CLINICAL TOXICOLOGY Module 4

Lecture Mechanisms of Target Organ Toxicity

Term Definition • For benign neoplasms, the tissue of

Cancer a disease characterized by origin is frequently followed by the suffix
genomic mutation, modified “oma”; for example, a benign fibrous
gene expression, cell
neoplasm would be termed fibroma,
proliferation, and aberrant
cell growth. and a benign glandular epithelium
Neoplasia New growth or autonomous termed an adenoma.
growth of • Malignant neoplasms from epithelial
tissue origin are called carcinomas.
Neoplasm The lesion resulting from the • Malignant neoplasms derived from
neoplasia
mesenchymal origin are referred to as
Benign Lesions characterized by
expansive sarcoma.
growth, frequently exhibiting • Thus, a malignant neoplasm of fibrous
slow tissue would be a fibrosarcoma while
rates of proliferation that do that derived from bone would be an
not osteosarcoma.
invade
• Similarly, a malignant neoplasm from the
surrounding tissues
Malignant Lesions demonstrating liver would be a hepatocellular
invasive growth, carcinoma while that derived from skin
capable of metastases to squamous epithelium is referred to as a
other tissues squamous cell carcinoma.
and organs • Table 8-3
Metastases Secondary growths deriv ed
Features of Genotoxic and Non-genotoxic
from a
primary Carcinogens
malignant neoplasm
Genotoxic carcinogens
Tumor Lesion characterized by
• Mutagenic
swelling or increase in size,
may or may not be • Can be complete carcinogens
neoplastic; grossly visible • Tumorigenicity is dose responsive
lesion • No theoretical threshold
Cancer Malignant neoplasm
Carcinogen A physical or chemical Non-genotoxic carcinogens
agent that causes • Non-mutagenic
or induces neoplasia • Threshold, reversible
Genotoxic Carcinogens that interact • Tumorigenicity is dose responsive
with DNA • May function at tumor promotion stage
resulting in mutation
• No direct DNA-damage
Non-genotoxic Carcinogens that modify
• Species, strain, tissue specificity
gene
expression
but do not damage DNA

• In classifying neoplasms, the

nomenclature reflects both the tissue or
cell of origin, and the characteristics of
the type of tissue involved.
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Multistage Carcinogenesis
Characteristics of the Stages of Carcinogenesis
Process
Initiation
DNA modification
Mutation
Genotoxic
One cell division necessary to lock-in mutation
Modification is not enough to produce cancer
Nonreversible
Single treatment can induce mutation
Promotion
No direct DNA modification
Non-genotoxic
No direct mutation
Multiple cell divisions necessary
Clonal expansion of the initiated cell population
Increase in cell proliferation or decrease in cell death
(apoptosis)
Reversible
Multiple treatments (prolonged treatment) necessary
Threshold
Progression
DNA modification
Genotoxic event
Mutation, chromosome disarrangement
Changes from preneoplasia to neoplasia
benign/malignant
Irreversible
Number of treatments needed with compound unknown
(may require only single treatment)
Initiation
• Initiating agents lead to genetic
changes including mutations and
deletions.
• Fate of initiated cells:
1. the initiated cell can remain in a
static nondividing state through
influences by growth control either
via normal surrounding cells or
through endocrine influence;
2. the initiated cell may possess
mutations incompatible with viability
or normal function and be deleted
through apoptotic mechanisms;
3. the cell, through stimuli such as
intrinsic factors or from chemical
exposure, may undergo cell division
resulting in the growth in the
proliferation of the initiated cell.
LECTURE
Promotion
• The second stage of the carcinogenesis
process (the promotion stage) involves
the selective clonal expansion of
initiated cells to produce a
preneoplastic lesion.
• Exogenous and endogenous agents
that function at this stage are frequently
referred to as tumor promoters.
Progression
• Involves the conversion of the
preneoplastic lesions to a neoplasm.
• additional genotoxic events occur
resulting in additional DNA damage
including chromosomal damage such
as aberrations and translocations.
Mechanisms of Action of Chemical Carcinogens
Hallmarks of Cancer
Eight properties of neoplastic cells that impart and contribute to
their ability to independently grow and eventually metastasize
1. Sustaining cell proliferation
2. Resisting cell death (apoptosis)
3. Inducing angiogenesis
4. Enabling replicative immortality
5. Activating invasion and metastasis
6. Evading growth suppressors
7. Reprogramming of energy metabolism
8. Evading immune destruction
Chemicals that induce cancer have been
classified into one of two broad categories:
genotoxic (DNA-reactive) agents and non-
genotoxic (epigenetic) agents.
Genotoxic (DNA-reactive) Agents
• Genotoxic compounds interact with
nuclear DNA of a target cell producing
unrepaired DNA damage that is
inherited in subsequent daughter cells
• DNA-reactive carcinogens can be
further subdivided according to whether
they are active in their parent form (i.e.,
direct-acting: chemicals that can
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directly bind to DNA without being Classes of Genotoxic Carcinogens

metabolized) and those that require
1. Polyaromatic hydrocarbons
metabolic activation (i.e., indirect-
2. Alkylating agents
acting carcinogens: compounds that
3. Aromatic Amines and Amides
require metabolism in order to react
with DNA).

Direct-Acting (Activation-Independent)
Carcinogens
• These chemicals are also defined as
ultimate carcinogens.
Indirect-acting Genotoxic Carcinogen
• Procarcinogens are stable chemicals
that require subsequent metabolism to
be carcinogenic; parent compound.
• proximate carcinogen- metabolite form;
intermediate
• ultimate carcinogen- metabolite form;
final
Mutagenesis
• The reaction of a carcinogen with
genomic DNA either directly or indirectly
may result in DNA adduct formation or
DNA damage, and frequently produces
a mutation.
Damage by Alkylating Electrophile
Inorganic Carcinogens
• Metals
Non-genotoxic (Epigenetic) Carcinogens
• Cytotoxicity- mode of action non-DNA
• Receptor M ediated
▪ P450 induced- organ specific
▪ Peroxisome Proliferator–Activated
Receptor
• Hormonal mode of action- tissue-
specific agents
▪ Trophic hormones are known to
induce cell proliferation at their
target organs.
▪ Estrogenic agents- Estrogen and
estrogen-mimic chemicals can
induce tumors in estrogen-
dependent tissue.
▪ Thyroid Hormone-A reduction of
thyroid hormone concentrations
(T4 and/or T3) and increased
thyroid-stimulating hormone (TSH)
have been shown to induce
neoplasia in the rodent thyroid.

DNA Repair

• Mechanism:
▪ Mismatch Repair of Single-Base
Mispairs
▪ Excision Repair
▪ Homologous Recombination and
Nonhomologous End-Joining
Repair of DNA
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Responses of the Liver
• Cell Death—Based on morphology, liver
cells can die by two different modes,
necrosis or apoptosis.
▪ Necrosis is characterized by cell
swelling, leakage, nuclear
disintegration (karyolysis), and an
influx of inflammatory cells.
▪ Apoptosis is characterized by cell
shrinkage, nuclear
fragmentation, formation of
apoptotic bodies, and a lack of
inflammation.
• Hepatocyte death can occur in a focal,
zonal, or panacinar (widespread)
pattern.
• Mechanisms o toxicant-induced injury to
liver cells include:
▪ lipid peroxidation
▪ binding to cell macromolecules
▪ mitochondrial damage
▪ disruption of the cytoskeleton,
and
▪ massive calcium influx.
LECTURE
• Canalicular Cholestasis—Defined
physiologically as a decrease in the
volume of bile formed or an impaired
secretion of specific solutes into bile. It is
characterized by:
▪ elevated serum levels of bile salts
and bilirubin
▪ Jaundice
▪ Bright yellow/dark brown urine
▪ It may be transient or chronic
• Bile Duct Damage—Damage to the
intrahepatic bile ducts (which carry bile
rom the liver to the GI tract) is called
cholangiodestructive cholestasis.
▪ sharp elevation in serum alkaline
phosphatase activity.
▪ Initial lesions following a single
dose of cholangiodestructive
agents include swollen biliary
epithelium.
▪ Chronic administration of
chemicals that cause bile duct
destruction can lead to biliary
proliferation and fibrosis
resembling biliary cirrhosis.
▪ A rare response is the loss of bile
ducts, a condition known as
vanishing bile duct syndrome. It is
persisting problem has been
reported in patients receiving
antibiotics, anabolic steroids,
contraceptive steroids, or the
anticonvulsant carbamazepine.
• Sinusoidal damage- The sinusoid is, in
effect, a specialized capillary with
numerous fenestrae or high
permeability.
▪ Functional integrity of the sinusoid
can be compromised by:
▪ dilation or blockade of its lumen;
▪ progressive destruction of its
endothelial cell wall.
➢ veno-occlusive disease
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➢ exposure to pyrrolizidine cells, the ductular “bipolar” progenitor

alkaloids
• Disruption of the Cytoskeleton
▪ Phalloidin (from a mushroom)
▪ microcystin (from blue-green
algae)
cells, and the periductular stem cells.
▪ The rare, highly malignant
angiosarcomas are derived from
sinusoidal lining cells.
▪ Hepatocellular cancer has been
linked to abuse o androgens,
alcohol, and a high prevalence of
aflatoxin-contaminated diets.

• Fatty Liver—or steatosis is defined

biochemically as an appreciable
increase in the hepatic lipid (mainly
triglyceride) content, which is < 5 wt% in
the normal human liver.
▪ acute exposure to
hepatotoxicants like carbon
tetrachloride, ethanol and some
drugs can induce steatosis.
▪ drug-induced steatosis is
reversible and does not lead
▪ to death o hepatocytes.
▪ The metabolic inhibitors
methionine, puromycin, and
cycloheximide cause fat
accumulation without causing
cell death.

• Fibrosis and Cirrhosis—Hepatic fibrosis

(scarring) is characterized by the
accumulation of extensive amounts of
collagen fibers, in response to direct
injury or to inflammation.
▪ The primary cause of hepatic
fibrosis/cirrhosis in humans
worldwide is viral hepatitis.
▪ However, biliary obstruction and,
in particular, alcoholic and NASH
are of growing importance or the
development of hepatic fibrosis.

• Tumors—Chemically induced neoplasia

can involve tumors that are derived
from hepatocytes, bile duct progenitor
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Examples of Hepatotoxicants
1. Paracetamol
2. Ethanol
3. Allyl Alcohol
4. Carbon tetrachloride
5. Aflatoxins
6. Pyrrolizidine Alkaloids
7. Metals

• Adaptation following toxic insult • Chronic Kidney Disease

▪ Severely injured- cell death
▪ Non-lethal injury- cell repair
and/or adaptation
▪ Uninjured- compensatory
hypertrophy, cellular adaptation,
and cellular proliferation
▪ Analgesics, lithium, cyclosphorine
▪ Progressive deterioration of renal
function
• Acute Kidney Injury
▪ Abrupt declining in GFR
• Examples of nephrotoxicants
▪ Heavy metals
▪ Halogenated hydrocarbons
▪ Mycotoxins
▪ Therapeutic agents
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➢ APAP
➢ NSAIDs
➢ Aminoglycosides
➢ Amphotericin B
➢ Cyclosporine
➢ Cisplatin
➢ Radiocontrast agents

Toxic Responses of the Respiratory System