Toxicology is the study of poisonous
substances, their actions on the living organism, their detection by laboratory
and other methods and measure taken to counteract their biologic effects.
Toxicology is the study of the adverse
effects of chemical on living organisms. The toxicologist is especially trained
to examine the nature of these adverse effects (including their cellular,
biochemical and molecular mechanism of action) and to assess the probability of
their occurrence. The variety of potential adverse effects and the diversity of
chemicals present in our environment combine to make toxicology a very broad
science.
Clinical toxicologists are physicians
who receive specialized training in emergency medicine and poison management.
Concept of a poisonous
substance
1. Poison has
been defined as any drug known to the pharmaceutical or medical profession,
which is liable to be destructive to adult human life if taken in quantities of
60 grains or less.
2. Poison in a
strict sense is a substance which upon entering into solution in the blood or
by chemically acting upon it, is capable of causing serious bodily injury,
disease or death. In a broad sense, it is any substance which independent of any
mechanical action causes serious bodily injury, disease or death when applied
to, introduced into or developed within the body.
3.
Poison is any agent capable of
producing a deleterious response in a biologic system, seriously injuring
function or producing death. Paracelsius noted: “All substances are
poisonous; there is none which is not a poison. The right dose differentiates a
poison and a remedy.”
Different areas of toxicology
1. Descriptive
toxicology
– concerned directly with toxicity testing, which provides necessary
information for safety evaluation and regulatory requirements. The concern may
be limited to effects on humans, as in the case of food additives.
2. Mechanistic
toxicology
– is concerned directly with elucidating the mechanisms by which chemicals
exert their toxic effects on living organisms.
3. Regulatory
toxicology
– is concerned with the responsibility of deciding on the basis of data
provided by the descriptive toxicologist if a drug or other chemical possess a
sufficiently low risk to be marketed for a stated purpose.
Three specialized areas of
toxicology
1.
Forensic toxicology – is a hybrid
of analytical chemistry and fundamental toxicology principles. It is concerned with
the medico–legal aspects of the harmful effects of chemical on human and
animals. The expertise of the forensic toxicologist is primarily invoked to aid
in establishing cause of death and elucidating its circumstances in a
postmortem investigation.
2.
Clinical toxicology – designates
an area of professional emphasis within the realm of medical science concerned
with disease caused by, or uniquely with, toxic substances.
3.
Environmental toxicology – focuses on
the impacts of chemical pollutants found in the environment on biological
organisms. Although toxicologist concerned with the effect of environmental
pollutants on human health fit within this definition, it is most commonly
associated with studies on the impacts of chemicals on non – human organisms
such as fish, birds, and other terrestrial animals.
Ecotoxicology – is a
specialized area within environmental toxicology that focuses more specifically
on the impacts of toxic substances on population, dynamics within an ecosystem.
The transport, fate and interactions of chemicals in the environment constitute
a critical component of both environmental toxicology and ecotoxicology.
Types of poison
1. Corrosive
poison
– an agent whose content chemically causes local destruction of tissues.
2. Cumulative
poison
– an agent which increases suddenly the intensity of action after the slow
addition of poison.
3. True poison – an agent
which is still a poison no matter how diluted it is.
Type of poisoning
1.
Acute poisoning – one in
which there is a prompt and marked disturbance of function or death within a
short time and is due to:
a. Excessive
single dose
b. Several small
doses but frequent
2.
Chronic poisoning – there is a
gradual deterioration of function of tissues and may or may not result in
death. It may be produced by:
a. Taking several
small doses at long intervals
b. Taking only
toxic doses of the drug
GENERAL
MECHANISM OF TOXICITY
All chemicals produce their toxic
effects by alterations in normal cellular biochemistry and physiology. A
thorough understanding of the biochemical and molecular sites and modes of
action of specific drugs and chemicals is an essential part of toxicology.
Although many toxic responses are
ultimately of cell death and loss of critical organ function, other responses
may be the result of biochemical and pharmacological imbalances in normal
physiological processes that do not result in cell death. There are many ways in
which chemicals can interfere with normal biochemistry and physiology, and a
brief overview of some general sites of toxic action is useful in appreciating
the diversity of biochemical and cellular process that underlie toxic response.
General mechanism of toxic
action
1.
Interference with normal receptor–ligand
interactions
Receptors are
macromolecular components of tissues with a drug or chemical (ligand) interacts
to produce its characteristics biologic effects.
Receptor–ligand
interactions are generally highly stereo specific and small changes in chemical
structure can drastically reduce or eliminate the effect.
The adverse
effects of many chemicals are related to their ability to interfere with normal
receptor–ligand interactions. This is especially true with neurotoxicants, as
the function of the nervous system is highly dependent on a diverse array of
receptor–ligand interactions.
a. Neuroreceptors
and neurotransmitter (e.g. atropine,
strychnine, LSD, d– tubocurarine, organophosphates, anti–histamines)
b. Hormone
receptors (DES, TCDO, goitrogens)
c. Enzyme
activity (organophosphates, cyanide, sodium fluoroacetate)
d. Transport
proteins (carbon monoxide, nitrates)
2.
Interference with membrane function
The
maintenance and stability of excitable membrane is essential to normal
physiology. Chemicals can perturb excitable membrane function in many ways. For
example, the flux of ions across neuronal axons is blocked by chemicals that
act as ion channel blockers. The marine toxins, saxitonin, produce its
paralyzing effects by blocking sodium channel in excitable membranes.
Tetradotoxins, derived from the gonads and other organs of the puffer fish, is
structurally quite different from saxitonin yet acts in essentially the same
manner. The insecticide DDT produces the neurotoxic action by interfering with
the closing of sodium channels, thus altering the rate of repolarization of
excitable membranes. Organic solvents appear to produce their CNS depressant
effects via non–specific alterations in membrane fluidity, largely as a
property of their lipid solubility, rather than binding to specific
macromolecular receptor.
3.
Interference with cellular energy
productions
Many chemicals
produce their adverse effects by interfering with the oxidation of
carbohydrates to produce adenosine triphosphate (ATP). This interference can
occur by blocking effective delivery of oxygen to tissues. For example,
chemical oxidation of the iron hemoglobin (methemoglobin) by nitrates also
interferes with oxygen delivery, as methemoglobin does not effectively bind
oxygen. Utilization of oxygen in the tissues is blocked by cyanide, hydrogen
sulfide and azide because of their affinity to cytochrome oxidase. The ultimate
formation of ATP via oxidation of carbohydrates can be blocked by other sites
as well.
The consequences
of ATP depletion are many and include effects above, such as interference with
membrane integrity, ion pumps and protein synthesis. Significant energy
depletion will inevitably lead to loss of cell function and perhaps cell death.
Examples:
a. Oxygen
delivery to tissues (CO, nitrites)
b. Uncoupling of
oxidative phosphorylation (nitrophenols, organotins)
c. Inhibition of
electron transport (rotenone, antimycin A)
d. Inhibition of
carbohydrate metabolism (fluoroacetate)
4.
Binding to molecules
a.
Interference with enzyme functions
Many toxic
substances exert their efforts via binding to the active sites of the enzymes,
or proteins that are critical to cellular function. For example, hydrogen
cyanide binds to the ferric ion atom in cytochrome a+a3 (cytochrome oxidase)
which blocks the terminal event in electron transport. This single site of
action responsible for the rapid and often fatal toxic effects of cyanide and
understanding of this mechanism led to the development of specific antidotes to
cyanide poisoning.
Carbon
monoxide binds tightly to the reduced form of iron in hemoglobin, reducing the
delivery of oxygen on tissues. Although this has for so many years been thought
to be the sole mechanism of toxicity of carbon monoxide, there is evidence to
suggest that CO also binds to cytochrome a+a3.
Many toxic
trace metals such as lead, mercury, cadmium and arsenic bind to proteins with
free sulfhydryl groups, which contribute to their toxicity. Chemical–induced
porphyrias from lead, mercury and other metals, as well as certain halogenated
hydrocarbons (e.g. hexachlorobenzene) result, in part, from the inhibition of
specific enzyme in the heme biosynthetic pathway.
b.
Lipid peroxidation (CCl4,
paraquat, ozone)
Although some
of the processes discussed above are capable of producing adverse physiological
responses without the actual death of cells in any tissues or organ, other
processes will eventually lead to loss of organ function and death of cell.
This is especially true if exposure to the toxic substance occurs on chronic
bases where tissue injury can accumulate from repeated cytotoxic episodes. The
specific sequence of events leading to cell injury and death is complex and not
fully understood. The most thorough understanding of the process leading to
chemical induced cell death comes from studies on liver cells.
For most
chemicals causing tissue necrosis, the initial step appears to be the formation
of a reactive, electrophilic intermediate, often free radicals. Formation of
free radicals may occur via enzyme–mediated one or two electron oxidations, as
well as from the autooxidation of small molecules to such as reduced flaviness and thiols. Electron transfer from
transition metals such iron to oxygen containing molecules can also initiate
and propagate free radical reactions. The initiation of lipid peroxidation via interaction of free radicals with
polyunsaturated fatty acids to form lipid peroxyradicals (ROO), which then
produce lipid cell injury and death. Peroxidative damage to membrane lipids
could then lead to a loss membrane integrity and rupture of the cell membrane.
c.
Oxidative stress
It is now
recognized that lipid peroxidation by itself may not be sufficient to induce
cell death. In addition to inducing lipid peroxidation, electrophilic intermediates
may also covalently interact with other nucleophilic sites in the cell, including
glutathione (GSH) and thiol– containing protein which results in “oxidative
stress” to the cell. Depletion of intracellular stores of glutathione appears
to be required before significant oxidative stress occurs. As many critical
enzymes in the cell require one or more reduced thiols (SH–group) to maintain
their activity, oxidative stress in excess of that necessary to deplete
intracellular GSH can lead to oxidation of protein thiols to form disulfide
linkages, thereby destroying enzymatic activity. Although the direct covalent
of electrophilic chemicals with protein thiols may contribute to enzyme
inhibition, it appears that the majority of loss of activity of thiol–containing proteins is a result of reversible oxidation of the thiol groups
that occurs as a result of oxidative stress. One group of thiol–containing
enzymes that may play a critical role in cell injury and death as result of
oxidative inactivation (oxidative stress) is calcium–transporting ATPases.
d.
Nucleic acid
There are
numerous nucleophilic sites within DNA that may readily react with
electrophilic chemicals. Alkylation of the O–6 position of guanine appears
important in the mutagenicity and carcinogenicity of nitrosoamines and other
chemicals that readily form methyl carbonium ions. However, other sites, such
as N–7, N–2 and C–2 positions of guanine, may also be important sites of DNA
adduct formation with other electrophilic chemicals. Adduction of DNA with
exogenous chemicals may alter the expression of critical gene products
necessary for survival of the cell and thus binding to DNA may lead to cell
death. However, if perhaps more significant is the production of somatic
mutation through chemical DNA adduct formation that may serve as the initiating
event in chemical carcinogenesis. As with DNA, ribonucleic acid (RNA) also
contains nucleophilic sites, and thus critical intracellular function of RNA,
e.g., protein synthesis, maybe perturbed by covalent interaction of
electrophilic chemicals with RNA.
5.
Perturbation of calcium homeostasis
Interference
with normal process responsible for intracellular calcium homeostasis appears
to play a critical role in chemical mediated cell injury and death. Calcium
accumulates in tissues following necrotic injury and death from ischemia,
immunological response and a variety of toxic agents. Disruption on
intracellular Ca2+ homeostasis can result from enhanced Ca2+
influx, release of Ca2+ from intracellular stores and inhibition of
Ca2+ extrusion at the plasma membrane.
A wide variety
of cytotoxic agents, including nitrophenols, quinones, peroxides, aldehydes,
dioxins, halogenated alkanes and some metal ions, have been shown to disrupt Ca2+
homeostasis. Increased cellular calcium has been shown to disrupt Ca2+
homeostasis. Increased intracellular calcium has been associated with the
development of membrane abnormalities (blebbing) in isolated cells, which
appears to be a general phenomenon associated with the toxic and ischemic cell
injury and death.
Ca2+
plays a key role as a second messenger in the regulation of many intracellular
functions. For example, normal cytoskeletal organization is perturbed when
intracellular Ca2+ increases apparently as a result of calcium–
mediated dissociation of action of microfilaments and an activation of
phospholipases and proteases. Although normally, the Ca2+ mediated
activation of phospholipases plays a protective role of removing peroxidized
phospholipids form damaged membranes. When activated by non– physiologic changes
in Ca2+ concentration phospholipases may enhance membrane
phospholipid breakdown, which may lead to cell injury and death. It is also
known that an increase in intracellular Ca2+ can activate non–
lysosomal proteases. Although the endogenous substrates for these proteases
have not been fully characterized, they appear to act as cytoskeletal proteins.
The importance of these proteases in the processes of cell death is
demonstrated by the fact inhibitors of Ca2+ activated proteases
delay or prevent the appearance of cytotoxic effects.
Ca2+
can also activate certain endonucleases, which result in DNA fragmentation and
chromatin condensation. Although this process is an important physiological
“programmed” cell death that occurs naturally as a part of tissue growth and
differentiation (apoptosis) chemically mediated premature activation of this
enzyme via a perturbation in Ca2+ homeostasis may contribute to the
cytotoxic action of some toxic substances.
6.
Toxicity from selective cell loss
Selective
death cell loss within an organ or tissue may also result in toxicologic
effects that are quite specific and in some instances other disease processes.
For example, high doses of manganese, or the illicit street drug 1–
methyl–4–phenyl–1,2,5,6–tetrahydropyridine (MPTP), cause selective damage to
dopaminergic cell in the basal ganglia in the brain, producing a neurological
condition nearly indistinguishable from Parkinson’s disease. Some chemicals,
both synthetic (e.g. Amitrole) and naturally occurring (e.g. 5 –vinyloxazolinethione
from the rape seed plant), stimulate the growth of the thyroid gland and
reduction of excess thyroid hormone, resulting in a pathological condition
indistinguishable from goiter. Conversely, other chemicals may selectively
accumulate in the thyroid gland, where they reach toxic concentrations and
destroy the thyroid cells. (e.g. propylthiouracil).
The developing
embryo is also quite sensitive to many toxic substances. Because in the early
stages of embryonic growth cells may have pluripotent potential (can
differentiate into a variety of mature cell types), loss of even a few cells
can have major consequences, leading either to embryonic death (i.e.,
miscarriage) or some form of congenital malformation (birth defect). For
example, the administration of the anti–nausea drug thalidomide to pregnant
woman at a specific stage of fetal development resulted in the cytotoxic loss
of early limb bud cells, with the consequence that children were born with
severely underdeveloped or missing legs and or arms.
7.
Non–lethal genetic alterations in
somatic cells
As noted
above, the covalent interaction of xenobiotics with DNA can result directly in
the death of the cell but may also result in the initiation of a complex series
of events that may ultimately result in cancer. Chemicals that can produce a
carcinogenic response via somatic mutations are called genotoxic
carcinogens. The vast majority of chemically induced lesions in DNA are
repaired but some may escape repair or be repaired incorrectly leading to the
introduction of a mutated cell. If the mutation occurs in a somatic cell, then
the genetic lesion cannot be passed onto future generations but could serve as
a precursor for the eventual development of cancer.
It is
currently thought that genotoxic chemicals can induce cancer by activating
cellular “proto–oncogenes.” Proto–oncogenes, when aberrantly expressed, confer
on a cell feature of a cancerous phenotype. Many of the gene products from
oncogenes determine a cell response to growth– stimulating factor and or
differentiation. In normal cells, the expression of proto–oncogenes is tightly
controlled for the specific requirement for growth and or differentiation. In
addition to the direct, covalent interaction of a xenobiotic with DNA, proto–oncogenes
may be activated via a number of xenobiotic events, such as alterations in
chromosome structure (e.g. rearrangement or deletions), interference with DNA
replication, interference with DNA segregation or interference with DNA repair.
Although
(alterations) activation of proto–oncogenes via or genotoxic event is one
mechanism by which chemicals can induce cancer, it has been recognized for
decades that cancer is a multi–step process and that some non–genotoxic
chemicals may enhance the incidence of cancer, presumably through some
mechanism other than by damaging DNA. Chemicals that are by themselves
generally incapable of inducing cancer but enhance the development of tumors
when given after an “initiator” are called tumor promoters.
Tumor
promoters act by enhancing the probability of an initiated cell developing into
tumor. Stimulation of an “initiated” cell into cell division and clonal
expansion (e.g. mitogenic effect) appear to be a common feature of all tumor
promoters. There is a variety of mechanism by which chemicals could act as
tumor promoters. They could act directly as growth factors or interact with
modified growth factor receptors, they could stimulate the production and
release of endogenous growth factors; they could shift differentiated cells
from a resting state (Go) to a cell cycle phase (G1),
they could induce normal reparative cell growth to neighboring cells via a
cytotoxic effect; they could inhibit normal cellular differentiation, which is
necessary to ensure that mature cells stop dividing or they could interfere with
normal cells–cell communication, which is important in regulation of normal
cellular growth.
Although birth
defects are most commonly induced via cytotoxic events are usually evident at
birth, it is also possible to have delayed adverse effects developing in
offspring that arise via genetic mutations induced in utero. For example, the
synthetic estrogen diethylstilbesterol (DES) has b been claimed responsible for
vaginal cancers in women who are exposed in uterus because their mother DES to
reduce the chance of miscarriage. Fortunately, there are very few examples of
such transplacental carcinogenesis.
CONCEPT OF AN
ANTIDOTE
An antidote is any agent which
neutralizes a poison or otherwise counteracts or opposes it or its effect.
Action of an antidote
1. Removes the
poison from the body – emetic and cathartic
2. Mechanically
prevent its absorption – demulcent
3. Change the
physical state or chemical composition – sodium sulfate for barium
4. Act upon the
functions of the body so as to overcome the effects of its absorption
Types of antidotes
a.
Chemical or true or specific antidote – is one
which makes the poison harmless by chemically altering it.
b.
Mechanical antidote – is an agent
that removes the poison without changing it, or so coats the surface of the
organ so that absorption is prevented.
c.
Physiological antidote (antagonist) – is an agent
that acts upon the system so as to counteract the effect of the poison.
Classification of toxic agents
1. According to
target organ
a. Liver
b. Kidney
c. Hematopoietic
system
2. According to
their use
a. Pesticides
b. Solvent
c. Food additive
3. According to
their source
a. Animal toxin
b. Plant toxin
4. According to
their effects
a. Cancer
b. Mutation
c. Liver injury
5. According to
physical state
a. Gas
b. Dust
c. Liquid
6. According to
labelling requirement
a. Explosive
b. Flammable
c. Oxidizer
7. According to
chemistry
a. Aromatic amine
b. Halogenated
hydrocarbons
8. According to
their poisoning potential
a. Extremely
toxic
b. Very toxic
c. Slightly toxic
Classification of poison
according to physical state
1. Gases
a. Carbon
monoxide
2. Volatitles
a. Ethanol
b. Other alcohols
3. Non–volatile
a. Pesticides
b. Amphetamine
group
c. Cocaine
d. Cannabinoids
e. Methadone
f.
Methaqualone
g. Opiates
h. Phencyclidine
i.
Propoxyphene
j.
Phenothiazine
Manner or method of
introduction
1. Gastro–intestinal
tract
2. Rectal mucosa
3. Sublingual
administration
4. Subcutaneous
route
5. Intramuscular
route (intravenous / intraarterial)
6. Thru lungs by
inhalation
7. Intrathecal
8. Skin
Storage depot
Accumulation
of the poison in the body is influenced by:
1. Plasma protein
binding usually to serum albumin
2. Fat solubility
3. Affinity for
mucopolysaccharide of connective tissue
4. Affinity for
bones (calcium, lead, arsenic, tetracycline)
Route of excretion of poison
1. Kidney – it
the most important excretory organ. Most polar substances are excreted
unchanged, while other substances must be metabolized and conjugated before
they can be excreted.
2. Hepatic and
fecal excretion – metabolite secreted into the bile are usually reabsorbed in
the gastrointestinal tract and excreted in the urine. Some pass into the feces.
3. Milk (breast)
4. Sweat (skin)
5. Saliva
(salivary gland)
1 comment:
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Postmortem Toxicology Analysis
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