All Flashcards
(185 cards)
1
Q
What happened in 1500BC?
A
Eber Papyrus recorded Eygptian use of hellebore, hemlock and opium
2
Q
What was the first use of poison?
A
San people of Kalahari,
Amazonian indians
3
Q
When was the first incidence of mass poisoning?
A
Athens/Sicyon poisoning Kirrha’s water supply with hellebore
4
Q
How did Socrates commit suicide?
A
Hemlock drink in 400BC
5
Q
What did Mithridates do?
A
Searched for theriac/universal antidote.
Found Mithridatum in 100BC
6
Q
When was the Lex Cornelia written?
A
32BC by Roman dictator Sula
7
Q
What are the oldest published books?
A
Nicander of Colophon published in 130AD
8
Q
When was arsenic trioxide discovered?
A
500AD Dark Ages
9
Q
What happened in the “Golden Age”?
A
Liber de Venesis published
Borgia and Medici families poisoned for wealth
Toffand of Naples, Catherine Deshayes Monvoisin professionals
Paracellus heralded the “the central dogma”
10
Q
When was the Renaissance?
A
14th-17th centuries
11
Q
What happened in the 17th-18th Century?
A
Ramazzini studied worker health/occupational
Fontana studied organ targetting of snake venoms
Percival Potts studied scrotal cancer in chimney sweeps as founder of industrial toxicology
12
Q
Who founded modern toxicology?
A
Orfila
13
Q
What happened in the 1800s-1900s?
A
Orfila wrote the Treatise of poisons
Thackrach studied industrial hygeine
Quinone isolated from Cinchona bark
Morphine isolated from opium
Reinsch and Marsh develop arsenic tests
Megendie, Bernard and Langley found pharmacology and physiology
Forensics, metabolism and animal testing developed
14
Q
When are the first cancers studied?
A
Yamagiwa and Ichikawa give rabbits cancers
benzopyrene discovered as first carcinogen
15
Q
What happened in the 1940s?
A
Schrader developed organophosphate pesticides, sarin and tabun nerve agents
Sir Rudolph Peters developed BAL to chelate heavy metals
Warkany studied teratology
Gregg linked rubella virus to birth defects
16
Q
What were the laws produced in 1950s?
A
Clean Air Act 1956
Delany clause 1958 stops food additives
17
Q
What were the disasters of the 1950s?
A
DDT insecticides
Minimata bay mercury poisoning
Thaidomide
18
Q
What is toxicology?
A
The study of the harmful effects of chemical/physical agents on living organisms, the mechanisms and conditions they occur in
19
Q
What is the natural chemicals?
A
Toxins
20
Q
Why are log(dose) -response S shaped?
A
To reduce clumping of data at low doses
Varying sensitivity of organisms
21
Q
What is 50% response known as?
A
Td50
22
Q
How are potencies compared?
A
Td50
23
Q
What is the threshold?
A
no detectable biological response
24
Q
What is the RfD?
A
NOAEL for most sensitive organism/safety factor of 100
25
What is the RfD safety factor composed of?
humans 10x more sensitive
| 10x slower clearance
26
What do steep dose-response curves suggest?
One molecular target that is crucial to life
27
What is response measured as?
All-or-nothing/quantal
28
What type of response do organophosphate nerve agents have?
Irreversible inhibition of Achesterase
29
What is hormesis?
Phenomenon where small doses of drug cause protective effects
30
What are examples of hormesis?
Biochanin A mitogen
Bromodeoslyuridine foetus death
Vitamin D
31
What are the aspects of exposure?
Route, Intensity, frequency, duration
32
What are the routes of entry?
Lipophilic transcellular absorption from lungs/GI/skin
Intravenous/intramuscular
Site of contact
33
How is bioavailability determined?
```
Rate and extent of delivery
Biological properties of organism
Physio-chemical properties of drug
metabolism
excretion
bioaccumulation in non-target
```
34
How are drugs delivered to tissues?
Paracellular diffusion from cardiovascular system
35
What rule determines bioavailability?
Fick's Law
36
What are the targets of drugs?
Cellular (no need to enter cells)
Sub-cellular (active transport/diffusion)
Molecular
37
Do drugs target all cells equally?
No
| Paraquat selective for lung epithelium
38
Does CO bind haemoglobin reversibly?
Yes! Just much higher affinity
39
What are the consequences of toxicant action?
Transient/sub-lethal
apoptosis in excess ATP
Necrosis
Long term abnormalities
40
What are the drugs that target Achesterase?
Sarin irreversibly
| Endrophonium reversible
41
What is toxicity?
f(chemical properties) x f(biological properties) x f(exposure)
42
What is risk equation?
exposure x hazard
43
What is the risk definition?
Probability harm will occur under defined conditions
44
What is hazard?
Qualitative potential of a drug to cause harm
45
What is a risk assessment?
use of scientific data and a clear set of assumptions to define the likely health risks of individuals/populations to hazardous materials and situations
46
Why is risk assessment difficult to determine?
Little information
| Lots of variables
47
What are the levels of experimental data that are used in a risk assessment?
In silico
In vitro
Animal
Clinical/epidemiological
48
What are the aspects of a risk assessment?
```
Hazard identification
Exposure-response characterisation
Assessment of exposure
Risk-benefit analysis
Risk managment
```
49
How is cytotoxicity measured?
Ames test for mutagenesis
50
Why are animal trials used in risk assessment?
To determine safe starting doses for clinical trials
51
What is the Threshold of Toxicological concern?
Strategy used in risk minimisation by in silico predictions to determine whether there is a need for further studies or if RfD is lower than threshold
52
Why must exposure be considered in risk assessment?
Size of exposed population
Dose, duration, frequency
Population characteristics (race, age)
53
When is a compound deemed safe?
All risks are acceptable
Balance of politics, economics, ethics, science and law
NEVER 100% SAFE
54
What is REACH?
Registration, Evaluation, Authorisation of CHemicals
| EU July 2007
55
What is the aim of REACH?
To protect human health and environment, reduce animal testing and transparent risk assessment
56
When must compounds be registered under REACH?
1 tonne
57
What are the most common causes of poisoning?
Accidental
58
What are the criteria for poisoning treatment?
Supportive ABCDE
| Specific treatments with antidotes
59
What are the 2 types of respiratory failure?
Type 1: fluid on the lungs (bronchorrea)
| Type 2: CNS depression, shallow breathing (bradycardia)
60
How is breathing maintained?
Recovery position, endotrachael tubes
61
What are the effects of TCA overdose?
Blocks Na channels
| Hypotension
62
How can TCA overdose be treated?
NaCO3 and NA vasopressor
63
How is MAOI OD treated?
hypertension reduced by nitroprusside vasodilator
64
What are the symptoms of circulatory shock?
```
tachycardia
venous dilation
cold, pale skin
low pO2
cardiac dysrythmias
lactate acidosis
```
65
What are the causes of circulatory shock?
haemorrhaging
poor cardiac output
loss of haemoglobin function
66
How is circulatory shock treated?
Dextran (high Mw) to stop tissue odoema
NaCO3 corrects lactate acidosis
Glucagon, dopamine, dobutamine for cardiac ouput
67
What the the disabilities produced by poisoning?
```
seizures
hypoglycemia
hyperthermia
agitation
delerium
```
68
How can exposure be reduced?
Dermal: washing
Inhalation: source removal
Excretion: diuresis, haemodialysis
GI: charcoal, gastric lavage, Ipec emesis, PEG bowel irrigation
69
What are the 2 types of diuresis and examples?
Acid NH4Cl for amphetamines
| Alkaline NaHCO3 for barbiturates and salicyclates
70
What does activated charcoal treat?
Exposure to organics
71
How are seizures treated?
Anticonvulsant benzodiazepenes
72
How is hypoglycemia treated?
dextrose
73
How is hyperthermia treated?
Dantrolone to reduce muscle overactivation
74
How can drugs be specifically treated?
Pharmacological reversal
Chelation
Regeneration of target
Protection of target
75
When can haemodialysis be used?
For small volumes of distribution
76
What are the drugs used for pharmacological reversal?
```
Atropine (Achesterase inhibitors)
Naloxone (Opiate)
Flumazenil (Benzodiazepenes)
Vitamin K (warfarin)
Folate, Leucovorin (methotrexate)
Hyperbaric O2 (CO)
Ethanol, fomepizole (inhibit ADH to prevent metabolism of methanol/ethylene glycol)
```
77
What are the chelating agents?
```
Dimercaptoethanol, DMSA (heavy metals)
EDTA, DMSA (Lead)
Deferoxamine (iron)
Penicillamine (Copper)
Thiosulphate (cyanide)
Digoxin-specific antibodies
Snake antivenoms
```
78
How can targets be regenerated?
Pralidoxime displaces organophosphates from Achesterase
| Methylene blue regenerates methaemoglobin
79
How can drug targets be protected?
4-DMAP/ sodium nitrite prescursor for methaemoglobin dummy for cyanide
Methionine and N-acetyl cysteine for glutathione synthesis and detoxification of N-acetyl-p-benzoquioneimine product of paracetamol metabolism
80
What are the toxidromes?
```
Cholinergic
Anticholinergic
Benzodiazepenes
Opiate
Sympathiometric
```
81
What are the symptoms of a cholinergic toxidrome?
```
Diarrohea
Urination
Miosis
Bronchorrea
Bronchospasm
Emesis
Lacrimination
Salivation
Seizures
Bradycardia
Convulsions
```
82
What causes a cholinergic toxidrome?
Overactivation of parasympathetic NS
83
What are the symptoms of an anticholinergic toxidrome?
```
Dry mouth
Dilated pupils
Urinary retention
Consitpation
Blurred vision (cyclopegia)
Red skin
Tachycardia
Confusion
```
84
What causes the anticholinergic toxidrome?
Blocking of parasympathetic NS
| e.g. nerve agents acting on Achesterase
85
What are the symptoms of a sympathiometric toxidrome?
```
Dilated pupils
Diaphoresis
Agitation
Tachycardia
Dysrhythmias
Hypertension
Hyperpyrexia
```
86
What causes a sympathiometric toxidrome?
Sympathetic NS
| amphetamines
87
What are the symptoms of an opiate toxidrome?
```
GI inhibition
Hypothermia
Hypoglycemia
Hypotension
Dysrhythmias
Bradycardia
Miosis
Sedation/lethargy
```
88
What are the symptoms of a benzodiazepenes toxidrome?
Drowsy
Ataxia
Coma
89
How was opium produced by Eygptians?
Dried latex of Papaver somniferum contains 10-100mg
20% morphine
2.5% codeine
Diacetylated to produce heroin
90
When were opiates isolated for use?
seturner isolated morphine in 1807
codeine in 1830s
Heroin in 1874
Heroin rediscovered by Hoffman in 1897
91
When were opiates first regulated?
1914 Harrison Act in USA
| 1960s UK
92
What are the endogenous equivalents of opiates?
endorphins
enkephalins
dynorphins
93
What are the 3 types of opiod receptors?
µ
δ
κ
94
What symptoms do opiates cause?
CNS depression, analgesia, sedation, pain relief, feelings of normality, formication
95
How is opiate addiction treated?
Withdrawal with Methadone (oral), buprenorphine, naltrexone
96
When was the drug misuse act published?
1971
97
What are Nutt's criteria?
```
Specific/related harm & mortality
mental impairment
dependance
loss of tangiables
crime
economics
families
injury
community
environmental
international
```
98
Is tolerance is developed with opiates?
Yes, high tolerance
99
What effects do amphetamines have?
```
Sympathiometric toxidrome
Appetite supression
Psychostimulant by mimicking monoamines
combat fatigue
long term tolerance, addiction
misuse causes paranoid schizophrenia
```
100
What are the uses of amphetamines?
Nasal decongestants (ephedrine, Benzedrine)
ADHD (methylphenidate)
Anti-obesity (Fenfluramine, phentermine, phen-fen)
Narcolepsy (modafinil, dexamphetamine)
101
What are plant-derived legal highs?
Cathione like structures derived from khat
| e.g. Mephedrone
102
What are the symptoms of ecstasy use?
Amphetamine-like effects
Hyponatremia
Hepatotoxicity
Serotonin syndrome
103
What is the structure of most microbial toxins?
Large Mw enzymes
104
What lifestyle do clostridia spp. bacteria have?
Anaerobic spore forming
105
What is the structure of botulin?
150kDa
N-light protease- heavy endocytosis - heavy targetting
7 forms but not C/D in humans
106
What symptoms does botulism poisoning have?
Descending paralysis
| Death by respiratory failure
107
How can botulism be treated?
Antibacterials,
antitoxin
charcoal to adsorb
108
How does botulism act?
H chain targets polysailgangliosides on nerve cells
endocytosis
Acid endosome cleaves S-S to release Zn protease light chain
H chain pores in vesicle
Targets SNAREs to inhibit neurotransmitter release
109
What are mycotoxins?
Diverse range of non-peptide toxins released from filamentous fingi
110
What is ergotism?
Ergot alkaloids produced by claviceps purpurea in cereal crops
Causes hallucinations, nausea, vasoconstriction, burning, hypertension, thromboembolis, gangrene (St Antony's fire)
111
What is botulin toxin used for?
Treatment of dystonias, strabismus, nystagmus
112
What are the medical uses of ergots?
vasoconstriction, parturition and uterus contraction
| ergotamine and ergometrine
113
What are the amatoxins?
heat stable bicyclic octapeptides produced by mushrooms and absorbed from GI tract
Target RNA pol2
Hepatotoxic and nephrotoxic
114
What effects does aflatoxin have?
Acute doses: oxidised to bind guanine causing hepatotoxicity
| Chronic low exposure: cancer amplified by Hepatitus
115
Can Ricin toxicity be treated?
Not directly
116
What mechanism does ricin have?
B chain targets Galactose and NAG
Endocytosis
5% reterotranslocation to ER
A chain release
Blocks 28S rRNA/60S ribosome by adenylation of A4324
No binding of elongation factors for protein synthesis
117
What is ricin?
A type 2 Ribosomal Inhibitory Protein
118
What are the main animal toxins?
Snake venoms- mostly elapidae family
119
How can envenomation be treated?
```
Immobilisation,
antivenoms
pain relief
wound care
fluid replacement
```
120
What do snake venoms contain?
Tissue digestion, myotoxins, cardiotoxins, haemolysins, anticoagulants
β neurotoxins for degradation or upregulation of neurotransmission
121
What are the 4 snake families?
Viperidae (crotalids with Achesterase)
Colubridae
Atractraspidae (sarafotoxins cause vasoconstriction)
Elapidae (α neurotoxin for Achesterase)
122
What is environmental toxicology?
Impact of chemicals on communities of organisms and their habitats
123
What are the problems with chemical disposal by dispersal?
Persistance
Bioconcentration in organisms (intake>excretion)
Biomagnification through food chain
124
Where is environmental mercury found?
Ion in air
element in soil
ion in water
biomethylation to methyl-Hg in microorganisms
125
Which forms of mercury are neurotoxic?
elemental and organic are lipophilic so accumulate in CNS
Ionisation traps
Irreversible loss of motor function
126
What toxicity does inorganic mercury have?
Accumulation blocks tubules in kidneys
127
Where is organic Hg found?
pesticides
128
Why is mercury toxic?
Biomagnifies as lipophilic
129
How does inorganic mercury block anti-toxic buffering?
Binds to thiols in metallothioneins
130
What aspects of cell function does Hg target to cause toxicity?
Binds to thiols in proteins
| Inhibits neuronal transmission, Ca homeostasis, glycolysis, TCA, ETC
131
What was the Minimata Bay disaster?
Japan, 1954
| Pesticide plant released Organic-Hg into water, biomagnification into fish and humans
132
What form is Inorganic mercury found?
HgCl
133
What industries use elemental mercury?
Dental,
Gold/silver extraction,
Chlor-alkali
biocides
134
What is industrial toxicology?
Risks associated with manufacture, transport, disposal and recycling of chemicals
135
Who studied industrial toxicology in the 18-19th century?
Ramazzini,
Percival Pott
George Baker
Charles Thackrah
136
When were the factories acts brought in?
1830s-1890s
137
What did the factories acts do?
Improve worker conditions
138
When were Health and safety legislations first developed?
1895-1974
139
What is the purpose of Health and Safety laws?
To prevent exploitation of workers, protect their rights
140
What is the structure of Asbestos?
Crystalline SiO2-Mg/FeO-SiO2
141
What are the 3 types of asbestos?
Chrysolite serpentine fibres
Crocidolite amphibole fibres
Amosite inflexible amphibole fibres
142
What are the useful properties of asbestos?
Inert to heat and chemicals
143
Which type of asbestos is most common?
Chrysolite
144
When were the dangers of asbestos first observed?
Lucy Deane 1890s
| Cancer 1950s
145
What is the threshold for asbestos?
There isn't one- EU ban from 2006
146
What biological damage does asbestos cause?
Inhaled as dust sized particles that are not biodegraded
Inflammation
Epithelial cell damage causes fibrosis by production of inflexible Type 1 collagen
Fe acts to induce free radical-DNA damage and mesothelialoma
147
Which other compounds have similar affects as asbestos?
Some minerals and plant fibres
148
When was radiation first discovered?
1895 Roentgen discovered Xrays
1896 Bequerel discovered Uranium salts
1898 Curies discovered Radium
149
What are the Laws of Bergonie and Tribondeau?
young, undifferentiated, rapidly dividing and metabolically active cells are most susceptible to Xrays
150
What was the first observation of radiation causes teratogenesis?
1920s Xrays
151
What was radium used in watch dials?
Late 1920s
152
What did the radium watch painters suffer?
Osteoblast degradation of bone stem cells in jaw as Radium226 accumulates in bone and produces α particles
153
What are the main incidents of radiation disasters?
Windscale 1957
3 Mile Island 1979
Chernobyl 1986
Fukushima 2011
154
What main cancer does radiation disasters cause??
I131 causes thyroid cancers in children
155
What are the 2 types of ionising radiation?
EM
| subatomic particles
156
What are the types of radiation-causing sub-atomic particles?
α 2H+ and 2 neutrons
| β e- and positron
157
How does ionising radiation cause damage?
Interacts directly with molecules or through generation of ROS to remove electrons
Cell death or compromised DNA integrity
158
What are the sources of radiation?
80% natural: atmosphere or terrestrial
| Medical, internal, nuclear
159
How is radon gas produced?
Uranium 238 - radium 226 - radon 222 in granite
| gas inhaled and produces α particles
160
What is the limit of occupational exposure?
20mSv
161
What is the range of normal exposure?
2.7mSv
162
What is the measurement of radiation?
Gy: 1J/kg tissue
Sv: 1Gy x Wt due to varying effects in each tissue of each radiation. Can be added together
163
What is the Linear Energy Transfer of radiation?
The probability of collisions based on size and speed of particles
Used as weighting to convert Gy to Sv
164
What are the weightings of different types of radiation?
Xrays/γ rays/ β particles = 1
α particles = 20
protons = 2
neutrons = 5-20
165
What are the 2 types of radiation damage?
Deterministic: 5.5mSv increase in frequency and severity with dose
Stochastic: No increase in severity with dose. No threshold
166
How can ROS damage be reduced?
Superoxide dismutase with CuZn in cytoplasm or Mn in mitochondria
Catalase in peroxisomes
glutathione peroxidases
Anti-oxidants Vitamin C, GSH, Vitamin E,
167
What are the effects of acute radiation doses?
100Gy causes CNS damage instantly
10-50Gy causes GI damage and death over weeks
2-5Gy causes radiation sickness (haematopoetic cell death)
168
What is the time sequence of radiation sickness?
Prodromal
Latent
Overt illness
Recovery or Death
169
What are the symptoms of radiation sickness?
Prodromal lethary, anorexia, vomiting, diarrohea, fever due to acute cell death.
Overt illness caused by significant cell death of RBCs and WBCs
170
How many cancers develop each year?
14million diagnoses
| 8million deaths
171
What are the classifications of carcinogens?
```
Alkylating agents
aromatic amines
azo dyes
nitroso compounds
Polycyclic aromatic hydrocarbons
```
172
How are PAHs produced?
combustion of hydrocarbons
173
How do PAHs enter human body?
Through diet (bioaccumulate), inhalation and skin
174
What are the structure of PAHs?
planar with a phenanthrene nucleus to intercalate to DNA using bay regions and high electron density k region
175
What are the theories behind PAH carcinogenity?
Pullman's electronic theory
| Miller and Brooks/Lawley showed covalent binding to proteins and DNA
176
How are PAHs activated?
K-region epoxides produced by Cytochrome P450s IA1 IA2 IB1
Conversion to 7,8-thiol as prosimate carcinogen
Trans formation 9,10-epoxidation
177
How does the ultimate carcinogen bind to DNA?
9,10 epoxide forms carbonium ion which opens ring. carbocation binds to N or NH2 of guanine
178
How much of the K-region epoxide is detoxified?
95% by hydrolases producing trans-diol which spontaneously isomerises to phenols for glucoronidation or glutathione-conjugation
179
How does PAH act on DNA indirectly?
```
Binds to Aryl-hydrocarbon type 1 nuclear receptor
Increases Cytchrome P450 synthesis
Phototoxicity
CVD
Teratogenesis
```
180
How frequently do covalent events cause mutagenesis in a cell?
10^4 to 10^6 per cell per day
181
How does UV light induce DNA damage?
Formation of T/C photodimers with cyclobutane
182
Which genes are mutated in cancer?
tumour supressor or oncogenes
183
How is DNA damage repaired?
Nucleotide excision repair
| Trans-lesion synthesis
184
How does nucelotide excision repair occur?
XP proteins detect global or transcription-coupled distortion to create scaffold for helicase to unwind gene.
Endonuclease removes 27-29bp fragment which is filled by high fidelity polymerase
185
What does Trans-lesion synthesis do?
Repairs DNA based with low fidelity Polymerase η to introduce T mutations
