Chemical Mechanisms of Metal Toxicology

1. Variability in Metal Toxicity

 The chemical basis of metal toxicology is complex and not uniformly
applicable to all metals due to their diverse chemical properties and
varied toxic effects.
2. Reactivity of Ionic Metals
 Metals in their ionic forms are highly reactive and capable of
interacting with biological systems through various potential ligands
within a cell.
3. Specific Metal Binding
 Metals like cadmium and mercury show a preference for binding to
sulfur in proteins, impairing biomolecule functions through steric
rearrangements, which can inhibit enzyme activities.
4. Molecular Mimicry by Metals
 Toxic metals can mimic essential metals, binding to physiological
sites and disrupting important cellular functions. This includes
replacing essential metals in metabolic and signaling pathways,
contributing to toxicity.
5. Oxidative Damage Mediated by Metals
 Metals can serve as catalytic centers for redox reactions, leading to
oxidative modifications of biomolecules such as proteins and DNA,
which are significant in the carcinogenicity of certain metals.
6. Displacement of Redox Active Elements
 Metals like cadmium can cause oxidative stress by displacing redox-
active essential elements like iron, leading to oxidative cellular
damage.
7. Formation of DNA and Protein Adducts
 Reactive metal species can form DNA and protein adducts, which
are important in the genotoxicity of metals like chromium.
8. Induction of Aberrant Gene Expression
 Metals can trigger abnormal gene expression leading to adverse
biological effects. For instance, nickel can influence gene expression
related to carcinogenesis under specific conditions.
9. Illustrative Mechanisms and Examples
 Various mechanisms are highlighted, such as the inhibition of heme
synthesis enzymes by lead and the disruptive effects of metals like
thallium and arsenic, which mimic essential elements, causing
cellular dysfunction.
Factors Impacting Metal Toxicity
1. Exposure-Related Factors
 Dose, Route, Duration, and Frequency: The level, method,
length, and frequency of exposure to metals significantly affect their
toxicity. For example, inhalation primarily affects the lungs due to
metals' reactivity at the point of entry.
2. Host-Based Factors
 Age, Gender, and Biotransformation Capacity: Age influences
sensitivity to metal toxicity, with children and the elderly typically
more vulnerable. Children have higher gastrointestinal absorption
rates, particularly for metals like lead, making them susceptible to
neurotoxicity and other toxic effects, such as transplacental
carcinogenesis noted in metals like arsenic and chromium.
3. Chemical-Related Factors
 Metal Compound and Speciation: The toxicity of metals can vary
with their chemical form; for example, methylmercury is a potent
neurotoxin, whereas inorganic mercurials affect the kidney primarily.
The oxidation state of a metal, like chromium, can differentiate its
toxicity.
4. Lifestyle Factors
 Smoking and Alcohol Ingestion: Lifestyle choices can modify the
level of metal intoxication. Smoking increases the body's cadmium
load, and alcohol affects metal toxicity by altering diet and essential
mineral intake, and changing hepatic iron deposition.
5. Dietary Factors
 Diet Composition: The type of diet can influence the
gastrointestinal absorption of metals, affecting the overall toxicity
levels in the body.
6. Essentiality of Metals
 Homeostasis and Toxicity Thresholds: Essential metals are
incorporated into bodily systems for safe transport, storage, and
utilization. However, exposure to both essential and non-essential
metals must be balanced as they can display a "U"-shaped dose-
response curve where both deficiency and high exposure levels can
lead to toxicity. Nonessential metals like cadmium can disrupt this
balance by mimicking essential elements and binding to their
biological targets.
7. Adaptive Mechanisms
 Cellular and Organismic Adaptations: Organisms can adapt to
metal exposure through mechanisms such as enhanced efflux,
sequestration in inert forms, or overexpression of proteins like
 metallothionein that reduce toxicity. Such adaptations can be critical
for immediate survival but might contribute to long-term toxicity by
allowing damaged cells to persist that would otherwise be
eliminated, potentially leading to carcinogenesis.
Overview of Arsenic: Toxicity, Uses, and Exposure
1. Historical Significance and Naming
 Origins of the Name: The term "arsenic" originates from the
Persian word "Zarnikh," translated to Greek as "arsenikon," meaning
"yellow orpiment." This metalloid has been known as both the
"Poison of Kings" and the "King of Poisons" due to its notoriety and
historical use.
 Discovery: Arsenic was first isolated around the year 1250.
2. Medical Applications
 Uses in Medicine: Historically used as a drug, arsenic compounds
remain effective today, particularly in treating acute promyelocytic
leukemia.
3. Chemical Forms of Arsenic
 Inorganic Forms: Arsenic exists primarily in trivalent and
pentavalent forms. Common trivalent compounds include arsenic
trioxide and sodium arsenite. Pentavalent compounds are typically
found as sodium arsenate, arsenic pentoxide, and arsenic acid.
 Organic Forms: Organo-arsenical compounds such as arsenilic
acid, arsenosugars, and several methylated forms are also notable,
with these being products of inorganic arsenic biotransformation in
various organisms, including humans. Gaseous arsenical, arsine
(AsH3), is another significant form.
4. Occupational Exposure
 Industry Risks: Workers in the pesticide, herbicide, and smelting
industries may face high levels of exposure to arsenic through
fumes and dust.
5. Environmental Exposure
 Drinking Water: Arsenic contamination in drinking water, often
from natural geological sources, poses significant health risks. While
most U.S. drinking water contains arsenic levels below 5 μg/L, in
Bangladesh, approximately 25 million people are exposed to arsenic
levels exceeding 50 ppb.
 Other Sources: Additional environmental exposure can occur
through the burning of arsenic-rich coal and possibly from wood
treated with arsenical preservatives.
6. Dietary Exposure
  Seafood: A major source of dietary arsenic, especially in seafood, is
arsenobetaine, an organic form of arsenic which is much less toxic
than its inorganic counterparts.
Toxicokinetics of Inorganic Arsenic: Absorption,
Metabolism, and Excretion
1. Absorption and Distribution
 Gastrointestinal Absorption: Inorganic arsenic is efficiently
absorbed (80–90%) from the gastrointestinal tract.
 Distribution: Once absorbed, arsenic is distributed throughout the
body.
 Less Soluble Forms: Arsenic compounds with low solubility, such
as arsenic trioxide and gallium arsenide, are absorbed less
efficiently.
2. Metabolism
 Methylation Process: Arsenic is often metabolized by methylation
in the body. Historically considered a detoxification process, recent
findings indicate that methylated trivalent arsenicals are highly
toxic.
 Enzymatic Reduction and Methylation: Arsenate (As5+) is
reduced to arsenite (As3+) by arsenate reductase, then methylated
to form methylarsonate (MMA5+) and dimethylarsinic acid (DMA5+)
by arsenic methyltransferase using S-adenosylmethionine as a
methyl group donor.
 Toxic Intermediates: Intermediate metabolites such as
methylarsonous acid (MMA3+) and dimethylarsinous acid (DMA3+)
are particularly toxic.
3. Excretion
 Primary Route: Arsenic is primarily excreted in the urine, with 50–
80% of ingested arsenic expelled over 3 days.
 Biological Half-Life: The whole-body biological half-life of ingested
arsenic is about 10 hours, while methylated arsenicals have a half-
life of approximately 30 hours.
 Additional Excretion Routes: Arsenic is also excreted through
desquamation of the skin and in sweat, especially during intense
sweating. It accumulates in forming fingernails and hair.
4. External Signs of Exposure
 Biomarkers of Exposure: The presence of transverse white bands
across fingernails, known as Mees' lines, appears about 6 weeks
after the onset of arsenic toxicity symptoms and serves as a
biomarker of exposure. Arsenic levels in fingernails and hair indicate
 both current and past exposures, while urinary arsenic is a reliable
marker for current exposure.
5. Factors Influencing Metabolism
 Variability in Methylation: Significant variations in arsenic
methylation are influenced by age, sex, and possibly genetic
polymorphisms. These differences may alter the toxicological
impacts of arsenic, particularly during sensitive periods such as
pregnancy.
Toxicity of Arsenic: Acute Poisoning and Its Effects
1. Symptoms of Acute Arsenic Poisoning
 General Symptoms: Fever, anorexia, and hepatomegaly (enlarged
liver).
 Skin and Mucosal Damage: Melanosis (dark pigmentation of the
skin) and severe damage to the mucous membranes of the
gastrointestinal tract, including irritation, vesicle formation, and
sloughing.
 Cardiac Issues: Cardiac arrhythmia, which can escalate to cardiac
failure in severe cases.
2. Neurological Effects
 Peripheral Nervous System: Sensory loss in the peripheral
nervous system is a common effect, characterized by Wallerian
degeneration of axons. This condition appears 1–2 weeks after
exposure to large doses but is reversible if exposure ceases.
 Central Nervous System: Encephalopathy can manifest as
headache, lethargy, mental confusion, hallucinations, seizures, and
coma.
3. Hematological Effects
 Blood Cell Depletion: Anemia and leucopenia, specifically
granulocytopenia, can occur a few days after high-dose exposure
but are typically reversible.
 Arsine Gas Exposure: Exposure to arsine gas, a byproduct of
arsenic in nonferrous metal production, leads to acute hemolytic
reactions. Symptoms include nausea, vomiting, shortness of breath,
and headaches, with severe cases resulting in hemoglobinuria, renal
failure, jaundice, and anemia.
4. Clinical Use of Arsenic
 Therapeutic Risks: Intravenous arsenic infusion used in treating
acute promyelocytic leukemia can be significantly toxic, and fatal in
susceptible patients. There have been reports of sudden deaths
associated with its use.
5. Mortality and Morbidity
 Fatality Rates: Ingestion of large doses (70–180 mg) of inorganic
arsenic can be fatal. Similarly, exposure to arsine gas can be fatal in
up to 25% of reported cases, with even nonfatal cases potentially
leading to severe health complications.
Chronic Toxicity of Inorganic Arsenic: Target Organs and
Health Effects
1. Skin Changes and Cancer
 Pigmentation Changes: Chronic exposure to inorganic arsenic can
lead to diffuse or spotted hyperpigmentation and hypopigmentation,
typically appearing between 6 months to 3 years after exposure
begins.
 Hyperkeratosis: Following pigmentation changes, palmar-plantar
hyperkeratosis often develops, which can lead to skin cancer with
prolonged high-level exposure.
2. Liver Damage
 Initial Symptoms: Long-term arsenic exposure may initially
present as jaundice, abdominal pain, and hepatomegaly.
 Progression to Severe Diseases: Chronic exposure can progress
to liver diseases such as cirrhosis, ascites, and potentially
hepatocellular carcinoma.
3. Neurological Effects
 Peripheral Neuropathy: Low-level repeated exposure can lead to
peripheral neuropathy, starting with sensory impairments like
numbness and evolving to painful sensations and muscle weakness.
Histological examination shows dying-back axonopathy and
demyelination, with these effects being dose-related.
4. Cardiovascular Diseases
 Association with Cardiovascular Issues: There is a documented
link between inorganic arsenic ingestion through drinking water and
cardiovascular disease, including peripheral vascular disease.
 Severe Manifestations: Chronic exposure in certain regions like
Taiwan can lead to severe vascular diseases, including Blackfoot
disease, characterized by acrocyanosis, Raynaud's phenomenon,
and potentially gangrene of the lower extremities.
5. Potential Link to Diabetes
 Inconsistent Findings: Some studies, especially in Taiwan and
Bangladesh, suggest a potential increased risk of diabetes mellitus
associated with high arsenic exposure, though findings from
occupational exposures remain inconsistent.
6. Immunotoxic Effects
 Hematologic Impact: Chronic arsenic exposure may interfere with
heme synthesis, increasing urinary porphyrin excretion, which has
been proposed as a biomarker for arsenic exposure.
7. Research Needs
 Need for Further Studies: Additional research is necessary to
clarify the links between inorganic arsenic exposure and various
chronic health outcomes, including its potential role in diabetes and
other systemic diseases.
Mechanisms of Arsenic Toxicity and Carcinogenicity
1. Reactivity with Thiol Groups
 Trivalent Arsenic Compounds: These compounds are thiol-
reactive, meaning they can inhibit enzymes or alter protein
functions by reacting with proteinaceous thiol groups.
2. Mitochondrial Disruption
 Pentavalent Arsenate: Acts as an uncoupler of mitochondrial
oxidative phosphorylation. This disruption is likely due to its
competitive substitution (mimicry) of arsenate for inorganic
phosphate in ATP (adenosine triphosphate) formation.
3. Hemolytic Properties of Arsine Gas
 Formation and Impact: Arsine gas, formed by the reaction of
hydrogen with arsenic, is a potent hemolytic agent, breaking down
red blood cells.
4. Oxidative Stress and DNA Damage
 Generation of Oxidants: Arsenic and its metabolites can induce
oxidative stress, leading to oxidative DNA damage.
 Alteration in DNA Methylation and Stability: Changes in DNA
methylation status and genomic instability are noted, along with
impaired DNA damage repair mechanisms.
 Enhanced Cell Proliferation: Arsenic can lead to increased cell
proliferation, a key factor in carcinogenesis.
5. Chromosomal Effects
 Induction of Chromosomal Abnormalities: Despite not being a
strong mutagen, arsenic can induce chromosomal abnormalities,
aneuploidy (abnormal number of chromosomes), and micronuclei
formation in cells.
6. Comutagenic and Cocarcinogenic Roles
  Interactions with Other Carcinogens: Arsenic can act as a
comutagen and/or cocarcinogen, enhancing the effects of other
carcinogens.
7. Organ-Specific Mechanisms
 Variability by Organ: Some mechanisms of arsenic toxicity and
carcinogenicity may be specific to particular organs, suggesting a
complex interaction with different tissue types.

Carcinogenicity of Arsenic: Historical Observations and

Research Findings
1. Historical Recognition
 Early Observations: Over 110 years ago, Hutchinson noted a high
incidence of skin cancers in patients treated with medicinal
arsenicals.
 IARC Classification: The International Agency for Research on
Cancer (IARC) classifies arsenic as a known human carcinogen,
linking it to cancers of the skin, lung, urinary bladder, and
potentially the kidney, liver, and prostate.
2. Skin Cancers
 Types of Carcinomas: Arsenic-induced skin cancers primarily
include basal cell carcinomas and squamous cell carcinomas.
 Characteristics and Locations: These cancers often arise in areas
of arsenic-induced hyperkeratosis and may appear on non-sun-
exposed areas like the palms and soles. Basal cell cancers tend to
be locally invasive, whereas squamous cell carcinomas can
metastasize.
3. Experimental Models
 Animal Studies: Arsenic acts as a copromoter in rodent skin tumor
models and as a cocarcinogen with UV radiation in hairless mice.
These models help demonstrate arsenic's role in enhancing the
carcinogenic process.
4. Internal Tumors
 Human Associations: Exposure to arsenic is associated with
internal tumors in humans, notably affecting the urinary bladder,
lung, and potentially other organs like the liver and kidney.
 Animal Research: In rats, dimethylarsinic acid (DMA5+) has been
identified as a tumor initiator and promoter in the urinary bladder,
demonstrating urothelial cytotoxicity and proliferative regeneration
with continuous exposure.
5. Challenges in Carcinogenicity Studies
  Difficulty in Animal Studies: Confirming the carcinogenicity of
inorganic arsenic in experimental animals has been challenging,
with high doses required to produce changes, necessitating cautious
extrapolation to humans.
6. Transplacental Carcinogenesis Model
 Established Model in Mice: A model has been developed where
short-term exposure of pregnant mice to arsenic results in tumors in
multiple organs of the offspring, suggesting that arsenic exposure
during sensitive periods of development can lead to adult cancers.
 Mechanism Hypotheses: The resemblance of the tumor spectrum
to that caused by estrogenic carcinogens has led to the hypothesis
that arsenic may influence estrogen signaling, potentially explaining
its hepatocarcinogenic effects.
7. Synergistic Effects and Human Corollaries
 Synergistic Carcinogenic Effects: Studies have shown that
combining in utero arsenic exposure with postnatal synthetic
estrogen exposure significantly increases the incidence of malignant
tumors in the urogenital system.
 Impact on Young Adults: There is increased mortality from lung
cancer in young adults who were exposed to arsenic in utero,
underscoring the heightened sensitivity of the developing fetus to
arsenic carcinogenesis.

Key Points: Treatment of Arsenic Poisoning

Acute Arsenic Poisoning
 Symptomatic Management: Focus on fluid replacement and
blood pressure support.
 Chelation Therapy: Use of penicillamine, succimer (DMSA), and
dimercaptopropanesulfonic acid (DMPS) to remove arsenic from the
body, with DMPS noted for fewer side effects.
Chronic Arsenic Poisoning
 Limited Efficacy of Chelators: Chelation therapy generally
ineffective in alleviating symptoms, except in a limited trial with
DMPS.
Prevention
 Reducing Exposure: The best strategy to prevent chronic arsenic
poisoning is minimizing exposure to arsenic, particularly in
contaminated areas or water sources.