Chapters 1 & 2 - Intro Toxicology & The Action of Poisons Flashcards
1
Q
Definition of poison
A
Any solid, liquid or gas that, through either oral or topical routes, can interfere with life processes of cells of the organism.
This interference occurs by the inherent qualities of the poison without mechanical action and irrespective of temperature.
2
Q
Another term for poison
A
Toxicant
3
Q
What does the term ‘toxic’ describes?
A
The effects of a poison on living systems.
4
Q
What does the term ‘toxicosis’ describes?
A
The disease state that results from exposure to a poison (often used interchangeably with poisoning and intoxication)
5
Q
Definition of toxicity and how it is usually expressed.
A
The amount of a poison that, under a specific set of conditions, causes toxic effects or results in detrimental biologic changes.
It is usually expressed as milligrams (mg) of toxicant per kilogram (kg) or body weight.
6
Q
Definition of dosage (as in toxicity)
A
Amount of toxicant per unit of animal weight
7
Q
Definition of dose (as in toxicity)
A
Total amount of toxicant received per animal
8
Q
What is threshold dose of a toxic or adverse reaction?
A
The threshold above which detrimental effects can be measured.
9
Q
What is the lethal concentration (LC) and how it is expressed?
A
The lowest concentration of compound in feed or water that causes death.
Expressed as milligrams of compound per kilogram of feed and water.
10
Q
What is the acute lethal toxicity (expressed as LC50)?
A
Concentration of compound in feed or water that will kill 50% of animals exposed.
11
Q
Terms used to define toxicity (6)?
A
- Highest nontoxic dose (HNTD)
- Toxic dose-low (TDL)
- Toxic dose-high (TDH)
- Lethal dose (LD)
- Median lethal dose (MLD)
- Effective Dose 50 (ED50)
12
Q
What is the highest nontoxic dose (HNTD)?
A
The largest dose that does not result in clinical or pathologic drug-induced alterations.
13
Q
What is the toxic dose-low (TDL)?
A
The lowest dose that will produce alterations; administration of twice this dose is not lethal.
14
Q
What is the toxic dose-high (TDH)?
A
The dose that will produce drug-induced alterations and administration of twice this dose is lethal.
15
Q
What is the lethal dose (LD)?
A
The lowest dose that causes death in animal during the period of observation. Various percentages can be attached to the LD value to indicate doses required to kill 1% (LD1), 50% (LD50) or 100% (LD100).
16
Q
What is the median lethal dose (MLD)?
A
Equivalent to LD50: The lowest dose that causes death in 50% of animals.
17
Q
What is the Effective Dose 50 (ED50)?
A
The dosage of a drug or therapeutic agent that produces the desired effect in half of a population.
18
Q
Expression of safety for drugs (2) ?
A
Expressions of safety for drugs are given by comparisons of LD50 to the ED50:
- Therapeutic index (TI)
- Standard Safety Margin (SSM)
19
Q
What is the therapeutic index (TI)?
A
It is an expression of safety for drugs and is defined by the ratio of the LD50 to the ED50:
TI = LD50 / ED50
20
Q
What is the standard safety margin (SSM)?
A
It is an expression of safety for drugs and is defined by the ratio of the LD1 to the ED99 (more conservative than the TI).
SSM = LD1 / ED99
21
Q
Which of the expressions of safety for drugs is more conservative: Therapeutic Index (TI) or Standard Safety Margin (SSM)?
A
Standard Safety Margin (SSM) is more conservative than the Therapeutic Index (TI)
22
Q
Ranking to classify the relative toxicities of compounds (6)
A
Classification Toxicity
- Extremely toxic: < 1 mg/kg
- Highly toxic: 1-50 mg/kg
- Moderately toxic: 50-500 mg/kg
- Slightly toxic: 0.5-5 g/kg
- Practically nontoxic: 5-15 g/kg
- Relatively harmless: > 15 g/kg
23
Q
What is acute toxicity?
A
Term that describes the effects of a single dose or multiple doses during a 24-hour period
24
Q
What is acute LD50?
A
Patterned toxicity study designed to compare the most reproducible part of the dose-response curve for different chemicals under closely defined conditions of exposure.
25
Definition of LD50
Dosage that is lethal to 50% of animals exposed to a specific toxicant under defined conditions, including species, route of exposure, and duration of exposure.
26
Characteristics of LD50
1. The LD50 value **does not pertain to the severity of clinical signs** observed or the characteristic changes caused by the toxicant.
2. The LD50 value bears **no relationship to adverse effects** such as chronic toxicity, reproductive hazard or cancer risk.
3. The LD50 is **based on a 'quantal**' (all-or-none) **response of a population** of animals and is the **cumulative response to increasing dosage**. It is a _sigmoid_ graph when plotted on _linear coordinates_. Response is nearly linear at the LD50 and is most rapidly and reliably affected by dosage in this area.
4. The LD50 can be transformed to a _straight line on semilogarithmic_ or probit paper.
5. The **slope** of the dose-response curve **defines the margin between minimal and maximal toxic response.**
27
What does the slope of the (log)dose-response curve in LD 50 represents?
Defines the margin between minimal and maximal toxic response.
28
What is subacute toxicity?
It refers to repeated exposure and effects observed for 30 days or less.
29
What is subchronic toxicity?
Is the study of **exposure and effects for 1 to 3 months**.
Studies of 3 months are considered adequate to express all forms of toxicosis except carcinogenic effects and multigenerational (reproductive) effects.
30
What is chronic toxicity?
It is produced by prolonged exposure for 3 months or longer.
31
Compounds that are rapidly metabolized have about the same / greater / smaller chronic LD50 than single-dose LD50?
Have about the **same** chronic LD50 as the single-dose LD50, because the rapidly excreted compound has little opportunity to accumulate in the body.
32
What is the **chronicity factor**?
It is the ratio of the acute LD50 to chronic (90-day) LD50.
**Chronicity Factor = Acute LD50 / 90-day LD50**
Compounds with cumulative effects have a high chronicity factor.
33
Threshold Chronicity factor that indicates a relatively cumulative toxicant?
Chronicity factor **greater than 2** indicates a relatively cumulative toxicant.
34
Rank these species by Daily Dry Food Intake (% Body Weight):
Cat (adult, young), dog (adult, young), finishing cattle, dairy cow (gestating, lactating), ewe (lactating, nonlactating), pig (sow, feeder, finishing), mature horse
* Cat (kitten) = small puppy -- 8% body weight
* Feeder pig (15kg) -- 7%
* Dog (adolescent) -- 6%
* Finishing pig (70kg) -- 4.5%
* Ewe (lactating) = Lamb (30kg) = Cat (adult) -- 4%
* Sow (lactating) -- 3-4%
* Dog (adult) -- 3%
* Dairy cow (lactating) = Horse = Ewe (nonlactating) -- 2-3%
* Dairy cow (gestating) -- 1.8%
* Finishing cattle (600 kg) -- 1.5%
35
How many ppb are in 1 ppm?
1 ppm = 1,000 ppb
36
1 ppm = X ppb = X ppt?
1 ppm = 103 ppb = 106 ppt
37
How many grams in:
* Megagram
* kilogram
* miligram
* microgram
* nanogram
* picogram
* femtogram
* Megagram (M) = 106 gram
* kilogram (kg) = 103 gram
* miligram (mg) = 10-3 gram
* microgram (µg) = 10-6 gram
* nanogram (ng) = 10-9 gram
* picogram (pg) = 10-12 gram
* femtogram (fg) = 10-15 gram
38
How many mg/kg are in 1 ppm?
1 ppm = 1 mg/kg = 1 µg/g
39
How many acres and square meters are in 1 hectare?
1 hectare = 2,471 acres = 10,000 m2
40
How many inches are in 1 meter (m)?
1 m = 39.37 inches
41
How many square feet are in 1 acre?
1 acre = 43,560 square feet
42
How many grams are in 1 ounce (oz)?
1 g = 28.35 grams
43
How many grains are in 1 gram (g) ?
1 g = 15.43 grains
44
How many grams are in 1 pound (lb)?
1 lb = 453.6 grams
45
How many pounds are in 1 kg (kg)?
1 kg = 2.205 lb
46
How many kg are in 1 short ton?
1 short ton = 907.2 kg
47
How many ml are in 1 ounce (oz)?
1 oz = 29.6 ml
48
How many liters are in 1 quart (qt)?
1 qt = 0.946 l
49
How many liters are in 1 gallon (gal)?
1 gal = 3.785 l
50
How many pounds (lb) weight 1 gallon (gal) of water?
1 gal (water) = 8.35 lb = 3.78 kg
51
How many gallons and liters are in 1 cubic foot (cu ft)?
1 cu ft = 7.48 gal = 28.32 l
52
How many gallons and liters are in 1 bushel (bu)?
1 bu = 9.31 gal = 35.2 l
53
How many quarts and gallons are in 1 liter (L)?
1 L = 1.057 quarts = 0.264 gal
54
How many milliliters are in 1 teaspoon (tsp)?
1 tsp = 5 ml
55
How many milliliters are in 1 tablespoon (T)?
1 T = 15 ml
56
How many gallons are in 1 acre-foot?
1 acre-foot = 3.259 x 105 gal
57
How many cubic feet are in 1 cubic meter (m3)?
1 m3 = 35.3 cubic feet
58
How many ppb are in 1 g/ton ?
(short ton)
1 g/ton = 1.1 mg/kg = 1.1 ppb
59
Definition of toxicokinetics
It is the movement and disposition of toxicants in the organism
60
Response to chemicals is affected by toxicokinetic influence on:
## Footnote
a. rate and amount of absorption
b. distribution of chemical within the body
c. biotransformation
d. rate of excretion
e. all
e. All
61
Most transport of toxicants is initially by blood, and one absorbed, distribution depends on several factors:
* **Blood flow** to the organs / regions
* Different **membranes are traversed** and the nature of those membranes can affect absorption
* Accumulation of chemical in an area may not always be associated with toxicosis.
62
Examples of organs / tissues that can act as inert storage sites without toxic effects:
## Footnote
- chlorinated hydrocarbons
- lead
- arsenic
- chlorinated hydrocarbons: body fat
- lead: bone
- arsenic: hair
63
Mechanisms of chemical transport of toxicants across membranes?
* passive transport or simple diffusion
* active transport
* facilitated diffusion
* endocytosis (phagocitosis)
64
Characteristics of Passive transport or simple diffusion?
1. Is the **most common** means of toxican transport across membranes.
2. **Physical barrier** to molecular size of molecules relative to size of pores or channels.
3. Greater lipid solubilty allows greater distribution through the membrane. Molecules cross the lipid membrane best in teh uncharged form.
65
What is an acid (proton donor or acceptor?)
An acid is a substance that acts as a proton donor
66
What is a base (proton donor or acceptor?)
A base is a substance that accepts protons.
67
What is pK?
It is the negative logarithm of K (-log K) and is equal to the pH at which half of the acid molecules are dissociated and half are undissociated.
68
What is Ka?
Ka is the apparant dissociation constant.
69
When can molecules cross the lipid membrane best (ionized or un-ionized form)?
Molecules cross the lipid membrane best in the uncharged form. Ionization of weak acids or bases retards absortion.
70
For an acid with pKa = 3, could it be readily absorbed in the stomach with a pH = 2?
Yes.
The ionized portion is: 3 - 2 = 1; log10 1 = 10;
Thus, in an acid medium, the ration of un-ionized to ionized chemicals is 10:1, and the chemical could be readily absorbed.
[chemicals with acidic pKa are least ionized in an acidic medium, basic pKa are least ionized in a basic medium]
71
Which of the following is _true_ for facilitated diffusion:
## Footnote
- common transport system for xenobiotics
- compounds move along a concentration gradient
- energy is required
- transport system cannot be saturated
- compounds move along a concentration gradient
- **uncommon** transport system for xenobiotics
- energy is **NOT** required
- transport system **can** be saturated
72
What is the apparent **volume of distribution** (VD)
It defines the fluid volume in which a chemical seems to be dissolved. It is determined by the formula:
VD = weight of chemical distributed in the body /
plasma concentration of chemical at equilibrium
73
What does a VD greater than the total body volume suggests?
That the chemical is accumulated in a tissue depot
74
In what organs does xenobiotic excretion occurs mainly?
Kidneys (urine) and liver (bile);
[also via lungs, intestines, sweat, saliva and milk]
75
Routes of renal excretion of toxics?
Glomerular filtration (only free compounds with molecular weight \< 69,000) or active tubular secretion (proximal tubules).
76
Definition of clearance
Is the amount (volume) of plasma cleared of a specific xenobiotic each minute.
77
Formula to calculate clearance
Clearance = urinary drug concentration (mg/ml) x urine flow rate (ml/min) / plasma drug concentration (mg/ml)
78
What is 'half-life' [rate of elimination]?
Is the term used to define the time needed for one-half of a chemical to be eliminated from the body.
[Initial excretion is rapid but it becomes progressively less with each successive half-life period]
79
Cellular response of chemical toxicants (structural and metabolic mechanisms in the cell) (5)
1. **Altered membrane integrity**: interfere with fluid and electrolyte movement
2. **Cell volume regulation**: as a result of direct membrane damage or from loss of metabolic energy
3. **Abnormal accumulation of lipids and pigments** can occur as a result of metabolic defects.
4. **Protein synthesis** may be altered when nucleic acid control is disturbed and proteins are denatured.
5. **Growth regulation** may be disturbed as a result of DNA damage that either is not properly reparied or that exceeds homestoatic control.
80
Mechanism of how foreign compounds (xenobiotics) are biotransformed to electrophilic intermediates by the microsomal mixed function oxidases (MFOs) (3)
1. MFOs are a family of nonspecific enzymes that act primarily in the endoplasmic reticulum to promote phase I metabolism (oxidation of lipophilic xenobiotics), which prepares the xenobiotics for conjugation and excretion
2. Eletrophilic intermediates bind covalently to macromolecules:
1. e.g. lipids, proteins, DNA may be denatured by the binding
2. also bind to reduced glutathione (GSH), which is protective mechanism in the cell
3. Covalent binding to macromolecules has high correlation with cellular damage and carcinogenesis.
81
Major effects initiated after free radical formation in lipids and protein thiol groups.
1. **Lipid peroxidation** occurs because hydrogen from unsaturated lipid is available to quench the radical
1. the lipid radical reacts with oxygen to form a peroxyl radical
2. autocatalytic reactions continue: lipid molecules reacting with free radicals become free radicals themselves and propagate a chain reaction of damage.
3. Peroxidation damages organelle and membranes, reducing the structural integrity and control of selective absorption and active transport.
4. As membranes are damaged, there is loss of Ca+2 sequestration leading to marked increase in cytosolic calcium.
5. Loss of Ca+2 homeostasis leads to activation of phospholipases, autodigestion of membranes, loss of membrane function, swelling of cells and eventual irreversible cell injury and necrosis.
2. **Naturally occurring proteing thiol groups (e.g. glutathione) in cells may also be depleted.**
82
What defenses against free radicals are built into cells as antioxidants ? (4)
1. Superoxide dismutase
2. Catalase
3. Glutathione peroxidase
4. Vitamin E
83
Mechanism of action of **superoxide dismutase** as a cellular antioxidant
Superoxide dismutase is a copper- and zinc-dependent enzyme that catalyzes the reduction of superoxide anion to hydrogen peroxide.
84
Mechanism of action of **catalase** as a cellular antioxidant
Catalase (which is highly concentrated in peroxisomes of cells) catalyzes the conversion of hydrogen peroxide to water and oxygen.
85
Mechanism of action of **glutathione peroxidase** as a cellular antioxidant
**glutathione peroxidase** is a selenium-dependent enzyme that catalyzes the GSH-mediated conversion of hydroperoxides to water or alcohol.
86
Mechanism of action of **vitamin E** as a cellular antioxidant
87
Specific mechanims of intoxication (11)
1. Chemical injury
2. Necrosis of epithelial cells
3. Inhibition of or competition with enzymes
4. Interference with body metabolism or synthesis
5. Functional effects on the nervous system
6. Lesions of the central nervous system (CNS) or peripheral nervous system
7. Injury to the blood and vascular system
8. Exposure to agents with action similar to normal metabolites or nutrients
9. Immunosupression
10. Developmental defects
11. Carcinogenesis is a delayed effect of DNA damage
88
Specific mechanisms of intoxication: **Chemical injury**
1. Direct chemical injury to tissues alters the membrane-dependant homestoatic control of cell functions.
2. Damage occurs when cell membranes contact strong corrosives (acids), caustics (bases) or compounds that coagulate proteins or damage lipids in the cell membrane.
3. [Examples: acids, bases, phenols, aldehydes, alcohols, petroleum, distillates, some salts of heavy metals.]
89
Specific mechanisms of intoxication: **Necrosis of epithelial cells**
**Necrosis of epithelial cells**: systemic toxins.
1. **Energy deficit** (loss of ATP production) reduces active transport and control of electrolytes and water. Synthesis of proteins reduced.
2. **Ischemia** (reduced blood flow) due to toxicants can result in damage by causing cellular anoxia, which leads to an energy deficit.
90
Types of cells where is necrosis due to systemic toxins is most common (4)
Damage is most common in cells with high metabolic activity and cellular replication, e.g. renal tubules, hapatocytes, bone arrow, intestinal epithelium.
91
Specific mechanisms of intoxication: **Inhibition of or competition with enzymes**
1. Enzymes can be **inactivated or denatured** by direct chemical interaction with toxicants.
1. Alteration of spatial relationships and tertiary or quaternary structure
2. [severity and duration of poisoning can be influenced by the strength of the toxin-enzyme interaction]
2. **Competitive inhibition**: enzyme-inhibitor complex is reversible and the inhibitor is not changed by the reaction.
92
What enzymes within the tricarboxilic cycle (TCA) do oxalic acid (plant toxic) and fluoroacetate (rodenticide) inhibit (competitive inhibition) ?
oxalic acid (plant toxic) inhibit succinic dehydrogenase
fluoroacetate (rodenticide) inhibit aconitase
93
What enzymes do oxalic organophosphate and carbamate insecticides inhibit (competitive inhibition) ?
Cholinesterase.
94
Specific mechanisms of intoxication: **Interference with body metabolism or synthesis**
**Interference with body metabolism or synthesis** causes loss of products used for energy, structure components or growth.
1. **Uncoupling of oxidative phosphorylation**. The release of energy in the electron transport chain becomes uncoupled from the formation of energy by the phosphorylation of ADP to ATP.
1. Uncoupling agents increase oxygen utilization, but energy is dissipated as heat rahter than stored in high-energy phosphate bonds. Thus, body temperture rises.
2. **Inhibition of oxidative phosphorylation** results in limited oxygen uptake with lower ATP formation. The effects of **fatigue and weakness** are similar to oxidative uncouplers, but there is no fever.
3. **Inhibition of nucleic acid and protein synthesis** can be initiated by toxicants that injure DNA or that bind to ribosomes during transcription or translation. (a delay - latent period- is common)
4. **Interference with fat mobilization** occurs when toxins affect the rough endoplasmic reticulum. Results of this mechanism include:
1. r_educed synthesis of lipid acceptor_ protein
2. r_educed incorporation_ of phospholipids and triglycerides _into transport lipoproteins,_ leading to accumulation of fat in the cell.
95
Two examples of oxidative uncouplers
**Dinitrophenol** and **Chlorophenol** fungicides
96
Three substances with this mechanism of intoxication: 'inhibition of nucleic acid and protein synthesis'
Aflatoxin
Organomercurials
Amantine (i.e. *Amanita phaloides* mushroom toxin)
97
Specific mechanisms of intoxication: **Functional effects on the nervous system** (3)
1. **Normal reflexes may be enhanced** by blocking the inhibitory neurotransmitters of the reflex arc. This results in uncontrolled reflexes ending as tetanic seizures.
2. **Toxicants can change the permeability of nerve cell membranes to ions**. Sodium and potassium currents are altered by poisons such as DDT and pyrethrins, changing the threshold for action potentials at the membrane.
3. **Inhibition of enzymes** essential to balanced synaptic function changes the characteristics of synaptic trasnmission.
98
Mechanim of intoxication of strychnine ?
strychnine **blocks glycine in the spinal reflex system,** it is an example of normal reflexes being enhanced by toxicants.
99
Mechanism of intoxication of organophosphate insecticides
Acetylcholinesterase inhibition
100
Specific mechanisms of intoxication: **Lesions of the central nervous system (CNS) or peripheral nervous system** (3)
Lesions of the central nervous system (CNS) or peripheral nervous system affect neuronal function or axonal transmission. Chronic and can be permanent.
1. **Neuronal necrosis** either:
1. **Direct** toxic effect: organomercurials impair neuronal protein synthesis.
2. **Indirect** toxic effect: anoxia induced by CO or cyanide causes secondary neuronal damage
2. **Demyelination** affects nerve transmission by altering the spread of the action potential along the axon
3. **Impaired transport within the axon** results in slow, progressive impairment of axonal transmission.
101
Specific mechanisms of intoxication: **Injury to the blood and vascular system** (3)
1. **Hypoplasia or aplasia of cellular components of blood** may result from direct toxic effects on bone marrow precursor cells.
2. **Hemoglobin** may be affected by:
1. **Synthesis may be reduced**, with resultant anemia and/or high amounts of hemoglobin precursors, results in **porphyria**.
2. The **iron in hemoglobin may be oxidized from the ferrous to the ferric valence**, forming **methemoglobin**, which cannot carry oxygen (nitrite poisoning produces methemoglobin)
3. **Oxidative denaturation of hemoglobin** with formation of _Heinz bodies_ (denatured hemoglobin) increases both erythrophagocytosis and spontaneous hemolysis. (Cat hemoglobin is highly sensitive to Heinz body formation)
4. **Carbon monoxide**, which has high affinity for hemoglobin, may bind with hemoglobin to form carboxyhemoglobin (which cannot carry O2)
3. **Coagulopathy** from toxic interference with vitamin K results in spontaneous hemorrhages.
102
Mechanism of intoxication of rodenticide such as warfarin and brodifacoum ?
Rodenticides such as warfarin and brodifacoum **prevent the reactivation of vitamin K** needed to finalize the **synthesis of prothrombin and factors VII, IX and X**
103
Specific mechanisms of intoxication: **Exposure to agents with action similar to normal metabolites or nutrients** (2)
1. **Hormonal effects from exogenous estrongens** can mimic excessive activity of normal endogenours hormones. Estrogenic mycotoxins, plants and feed additives may alter reproductive cycles.
2. **Excessive levels of nutrients**, such as vitamin D, selenium and iodine, produce toxicosis in the same organs affected by deficiencies.
104
Specific mechanisms of intoxication: Immunosupression (5)
1. **Humoral and cell-mediated immunity:**
1. Reduced antibody synthesis,
2. interference with complement,
3. changes in delayed-type hypersensitivity,
4. altered neutrophil function, and
5. reduced lymphoblastogenesis.
105
Three examples of immunotoxicants
Heavy metals
Dioxins
Mycotoxins
106
Specific mechanisms of intoxication: **Developmental defects** (2)
1. Toxicant **exposure in the first trimester** of pregnancy results in **severe** effects that threaten survival of the fetus. Most teratogenic effects altering the morphology of the fetus occur in the first trimester of pregnancy
2. Toxican **exposure in the third trimester** results in **reduced growth of a fetus** that is already morphologically developed.
