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Toxicity of Metals

Katherine Squibb, Ph.D.Systemwide Program in Toxicology

March 6th, 2002Applied Toxicology - NURS 678

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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

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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

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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 useProduction or use of Cd containing plastic stabilizers

Production or use of Cd containing pigments

Jewelry manufacturing

• Environmental exposure:Contaminated foodstuffs

Tobacco consumption

Air

Water

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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

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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 salivationEffects: Hemorrhagic gastroenteritis, hepatic and

renal cortical necrosis, cardiomyopthy

Recovery can be rapid and without long term effects

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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


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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 resultof inhalation exposure

- obstructive lung disease (OLD)

- OLD results from chronic bronchitis with progressive

fibrosis of the lower airways, and emphysema

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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

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Role of MT in Mediating Cd-Induced Nephropathy

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Skeletal Effects of Chronic Cd Exposure:

Itai-Itai Disease

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• 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)

Itai-Itai Disease

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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

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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.

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Can we reduce our exposure to Pb to a safe level?

Some think not, especially for children

Recent/Ongoing Routes of Exposure:

• OccupationalPb production and smelting

Brass, Cu or Pb foundries

Pb soldering

Battery manufacturing

Demolition of old structuresBurning, scraping or sanding old paint

Indoor firing ranges

Ceramic glaze mixing

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Recent/Ongoing Routes of Exposure:

• General Population

Paint in houses built before 1978Soil 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 food1940s 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

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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

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Soft tissues - Liver, kidney, brain

Pb in CNS concentrates in gray matter andspecific nuclei

Highest concentration in hippocampus> cerebellum>

cerebral cortex and medulla

Pb crosses the placenta. Cord blood Pb and fetal

tissue concentrations correlate with maternalblood Pb concentrations

Tissue Distribution

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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

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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.

Toxic Effects of Pb in Children

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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

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Pharmacological changes:

1) Pb interference with

transmitter release by

substitution for Ca or Zn

or

2) Direct binding of Pb

to membrane receptors

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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

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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

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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

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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

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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 systolicpressure 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 vascularsmooth muscle, higher plasma renin activity and/or

alterations in ion pumps involved in contractility of

smooth muscle.


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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


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Toxicity of Metals:

Hg and As

Organo Metals

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Toxicity of Mercury (Hg)

Chemistry

Inorganic: Elemental Hgo (metallic mercury, quicksilver)

Low vapor pressure, off gases easilyIonic salts: Hg+1 (mercurous, Hg2Cl2 , calomel)

Hg+2 (mercuric, HgCl2)

Organic: R-Hg

Methylmercury CH3Hg+

Phenylmercury C6H5Hg+

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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

PaintsFungicides

Fur processing

Batteries

Felt hat industry

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Toxicity of Hg

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TK Clarkson

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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

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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”

Toxicity of Hg

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Molecular Mimicry

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Toxicity of Hg

Organic Mercury

Biotransformation occurs slowly as methyl Hgis 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

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Organic Hg Toxicity

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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.

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Toxicity of Arsenic (As)

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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

Environmental Forms of As

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Commonly Used Arsenical Compounds

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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

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Arsenic Toxicity

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Excretion

Excretion of As is mainly via the urine in

methylated and dimethylated forms

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

Arsenic Toxicity

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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

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

• Acute Exposure

Enlargement of liver (hemmorachic necrosis andfatty degeneration)

Peripheral neuropathy (sensory and motor) - axonal

degeneration. Delayed 1 to 2 weeks. Hearing

loss due to effect on auditory nerves. Reversible

if exposure stoppedHyperpigmentation of skin

Mee’s lines (white lines on fingernails)


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• 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)


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Teratogenicity

Well documented developmental effects of As

in ratsIn humans: Smelter workers (complicated by

exposure to other metals).

• Increased number of spontaneous abortions

• Decreased birth weight

• Increased number of offspring with birth defects

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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

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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

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Proposed Mechanism of Trivalent As Toxicity

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Proposed Mechanism of Trivalent As Carcinogenicity

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Is arsenic an essential element?

Should the U.S. drinking water standard for As

WHO guideline for As in drinking water is 10 ppbwhich 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

Current Controversies Surrounding Arsenic Toxicity

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