false but sincere accusations: e.g. consent in cases of rape
• Drugs may trigger aggression, violence, sexual activitye.g. issues of intent and consent
BUT
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CasesBenzo
Benzo + Alc Alcohol
A/D + AlcA/Depress
0
50
100
150
200
250
300
350
Sexual/Rape
Violent
Non-Violent
Total
NJB Criminal cases 1997 - 2008
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a/da/d + alc
alcoholbenzo+alc
benzo
0
10
20
30
40
50
60
70
80
violent
non-violent
sex & rape
Percentage of each class of crime associ-ated with drug alone or in combination
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Alcohol
Methanol = methyl alcohol = wood spirit (in methylated spirits)Ethanol = ethyl alcohol = beverages, surgical spirit (mild antiseptic) Propanol= propyl alcohol = industrial cleaning agent (e.g. printing)Butanol= butyl alcohol = industrial solvent
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1 unit = 10 ml abs alcohol;
= 3 or 4 times pub measures
Beer 4%Wine 12%Spirits 37.5%
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= 8 grams EtOH
Ethanol content of some domestic & medicinal products
% alcohol
Window cleaning products 10
Paint stripper 25
Hair tonics 25 – 65
Liquid hand washing detergents 1 - 10
Cough / cold medicines 3 - 25
Homeopathic / herbal medicines Variable but significant
Mouthwashes 14 - 27
Colognes & perfumes 40 - 60
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Alcohol pharmacokinetics
•Distributed in Total Body Water (TBW)•Concentration in TBW depends on dose •Rate of metabolism is effectively constant (except below 20 mg %)
•Rate of excretion in urine, breath and sweat is relatively insignificant but proportional to blood alcohol
Absorption of alcohol in the gastrointestinal tract of man
Comparison of the time course of blood alcohol concentration following approximately 60 grams of alcohol (6 single measures of whisky, USA) taken with and without food. Based on data from Widmark (1981) 1
Widmark EMP. Principles and applications of medicolegal alcohol determination. Davis, California, USA: Biomedical Publications,
1981;
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Volume of distribution
Total water(litres) =
8.7 33.6 42
Weight =
14.5 kg (3yr) 56kg (20yr) 70 kg (20yr)
Total body water is approximately 60% of lean body mass
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Alcohol metabolism• Alcohol metabolism occurs at approximately constant rate
– the rate is related to body size– the rate is increased by previous exposure to alcohol
• Two means of calculating– Rate of reduction of blood alcohol (used by Forensic Science
Laboratory)
Low = 10 “Average” = 18 High = 25
mg alcohol / 100 ml blood / hour– Chronic alcoholics can reach or even exceed 30 mg % / hr
– Rate of removal of alcohol from body• 120 mg alcohol/ kg body weight /hour = 8.5 gm /hr (70 kg man) approx
10ml /hrCopyright 2012 N.J.Birch
-30 -25 -20 -15 -10 -5 00
100
200
300
400
500
600
700
800
Backtracking blood alcohol from sampleRates of metabolism:
Low = 10, Average = 18, High = 25 , Alcoholic = 30 (mg alcohol / 100 ml blood / hr)
Time (hr)
Blo
od
alc
oh
ol
(mg
/ 1
00
ml
blo
od
)
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Alcohol in Breath & Urine
• Indirect measures• Blood alcohol is what is relevant to
behaviour and impairment of driving• Legal Limit for driving (UK)
– Blood 80 mg / 100 ml BLOOD– Breath 35 micrograms (g) / 100 ml BREATH– Urine 107 mg / 100 ml URINE
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Alcohol
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Early pharmacological
observations
• Macbeth Act 2 Scene 3• Enter MACDUFF and LENNOX.
• Macduff. Was it so late, friend, ere you went to bed, that you do lie so late?
• Porter. Faith, sir, we were carousing till the second cock: and drink, sir, is a great provoker of three things.
• Macduff. What three things does drink especially provoke?
• Porter. Marry, sir, nose-painting, sleep, and urine. Lechery, sir, it provokes and it unprovokes; it provokes the desire, but it takes away the performance:
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Effects of alcohol variable
Depends on:
• Body size, body fat, sex, age • Rate of metabolism• Previous alcohol intake
history• Presence of other drugsCopyright 2012 N.J.Birch
Blood alcohol concentration
mg /100 ml blood
Stage of alcoholic influence Clinical signs / symptoms
10 - 50 subclinical Behaviour nearly normal by ordinary observationSlight changes detectable by special tests
20 - 120 euphoria Mild euphoria, sociability, talkativeness.Increased self-confidence; decreased inhibitionsDiminution of attention, judgment, controlBeginning sensory and motor impairmentSlowed information processing
90 – 250 excitement Emotional instability; loss of critical judgmentImpairment of perception, memory and comprehensionDecreased sensory response; increased reaction timeReduced visual acuity, peripheral vision, glare recoverySensorimotor incoordination; impaired balance
180 - 300 confusion Disorientation, mental confusion; dizzinessExaggerated emotional states (fear, rage, sorrow etc)Disturbances of vision (diplopia etc) and of perception of colour, form, motion, dimensionsIncreased pain threshold Increased muscular incoordination; staggering gait; slurred speechApathy, lethargy
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250 - 400 stupor General inertia; approaching loss of motor functionsMarkedly decreased response to stimuliMarked muscle incoordination; inability to stand / walk;Vomiting; incontinence of urine/faecesImpaired consciousness; sleep or stupor
350 - 500 coma Complete unconsciousness: coma ; anaesthesiaDepressed or abolished reflexesSubnormal temperatureIncontinence of urine and faecesImpairment of circulation and respiration Possible death
450 + death Death from respiratory arrest
Blood alcohol concentration
mg /100ml blood
Stage of alcoholic influence Clinical signs / symptoms
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Alcohol is a depressant drug: it inhibits a range of processes including those which INHIBIT antisocial behaviour. These processes are learned through childhood to provide a basis for normal social living.Alcohol is therefore DISINHIBITORY
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Removal of successive layers of inhibitions leading to exposure of basic and instinctual behaviours
Loss of social controls, disinhibition
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a/da/d + alc
alcoholbenzo+alc
benzo
0
10
20
30
40
50
60
70
80
violent
non-violent
sex & rape
Percentage of each class of crime associ-ated with drug alone or in combination
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Disinhibition
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Removal of successive layers of inhibitions leading to exposure of basic and instinctual behaviours
Loss of social controls, disinhibition
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DisinhibitionLechery, sir, it provokes and it unprovokes; it provokes the desire, but it takes away the performance:
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The Great ProvokerLecherySexual behaviour in both female and male affected by alcohol (and other
sedating drugs)
Main effect is DISINHIBITION. Alcohol inhibits the inhibitory controls of socially and sexually acceptable behaviour learned during childhood.
ProvokesSexually explicit, provocative or “inappropriate”, uncharacteristic?, disinhibited behaviour. Potentially more violent, loss of coordination, emotional extremes, increased pain threshold, anterograde amnesia
UnprovokesSexual performance in both male and female is compromised. Penile / vaginal pressures, lack of secretions, delayed or inhibited ejaculation. Sedative effects. Vomiting, dizziness.
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Benzodiazepines•Diazepam (Valium®)•Temazepam• Nitrazepam (Mogadon®)• Flunitrazepam (Rohypnol®)• Midazolam• (zopiclone)
“Minor tranquilizers”
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CasesBenzo
Benzo + Alc Alcohol
A/D + AlcA/Depress
0
50
100
150
200
250
300
350
Sexual/Rape
Violent
Non-Violent
Total
NJB Criminal cases 1997 - 2008
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Benzodiazepines:• Act on Ascending Reticular Formation
(ARF) of the midbrain• ARF controls level of sensory input
– ↑= greater level of awareness (e.g. anxiety)
– ↓ = diminished level of awareness (e.g sedation)
• Also effects on memory mechanisms
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MemoryAlcohol & drug induced
MEMORY BLACKOUTS
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Drugs and Memory• Memory has four main divisions
– Acquisition– Working memory– Consolidation– Recall
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Failure leads to ANTEROGRADE amnesia
Failure leads to RETROGRADE amnesia
Sensory Register< 2 sec
Short Term Memorysecs - hours
limited capacity
Long Term Memoryhours - decades
'unlimited' capacity
Decay of information
Not saved
Not rehearsed
RECALL
Drugs & Alcohol
Trauma
Fading recollection
MoodDistractions
AttentivenessVigilance
RehearsalConscious or Unconscious
Rehearsal
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Benzodiazepine induced anterograde amnesia
• 22 yr old man, breaks up with girlfriend & attempts suicide• Parks car in entrance to farm & takes 20 + diazepam• Recovers several hours later, starts car, drives down road
erratically, misjudges next sharp bend and hits tree• Rescued by passing policemen and explains that he did not
deliberately drive into tree though knew he had taken O/D previously
• Ambulance to A & E• After a little wait becomes aggressive and denies that he has
been in car crash but remembers O/D• Had to be taken to scrap yard to see written off car before
convinced
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Diazepam overdose
Partial Recovery, Sets off in car
Collision with tree
A& E department Aggression, Anterograde amnesia
Anterograde amnesia
4 hours 5 mins 2 hours
Dia
zep
amMemory of overdose & suicide intent consolidated when Valium concentration low
Short term
memory
Memory of RTA not retained long-term
Memory of O/D & intent in long-term memory
Anterograde amnesia
Can still access the memory
Diazepam inhibits consolidation of
short-term memory
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Anterograde amnesia• Short term memory active at time but NO
LONG TERM MEMORY retained• Resulting absence of memory trace in long-term
historical record• May lead to CONFABULATION• Information consolidated from trusted internal /
external sources:– e.g. first account of friends or police, rationalisation
using existing prejudices, dreams and hallucinations.
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Rape?Copyright 2012 N.J.Birch
Pharmacological issues in rape cases
Did it happen?
Did she consent?
Was she able to consent?
Could he reasonably believe
that she did consent?
sleepconsciousness
memory dreams
previous behaviour
Prejudices & previous experiences
External sources of
information
Drugs &
alcohol
confabulation
Anterograde amnesia
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• ALCOHOL• Anaesthetics:
– Ketamine, gamma hydroxybutyrate
• Benzodiazepines: – Diazepam, temazepam, flunitrazepam
• Antidepressants– Amitriptyline, Dothiepin, Trimipramine, Trazodone
• Antipsychotics– Chlorpromazine, Thioridazine
• Antihistamines– Diphenhydramine, Brompheniramine, Chlorpheniramine
Drug Facilitated Sexual Assault (DFSA) _ DATE RAPE
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Aggression• Paradoxical, disinhibitory effects of
benzodiazepines
• Similar effects seen with alcohol
• Combination of benzodiazepines and alcohol exceptionally dangerous
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Paradoxical effects of Benzodiazepines
• Identified in British National Formulary and other prescribing guides
• Potential not usually recognised by General Practitioners or General Psychiatrists
• Violence often very extreme and apparently entirely unprovoked
• Particularly exacerbated by presence of alcohol
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alcoholbenzo+alc
benzo
0
10
20
30
40
50
60
70
80
violent
non-violent
sex & rape
% of each class of crime involving alco-hol and benzo-diazepines alone and in combination
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• If both benzodiazepines and alcohol are present you should assume that aggression and inexplicable violence may be more pronounced than might be expected following a relatively low level of provocation
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SleepMarry, sir, nose-painting, sleep, and urine.
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Hypnogram of a typical night’s sleep
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ParasomniasWhat you perceive is not necessarily a true
record of what is happening
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Confusional Arousal
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Murder & Manslaughter
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Post mortem redistribution of drugs
• Post mortem drug analyses should always be interpreted with caution.
• Major redistribution of drugs may occur• Blood in cadaver is not the same as living
blood• Believed to have been source of
miscarriages of justice• Main value is in establishing presence or
absence of drugs and whether large or small quantity present.
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Urine & Blood alcohol in samples taken at post mortem
Subject to other observations: • If (corrected) urine alcohol is higher than blood alcohol:
DEATH occurred after peak of blood alcohol (ELIMINATION PHASE)
• If blood alcohol is higher than (corrected) urine alcohol:
DEATH occurred in ABSORPTIVE PHASE (i.e. within 30 -90 minutes of last alcohol)
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Lawyers, including Judges, are not usually scientists though some are!
It is usually important to simplify your evidence without losing the fundamental truth
Similarly, juries may or may not have scientists or medical people in the group and it is a good tactic to find some analogy to explain your evidence or to use something as an example which is likely to be common knowledge.
Do not underestimate the ability of barristers to find any fundamental flaw in your evidence whether or not it is really significant in determining the truth or not. Once an error has been exposed it is likely to be highlighted repeatedly as a means of undermining everything else.
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• Science becomes dangerous only when it imagines that it has reached its goal
George Bernard Shaw• It is the business of science to be wrong
Robert Oppenheimer
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