Transcript general toxicology

GENERAL TOXICOLOGY
Aconitum wolf plaque
Aconitum lycoctonum
LD 1 – 5 mg
Hemlock
Conium maculatum
LD 150 - 300 mg
Red yew
Taxus baccata
Ricinus communis
Oil tree
Castor seeds contain 40-70% oil and about
20% of proteins, including ricin, which
represents one of the sharpest plant
poisons. Ricin causes agglutinations of red
blood cells, can damage the liver, kidney
and spleen. Poisoning is manifested burning
in the mouth, vomiting, diarrhea, intestinal
colic, headache, weakness, etc.
Possible misuse of ricin for terrorist attack
(easy isolation).
General Definitions
Paracelsus (1493-1541) :All substances are poisons; there is
none which is not poison. The right dose differentiates a poison
and a remedy.
(As2O3 400 mg, NaCl 250 g, destilled water 15 l)
Poison: Any chemical capable of producing a deleterious
response in a biological system, seriously injuring function or
producing death
Toxicology : The study of the adverse effects of chemicals on
living organisms.
Toxicologists : Trained to examine the nature of these effects
and to assess the probability of their occurrence.
Overview of toxicology
1. Biological systems are resistant to the toxic effect of
chemicals (lethal dose : ethanol=10g/kg, CdCl2= 225
mg/kg, TCDD=0.05 mg/kg)
2. Attempt of the body to protect itself from chemical
exposure -Defense mechanisms :
a) Barriers to absorption of chemicals (skin, gut)
b) Barriers to distribution of chemicals to critical organs
(blood-brain barrier, plasma protein binding, storage in
fat, uptake by kidney and liver for elimination)
c) Excretion of chemicals by urine, feces and liver
d) Biotransformation
e) Detoxication of chemicals (electrophilic chemicals,
reactive oxygen species, intracel.binding protein)
f) Repair of macromolecules (oxidative injury –8OHdG)
g) Apoptosis
h) Cell proliferation
i) Reflex physiological function
j) Alter Gene Expression
Mechanisms by which chemicals cause toxic effects
a) Toxic effects produced by : parent chemical, reactive
metabolite, reactive oxygen species
b) Toxicant interaction with macromolecules
c) Organ differences (kidney-concentrate chemical for excretion,
liver - high amount of drug metabolizing enzymes)
d) Subcellular sites of toxicity (nucleus, mitochondria,ER,
lysosome, peroxisome,cytoplasm)
e) Intra-organ differences (liver – centrilobular versus periportal,
kidney – proximal tubule and loop)
f) Age (fetus and newborn)
Factors controlling target organ toxicity
1.
2.
3.
4.
5.
Route of exposure
Distribution in the body
Metabolism
Excretion
Sensitization
Liver toxicity





Main defence against toxic agents - great detoxifying
capability
Toxicity is predominantly associated with lipid-soluble agents
Direct liver injury (alcoholic type, Reye´s Syndrome type,
toxic metabolite production, heavy metal damage)
Immune mediation of toxic liver injury (hepatocytic injury, bile
duct injury)
Chronic hepatotoxicity and neoplasia (vinyl chloride,
nitrosamines, aflatoxin, hormones, polyhalogenated
polycyclic hydrocarbons)
Chemical Exposure
A. Acute :
single exposure
Acute toxicity expressed as lethal dose – LD50
B. Subacute : less than 1 month
C. Subchronic : 1 – 3 months
D. Chronic : more than 3 months
The effect can be acute, chronic, and late. In the
late effect is long period of latency (at this time the
exposure is not condition). Incidence of symptoms
also in a few years (cancer).
Dose – response curves


Regardless of how a drug effect occurs—through binding or
chemical interaction—the concentration of the drug at the site of
action controls the effect. However, response to concentration may
be complex and is often nonlinear. The relationship between the
drug dose, regardless of route used, and the drug concentration at
the cellular level is even more complex.
Dose-response data are typically graphed with the dose or dose
function (eg, log10 dose) on the x-axis and the measured effect
(response) on the y-axis. Because a drug effect is a function of dose
and time, such a graph depicts the dose-response relationship
independent of time. Measured effects are frequently recorded as
maxima at time of peak effect or under steady-state conditions (eg,
during continuous IV infusion). Drug effects may be quantified at the
level of molecule, cell, tissue, organ, organ system, or organism.
Fig. 1 Hypothetical dose-response
curve.
Features of this curve :potency
(location of curve along the dose axis),
maximal efficacy or ceiling effect
(greatest attainable response), and
slope (change in response per unit
dose)
Fig. 2 Comparison of dose-response curves.
Drug X has greater biologic activity per
dosing equivalent and is thus more potent
than drug Y or Z. Drugs X and Z have
equal efficacy, indicated by their maximal
attainable response (ceiling effect). Drug Y
is more potent than drug Z, but its maximal
efficacy is lower.
Classification of Toxicants
Compound
LD50 (mg/kg) Toxicity
Ethanol
10,000
NaCl
Phenobarbita
l
Strychnine
4,000
150
2
Nicotine
1
TCDD
0.001
Botulinus
0.00001
slightly
moderately
very toxic
Super toxic
THRESHOLD vs NON-THRESHOLD
EFFECTS
Most Toxic effects are considered threshold
Cancer is usually considered a non-threshold
effect
Effects
1. Substances irritating mucose and skin (acids, bases,
oxidants).
2. Substances with narcotic effect (volatile solvents as
benzen, toluene, CCl4, C2H2Cl4, inhalation anaesthetics)
which are soluble in membranes, slow down
transmission of nervous impulse.
3. Substances inhibiting transfer of oxygen and electrons
(interaction with hemoglobin – CO, NO)
Substances changing hemoglobin to methemoglobin
(hemiglobin) Fe2+to Fe3+ - nitrites and chlorates
4. Substances inhibiting enzymes: ions of heavy metals
(Pb2+, Hg2+, Cd2+)
Glossary




Mutagen – A chemical agent or type of radiation such as
X-rays, cosmic rays, UV rays that causes mutations.
Mutation - A gene mutation is a permanent change in
the DNA sequence that makes up a gene. Mutations
range in size from a single DNA building block (DNA
base) to a large segment of a chromosome.
Mutagenesis is a process by which the genetic
information of an organism is changed in a stable
manner, resulting in a mutation. It may occur
spontaneously in nature, or as a result of exposure to
mutagens.
Teratogenesis is the production or induction of
malformations in an embryo or fetus.
Mutation - examples
H
N
O
N
CH
O
O
HC
N
CH3
O
C
N
C
H
CH3
dimer thyminu
NH2
OH
N
N
HO
N
HO
N
cytosin
uracil
NH2
OH
N
N
N
adenin
N
H
N
N
N
H
N
inosin
OH
OH
N
(CH3)2N-NO
N
H2N
N
N
H2N
N
H
N
CH3
N
N
7-methylguanin
guanin
O
OH
Aflatoxin B1
CH2CH2OH
N
N
OCH3
O
OH
N
H2N
O
H2N
N
N
7-hydroxyethylguanin
N
N
O
N
OH
O
O
aflatoxin B1 - guanin adukt
NH2
NH
N
N
N
adenin
N
H
CH2CHCl
N
N
N
N
H
ethenoadenin
Chemical carcinogens




1915 – coal tar was applied to test animals
(japanese pathologists) – skin cancer
Organic substances – polycyclic aromatic
compounds, aromatic amines, chlorinated
biphenyls, azo compounds, epoxides, aflatoxins,
nitrosoamines, ...
Inorganic substances – arsenic, chromium
(VI), cadmium, nickel
metal and polymeric implantates


thin layers, fibres, powders
asbestos
Mechanisms of effect of
chemical carcinogens


Main principle – carcinogen is covalently bound
to macromolecule – DNA, proteins,
phospholipids, ...
Sometimes the covalent bond is formed with the
metabolite of carcinogenic compound (product
of biotransformation)
Nitrosamines




They cause tumors in the experimental animals
We can find them in cigarette smoke, like
contaminants in preserved foods, and may be
formed in the gastrointestinal tract by metabolism of
nitrites used as preservatives
Probably metabolized by the P 450 cytochrome
system
Metabolically active metabolites can binds to DNA to
initiate the tumor response
O
O
O
O
O
O
O
O
O
O
O
O
CH3
Aflatoxin B1
O
CH3
Aflatoxin B1, 2,3 epoxid
O
HO
O
OH
Benzo(a)pyren
Benzo(a)pyren-7,8 epoxid
Benzo(a)pyren-7,8 diol-9,10 epoxid
Aflatoxin


The most potent hepatocarcinogen known
and occurs as a by-product of fungal
contamination of improperly stored food,
notably peanuts
Benzo(a)pyrene – typical example of the
polycyclic aromatic hydrocarbons (PAH)
Polycyclic aromatic hydrocarbons – PAHs




Potent atmospheric pollutants. Naphthalene is the
simplest PAH. PAHs occur in oil, coal and tar deposits,
and also in cooked foods(grilling meats, smoked fishes).
They are lipophilic - nonsoluble in water, the larger are
less volatile
Also formed by incomplete combustion of carboncontaining fuels (wood, diesel, fat, tobacco)
But they are used also as a raw material for the
production of drugs and paints – from gas tar
Benzopyrenes – PAHs toxicity is dependent on exact
isomer. The first known carcinogen was Benzo[a]pyrene
(found in cigarette smoke). 7 isomers of PAHs have the
carcinogenic, mutagenic and teratogenic effects.
CH3
Dibenz(a,c)antracen
Dibenz(a,h)antracen
CH3
7,12-dimethylbenz(a)antracen
Benzo(a)pyren
Benzo(e)pyren
O
O
O
dibenzofuran
Cl
Cl
Cl
Cl
polychlorované binenyly
O
Cl
Cl
O
Cl
2,3,7,8-tetrachlodibenzodioxin
dibenzodioxin
Cl
Cl
Polychlorinated dibenzodioxins and furanes –
PCDD/F






Dioxins are a group of chemically-related compounds that
persistent environmental pollutants
Solids, little soluble in water, sorption to scum and plankton,
High stability – decomposition by means of UV radiation,
they accumulate in the food chain, mainly in the fatty tissue
of animals
PCDD/F are side products of industrial production (e.g.
pesticides).
They are most toxic in parallel substitution of positions 2,3,7
and 8 – the most toxic 2,3,7,8- tetrachlorodibenzodioxin
TeCDD
Short-term exposure - skin lesions (chloracne), long-term
exposure - impairment of immune system, liver tissue,
endocrine system and another tissues , TCDD was
classified as a „human carcinogen“
O
Cl
O
Cl
Cl
O
Cl
O
dibenzodioxin
2,3,7,8-tetrachlodibenzodioxin
Cl
Cl
Cl
Cl
O
O
dibenzofuran
Cl
2,3,7,8-tetrachlordibenzofuran
Cl
Cl
Cl
Cl
polychlorované binenyly
Polychlorinated biphenyls - PCBs







Belongs to broad family made-man organic chemicals
(chlorinated hydrocarbons)
Manufactured from 1929 in USA, banned in 1979
Non-flammability, chemical stability, electric insulating
properties → electrical heat transfer, as plasticizers in
paints, plastics and so on
PCBs used in products were chemical mixtures made up
of a variety of individual chlorinated biphenyl
components (congeners – 207)
PCBs cause cancer and a variety of other adverse
effests like effects on the immune system, reproductive
system, nervous system and endocrine system
Disposal –PCBs do not readily break down and may
remain for long period of time cycling between air, water,
and soil.
Disposal is carried out in the blast furnace at high
temperature