Toxicity of Metals

Katherine Squibb, Ph.D.

Systemwide Program in Toxicology

March 6th, 2002

Applied Toxicology - NURS 678
 Toxicity of Metals

All metals are potentially toxic, yet may metals are essential
for life. Homeostasis is key to survival

Metals are frequently bound to proteins for transport

and storage.

Toxic (non-essential) metals often follow pathways of

chemically similar essential metals
Essential trace elements:

Co, Cr, Cu, Fe, Mg, Ni, Mo, Se, Zn

Non-essential (toxic) elements:

As, Ag, Au, Be, Cd, Cs, Li, Hg, Pb,

Sn, Sr
 Cadmium (Cd) Toxicity

• Occupation exposure:
Primary Cd (Pb, Zn or Cu) production industries (smelters)
Cd electroplating industry
Manufacture of Ni/Cd batteries
Welding Cd plated materials
Cd alloy manufacture and use
Production or use of Cd containing plastic stabilizers
Production or use of Cd containing pigments
Jewelry manufacturing

• Environmental exposure:
Contaminated foodstuffs
Tobacco consumption
Air
Water
 Cadmium (Cd) Toxicity

• Absorption dependents highly on route of exposure

Gastrointestinal tract - only 5%
Respiratory system - 90% can be absorbed

• Distribution:
Over 50% of total body burden is in liver and kidney
Half-life is very long (>10 yr);

• Metabolism: Cd is not metabolized by Phase I or Phase II

enzymes, however it does bind strongly to
metallothionein

• Elimination is very poor

 Cadmium Follows Zn Pathways

• Toxicity often through disruption of Zn mediated processes

• Excess Zn prevents many toxic effects of Cd

• Zn deficiency enhances Cd toxicity

• Hypothesized mechanism: Metallothionein (MT)

MT: - is a 6,000 dalton metal-binding protein
- has a high (30%) cysteine content
- is highly inducible by either Cd or Zn
- has very high affinity for Cd (K = 1023) and Zn (K= 1017)
- plays a role in Cd tolerance
- pre-induction of MT, decreases Cd toxicity
 Cadmium (Cd) Toxicity

Acute Toxicity:
Occurs at relatively high exposures
Target tissue is that first exposed
lung (inhalation)
G.I. Tract ( oral)
Dermal (generally not a problem)

Acute Oral Exposure (occurs rarely)

Symptoms: nausea, vomiting, abdominal cramping,
diarrhea, increased salivation
Effects: Hemorrhagic gastroenteritis, hepatic and
renal cortical necrosis, cardiomyopthy
Recovery can be rapid and without long term effects
 Cadmium (Cd) Toxicity

Acute Inhalation (occurs more frequently)

Symptoms: nasopharyngeal irritation, chest pain, head-
ache, dizziness, cough, dyspnea, nausea, chills
(metal fume fever)
Effects: pulmonary edema of non-cardiac origin, hepatic
and renal cortical necrosis
Approximately 20% of all cases are fatal due to
pulmonary edema. Long term effects can include
pulmonary fibrosis
 Cadmium (Cd) Toxicity
Chronic toxicity (inhalation or oral):

• Due to long half-life of Cd, chronic toxicity doesn’t

require a high level of exposure - dose is cumulative

• Chronic effects occur in:

- liver, kidney, skeletal system,
- cardiovascular system/hypertension
- possible human carcinogen

• Chronic pulmonary toxicity occurs only as a result

of inhalation exposure
- obstructive lung disease (OLD)
- OLD results from chronic bronchitis with progressive
fibrosis of the lower airways, and emphysema
 Cadmium (Cd) Toxicity

Chronic renal toxicity:

• Manifests as low MW proteinuria, amino aciduria, and

glucosuria

• Occassionally high MW proteinuria (albumin) also seen

• Nephropathy results from proximal tubule cell necrosis

• After onset of symptoms, effects are irreversible and even

progress
Role of MT in Mediating Cd-Induced Nephropathy
Skeletal Effects of Chronic Cd Exposure:
Itai-Itai Disease
 Itai-Itai Disease

• Itai-Itai Disease is a multi-system disorder characterized by:

- severe osteomalacia, osteoporosis and bone fragility
- disruption of calcium metabolism (increased excretion)
- nephropathy

• Affects primarily post-menopausal, multiparous women

• Occurs with high chronic cadmium exposure

• Nutritional deficiencies (Vit. D, Ca)

 Cd and Cancer

Cd exposure has been associated with cancer in humans with

tumors of the lung and prostate

In animals, Cd can induce cancers of the lung, prostate, testes,

hematopoietic system, liver and pancreas

However, Cd can also be tumor suppressive (liver, lung,

pancreas, and hematopoietic system)

Carcinogenicity may be related to MT gene expression in

different cell types and different tumor types
 Toxicity of Lead (Pb)

“If we were to judge of the interest excited by any medical subject

by the number of writings to which it has given birth, we could not
but regard the poisoning by lead as the most important to be known
of all those that have been treat of, up to the present time”
Orfila, 1817
In ancient Rome:
- Pb pipes were used to convey water in the city
- Pb was added to sweeten wine

Today, we continue to use Pb in ways that lead to human

exposure and Pb is the most ubiquitous of known toxic metals.
Can we reduce our exposure to Pb to a safe level?
Some think not, especially for children

Recent/Ongoing Routes of Exposure:

• Occupational
Pb production and smelting
Brass, Cu or Pb foundries
Pb soldering
Battery manufacturing
Demolition of old structures
Burning, scraping or sanding old paint
Indoor firing ranges
Ceramic glaze mixing
Recent/Ongoing Routes of Exposure:
• General Population
Paint in houses built before 1978
Soil and air near factories which use Pb
Drinking water from pipes with Pb solder
(especially if pH < 6.5)
Lead-soldered cans
Folk medicine/cosmetics
Gasoline exhaust emissions

Recent reductions in Pb exposure:

• Removal of Pb from gasoline
• Reduction in use of Pb-soldered cans for food
1940s dietary intake of Pb was 400-500 ug/day
1990s dietary intake of Pb is less than 20 ug/day
• Ban on the use of Pb in house paints
• Absorption
Gastrointestinal: Adults absorb 5-15%, retain about 5%
of absorbed dose
Children absorb about 40% and retain
about 32% of absorbed dose

Pulmonary: About 90% of Pb particles in outdoor air are

small enough to enter the alveoli.

• Tissue Distribution
Blood Pb: More than 90% of Pb in blood is in the
red blood cells. Blood Pb concentrations
are used to measure recent exposure to Pb
 Sensitivity of Children to Pb

Even though blood Pb levels are decreasing in the general

population, still 35% of inner city children have blood Pb
concentrations above 10 :g/dl (recommended by CDC to
prevent impairment of cognitive and behavioral development.

Due to:

• Higher exposure from Pb-based paint in homes and

urban dust due to childhood behaviors

• Higher rate of intestinal absorption in children and

nutritional deficiencies in iron and calcium which
enhance Pb absorption
Tissue Distribution

Bone - Largest and kinetically the slowest pool

t1/2 = >20 yr.
Contributes to maintaining blood Pb levels

Mobilization of Pb from bone occurs:

• During pregnancy and lactation which
can increase fetal exposure
• After menopause with onset of osteoporosis
which can increase exposure to soft tissues
Tissue Distribution

Soft tissues - Liver, kidney, brain

Pb in CNS concentrates in gray matter and
specific nuclei
Highest concentration in hippocampus> cerebellum>
cerebral cortex and medulla
Pb crosses the placenta. Cord blood Pb and fetal
tissue concentrations correlate with maternal
blood Pb concentrations
 Toxic Effects of Pb in Children

Lead encephalopathy occurs at 80 :g/dl

Symptoms: Begin with lethargy, vomiting, irritability,

loss of appetite and dizziness
Progress to ataxia, reduced level of
consciousness, coma and death

Pathology involves edema of brain due to extravasation

of fluid from capillaries, loss of neuronal cells
and increase in glial cells

Recovery is accompanied by epilepsy, mental retardation

optic neuropathy and blindness
 Toxic Effects of Pb in Children

Nervous system effects:

Psychomotor, cognitive and behavioral functional

alterations have been documented at lower Pb levels

Studies have reported a 2 to 4 point IQ deficit for each

:g/dl increase in blood lead within the range of
5 - 35 :g/dl. There does not appear to be a threshold
for this effect.
 Mechanism of Action of Pb on the
Developing Nervous System

Morphological changes:

Modification of the “neuronal circuitry”

Pb appears to alter the timed programming

of cell to cell connections in the developing brain

May occur through effects on the glial cells which

help form proper connections
Pharmacological changes:

1) Pb interference with
transmitter release by
substitution for Ca or Zn
or
2) Direct binding of Pb
to membrane receptors
 Toxic Effects of Pb in Adults

Peripheral nervous system preferentially affected:

Peripheral neuropathy is classic manifestation of Pb toxicity

at blood Pb levels above 40 :g/dl

“Footdrop” or “wristdrop” due to segmental

demyelination and axonal degeneration with
Schwann cell degeneration.

Sensory nerves are less sensitive than motor nerves

CNS effects (changes in mood and affect) occur at higher

blood levels than in children
 Toxic Effects of Pb in Adults

Hematological effects:

• Anemia occurs from shortened lifespan of red

blood cells

• Inhibition of pyrimidine-5-nucleosidase leads

to nucleotide accumulation which affects
membrane stability of red blood cells

• Impairment of heme synthesis limits recovery

of red blood cell populations
 Toxic Effects of Pb in Adults

Renal Effects: Lead nephropathy is one of the oldest

recognized effects of Pb exposure

Acute nephropathy (reversible) characterized by functional

changes in proximal tubule cells:
amino aciduria, glucosuria,
and ion transport

Also, see Pb inclusion bodies in

nuclei of proximal tubule cells
 Toxic Effects of Pb in Adults

Chronic Pb nephropathy is not reversible

Renal tubules atrophy and insterstitial fibrosis

increases in severity.

Glomerular filtration rate decreases

Increased mortality from chronic interstitial

nephropathy. Occurs at blood concentrations of
> 60 :g/dl
 Toxic Effects of Pb in Adults
Blood pressure effects:

Epi studies indicate positive association between

blood Pb concentrations and systolic blood pressure

Appears to be a 1.5-3.0 mm Hg increase in systolic

pressure for every doubling of blood lead in adult
males. In females, the increase seems to be less than
1-2 mmHg.

Mechanism may be altered sensitivity of vascular

smooth muscle, higher plasma renin activity and/or
alterations in ion pumps involved in contractility of
smooth muscle.
 Toxic Effects of Pb in Adults
Reproductive Effects:

Overt Pb toxicity associated with sterility and neonatal

deaths.
Reduction in sperm counts and motility at blood lead
concentrations of 40 :g/dl

Carcinogenic Effects:

• Classified as a 2B carcinogen by IARC

• In lab rat, Pb causes renal adenocarcinoma

• Studies with humans have been equivocal

Toxicity of Metals:
Hg and As

Organo Metals
 Toxicity of Mercury (Hg)

Chemistry

Inorganic: Elemental Hgo (metallic mercury, quicksilver)

Low vapor pressure, off gases easily
Ionic salts: Hg+1 (mercurous, Hg2Cl2 , calomel)
Hg+2 (mercuric, HgCl2)

Organic: R-Hg
Methylmercury CH3Hg+
Phenylmercury C6H5Hg+
 Toxicity of Hg

Sources of Exposure

Environmental: Natural degasing of earth crust

releases 2,700 to 6,000 tons/yr

Occupational: Chloralkali production

Gold mining
Dental medicine
Paints
Fungicides
Fur processing
Batteries
Felt hat industry
Toxicity of Hg
TK Clarkson
 Toxicity of Hg

Inorganic salts of Hg (Hg+1 and Hg+2)

Absorption in GI tract is low: 7-15%

Tissue distribution is primarily to kidneys. No

preferential accumulation in red blood cells
(RBC=plasma; kidneys>>> CNS)

Excretion occurs mainly through bile bound to GSH

Whole body half-life similar to Hg vapor,
about 40 days
 Toxicity of Hg

Organic mercury (R-Hg)

Absorption 90-95% in GI tract, also readily absorbed

through skin due to high lipid solubility

Tissue distribution is primarily to CNS, fetus, red blood

cells
(RBC>>>>>> plasma [10:1]; CNS>> kidney

Methyl Hg can also cross blood brain barrier by

“molecular mimicry”
Molecular Mimicry
 Toxicity of Hg

Organic Mercury

Biotransformation occurs slowly as methyl Hg

is broken down to Hg+2

Excretion occurs primarily through bile as Hg+2

10% excreted through urine

Whole body half-life is about 65 days

Organic Hg Toxicity
 Exposure to Hg from Dental Amalgams:
Is There Cause for Concern?

Excretion of Hg in urine after administration of chelator

correlates with the number of fillings in the patient

Calculated release of Hg from amalgams suggests this

could account for 30-50% of a person’s daily exposure
to Hg.
Toxicity of Arsenic (As)
 Environmental Forms of As

As has two stable oxidation states: As (III) and As (V)

Environmental As is mainly in the pentavalent form

Trivalent As is present where reducing conditions prevail

such as in deep groundwater
Commonly Used Arsenical Compounds
Occupational Populations at Risk for As Exposure

Smelters (processing of Cu, Au, and Pb ores

Manufacturers of arsenical compounds such as

pesticides and herbicides

Vinters and other agricultural users of arsenic-

containing products
Arsenic Toxicity
 Arsenic Toxicity

Excretion

Excretion of As is mainly via the urine in

methylated and dimethylated forms

Half-life of inorganic arsenic is about 10-30 hr

 Toxicity of Arsenical Compounds

• Arsine (gas) AsH3

Most toxic form. Causes hemolytic anemia

Death occurs from renal failure due to blockage
of tubules by lysed red blood cells
Hemolysis possibly due to inhibition of Na/K pump

• Inorganic Arsenic Compounds (As+3 and As+5)

Acute exposure: fever, anorexia, hepatomegaly,

melanosis, cardiac arrhythmias, cardio-
vascular failure
 Toxicity of Arsenical Compounds

Inorganic Arsenic Compounds (As+3 and As+5)

• Acute Exposure

Enlargement of liver (hemmorachic necrosis and

fatty degeneration)
Peripheral neuropathy (sensory and motor) - axonal
degeneration. Delayed 1 to 2 weeks. Hearing
loss due to effect on auditory nerves. Reversible
if exposure stopped
Hyperpigmentation of skin
Mee’s lines (white lines on fingernails)
 Toxicity of Arsenical Compounds

Inorganic Arsenic Compounds (As+3 and As+5)

• Chronic Exposure
Liver damage (jaundice, cirrhosis, acites)
Can measure increased liver enzymes in blood
Peripheral vascular disease (acrocyanosis)
Seen as gangreen (Blackfoot disease in towns
in Taiwan and Chile with high As in well water
Kidney damage: Effects on capillaries, tubules and
glomeruli
Ischemic heart disease (vascular effects)
Hearing loss (in children living near an As smelter)
Chronic encephalopathy (CNS)
Nasal spetum perforation (miners)
 Toxicity of Arsenical Compounds

Inorganic Arsenic Compounds (As+3 and As+5)

Teratogenicity
Well documented developmental effects of As
in rats
In humans: Smelter workers (complicated by
exposure to other metals).
• Increased number of spontaneous abortions
• Decreased birth weight
• Increased number of offspring with birth defects
 Toxicity of Arsenical Compounds
Inorganic Arsenic Compounds (As+3 and As+5)

Carcinogenicity
Liver: Seen in vinters; users of Fowler’s solution;
people drinking wine contaminated with
As pesticides

Skin: Users of Fowler’s solution and populations

in Taiwan consuming high As in drinking
water. Basal cell or squamous cell carcinoma
in areas not exposed to sun (soles of feet)

Lung: Copper smelters; workers in production of

As pesticides
 Proposed Mechanisms of Action of Arsenicals

Pentavalent As+5

AsO4 is isoteric and isoelectronic with PO4.

Can substitute AsO4 for PO4 in phoshoglyceraldehyde
dehydrogenase and phosphoglucomutase reactions
(glucose-6-arsenate can substitute for glucose-6-phosphate

Uncouples succinate respiration in mitochondria due to formation

of ADP-As which is unstable
Proposed Mechanism of Trivalent As Toxicity
Proposed Mechanism of Trivalent As Carcinogenicity
 Current Controversies Surrounding Arsenic Toxicity

Is arsenic an essential element?

Should the U.S. drinking water standard for As

WHO guideline for As in drinking water is 10 ppb

which corresponds to excess lifetime skin cancer
risk of 6 x 10-4 (based on Taiwan and Chile incidence)

Many city water supplies are naturally high in As

due to As content of bedrock minerals in area.
Can be as high as 1,000 ppb