ARSENIC

Toxicology of Metal

Dhamscen L. Escurel, MD
Zyra Mae F. Villamor, PTRP
OBJECTIVES

• General Objectives
▫ To be able to discuss the
OBJECTIVES

• Specific Objectives – At the end of this session,

the class should be able to:
TOPIC OUTLINE
I. Characteristics
A. Physical Properties
B. Chemical Properties
C. Major Groups
II. Application
A. Agricultural
B. Medicinal
C. Industrial
D. Military
III. Source of Generation
A. Environmental Fate
B. Environmental Levels and Human Exposure
C. Occupational Exposure
TOPIC OUTLINE
IV. Toxicity
A. Kinetics and Metabolism in Humans and
Animals
B. Effects on laboratory Animals and In vitro
systems
C. Effects on Humans
D. Route of Exposure and Target Organs
V. Safety and Control Measures
VI. Treatment
Fig. 1. Overview of Metal Toxicology. Source: Klaasen, C. (2008). Casarett and
Doull’s Toxicology The Basic Science of Poisons, 7th ed. Mc Graw Hill, USA.
CHARACTERISTICS
General
Physical Properties
Element category: Phase: solid
metalloid Density (near RT): 5.727 g·cm−3
Liq density at m.p. 5.22 g·cm−3
Atomic number: 33 Sublimation point
887 K,615 °C,1137 °F
Standard atomic weight
Critical point 1673 K
74.92160(2) g·mol−1
Heat of fusion (grey) 24.44 kJ·mol−1
Heat of vaporization 34.76 kJ·mol−1
Specific heat capacity (25 °C)
24.64 J·mol−1·K−1
PHYSICAL PROPERTIES

Found in the rock,

soil, water, air and
earth’s biosphere

Present in earth
crust with an average
concentration of 1.7
mg/kg.
PHYSICAL PROPERTIES
Byproduct of the
smelting of copper,
lead, cobalt, and
gold ores.

Pureform: gray,
odorless and
tasteless
CHEMICAL PROPERTIES
ARSENIC ALLOTROPES

1. Metallic Gray
• – semi metal
• - Brittle due to weak bonding
between layers
2. Yellow
• -least dense, most volatile,
most toxic
3. Black
• - similar structure to red
phosphorous
MAJOR GROUPS OF ARSENIC
COMPOUND

Organic Compound

Inorganic Compound

Arsine Gas and Substituted Arsines

CHEMICAL PROPERTIES

VALENCE STATES:
• 1. Arsine - -3
• 2. Elemental Arsenic - 0
• 3. Arsonium Metals - +1
• 4. Arsenites - +3
• 5. Arsenates - +5
ORGANIC ARSENIC
Contains Carbon

Found in water, natural gas and shale oil

Not easily metabolized and quickly excreted by the body

Major source: Fish and Seafood

Forms:
• 1. Arsenobetaine
• 2. Arsenosugars
• 3. Arsenolipids
INORGANIC ARSENIC

Combined with other elements aside from Carbon

Acutely toxic

Found in all rocks and many minerals

Metabolized - monomethylarsonic acid & dimethylarsinic acid

Classified as a Carcinogen in the 1980’s

Arsine Gas and Substituted Arsines

Used in organic synthesis and in the

processing of solid state electronic
components

generated inadvertently in industrial

processes when nascent hydrogen is
formed and arsenic is present.
Source: National Toxicology Program (2011). Arsenic Group Review. From
http://ntp.niehs.nih.gov/ntp/ohat/diabetesobesity/Wkshp/ArsenicGroupReviewV3formatted.pdf
Source: National Toxicology Program (2011). Arsenic Group Review. From
http://ntp.niehs.nih.gov/ntp/ohat/diabetesobesity/Wkshp/ArsenicGroupReviewV3formatted.pdf
APPLICATION
USE OF ARSENIC

Agricultural :
• Wood preservative
• Insecticides
• Termination and
poison
• Disease prevention
and growth
stimulation of
animals
USE OF ARSENIC

Medicinal:
• Use as poisons by
Ancient Greeks ,
Romans and
Chinese
• Arsphenamine for
syphilis and
trypanosomiasis
• Arsenic trioxide for
cancer, psoriasis
USE OF ARSENIC
• Industrial:
-lead in car batteries
- dezincification
-semiconductor metal in
integrated circuits

• Military:
- World War I - chemical
weapon which can induce
vesicant and lung irritant
SOURCE OF GENERATION
Environmental Fate

introduced into water

through the dissolution of
rocks, minerals and ores,
from industrial effluents,
including mining wastes, and
via atmospheric deposition.
Environmental Levels & Human Exposure
Air:
• Ambient air :
• Urban > Rural
• higher in industrial areas
• Indoor Air
• not generally found in indoor air,
although low levels of arsenic may be
present from environmental tobacco
smoke in homes with people who smoke
cigarettes.
Environmental Levels & Human Exposure
Water:
• Concentrations higher in
areas with volcanic rock and
sulfide mineral deposits;
anthropogenic sources
(mining and agrochemical
manufacture)

Food:
• varies widely due to fish and
shellfish intake; meat and
poultry
Occupational Exposure
Orchard workers
• a basis for understanding
some of the long-term effects
of occupational exposure to
arsenic.

Copper smelting
industry
• more extensive and have
established definitive links
between arsenic, a by-
product of copper smelting,
and lung cancer via
inhalation
Occupational Exposure

Dermal and neurological

effects were also
increased in some of
these studies

The pathway of exposure

for these workers was
mainly via inhalation of
arsenic dusts but could
also be from arsenic
trioxide vapors
Table 2. Occupational studies of arsenic and diabetes

Source: National Toxicology Program (2011). Arsenic Group Review. From http://ntp.niehs.nih.gov/ntp/ohat/
diabetesobesity/Wkshp/ArsenicGroupReviewV3formatted.pdf
Table 2 continued Occupational studies of arsenic and diabetes

Source: National Toxicology Program (2011). Arsenic Group Review. From http://ntp.niehs.nih.gov/ntp/ohat/
diabetesobesity/Wkshp/ArsenicGroupReviewV3formatted.pdf
TOXICOKINETICS
 KINETICS AND METABOLISM
IN ANIMALS AND HUMANS

Elemental Arsenic
• - poorly absorbed
• -largely eliminated
Organic Arsenic and Arsenic (V)
• - Rapidly and completely eliminated
via the kidneys
 KINETICS AND METABOLISM
IN ANIMALS AND HUMANS
Inorganic Arsenic
• Accumulates in the liver, kidney, bone,
skin and muscle
• Half life in Humans: 2 – 40 days
• Eliminated from the body by the rapid
urinary excretion of unchanged arsenic in
both the trivalent and pentavalent forms
and by sequential methylation to MMA
and DMA in both 3 and 5 valence states
 KINETICS AND METABOLISM
IN ANIMALS AND HUMANS
Inorganic Arsenic
• Humans:
• the capacity to methylate inorganic
arsenic is progressively, but not
completely, saturated when daily intake
exceeds 0.5 mg
• does not appear to cross the blood–brain
barrier
• transplacental transfer of arsenic
 KINETICS AND METABOLISM
IN ANIMALS AND HUMANS

Fig. 2. Klaasen, C. (2008). Casarett and Doull’s Toxicology The Basic Science of Poisons, 7th ed. Mc Graw Hill, USA.
Fig. 3. Urinary arsenic excretion. Source:National Toxicology Program (2011).
Arsenic Group Review. From http://ntp.niehs.nih.gov/ntp/ohat/
diabetesobesity/Wkshp/ArsenicGroupReviewV3formatted.pdf
EFFECTS OF ARSENIC
Fig. 4. Proposed mechanism of action of arsenic and the examples of
biochemical effects that result from this action. Source: Hughes, M (2011).
Arsenic Exposure and Toxicology: A Historical Perspective. Toxicological
Sciences, 123(2), 305–332.
EFFECTS ON LABORATORY ANIMALS
AND IN VITRO TEST SYSTEMS
Long term exposure
• Male Rats and Female
Rabbits :
• ↓ cardiac output
• ↓ stroke volume
• ingesting drinking-
water containing 50
mg of arsenic(III) per
litre for 18 and 10
months
EFFECTS ON LABORATORY ANIMALS
AND IN VITRO TEST SYSTEMS

Reproductive and
Developmental Toxicity:
• Chicks, Golden Hamsters and Mice:
Teratogenicity
• Arsenic is teratogenic when given by parental routes, it
is considerably less potent when given by the oral route.
EFFECTS ON LABORATORY ANIMALS
AND IN VITRO TEST SYSTEMS
Mutagenicity and related end
points:
• Cultured cell types including humans:
• chromosome breakage
• chromosomal aberrations and
• sister chromatid exchange
• * linear, dose-dependent fashion
EFFECTS ON LABORATORY ANIMALS
AND IN VITRO TEST SYSTEMS
• Mutagenicity and related end points:

- Mice : chromosomal damage in bone marrow

test

* The mechanism of arsenic genotoxicity is not clear, although several

mechanisms have been proposed, including reactive oxygen species
and the inhibition of deoxyribonucleicacid (DNA) repair
EFFECTS ON LABORATORY ANIMALS
AND IN VITRO TEST SYSTEMS
Carcinogenecity
• Not found to carcinogenic in traditional
bioassays
• act as promoters: ↑ the incidence of kidney
tumours was observed in male Wistar rats.
• specific genetic characteristics have shown
carcinogenic effects and these may be of value in
studying the potential mechanism by which
arsenic causes cancer.
EFFECTS ON HUMANS
Acute Toxicity:
• abdominal pain
• vomiting
• diarrhea
• muscular pain and
weakness
• flushing of the skin
• numbness and tingling of
the extremities
• muscular cramping
• the appearance of a
papular erythematous
rash
EFFECTS ON HUMANS
Acute Toxicity:
• - After a month:
• burning paraesthesias
of the extremities,
palmoplantar
• hyperkeratosis
• Mee’s lines on
fingernails
• Progressive
deterioration in motor
and sensory responses
EFFECTS ON HUMANS

Chronic Toxicity:
• General Aspects:
• Local effects in the mucous
membranes of the respiratory tract
and the skin.
• Involvement of the nervous and
circulatory system and the liver
• Cancer of the respiratory tract.
EFFECTS ON HUMANS
Chronic Toxicity:
• General Aspect via ingestion of food, drinking
water or medication:
• Vague abdominal symptoms-diarrhea or
constipation
• flushing of the skin, pigmentation and
hyperkeratosis
• vascular involvement, reported in one area to
have given rise to peripheral gangrene
EFFECTS ON HUMANS

Chronic Toxicity:
• Anemia and leukopenia
• Liver involvement particularly in
vineyard workers considered to have
been exposed mainly through drinking
contaminated wine.
• Skin cancer occurs with excess
frequency in this type of poisoning.
EFFECTS ON HUMANS

Chronic Toxicity:Vascular System

• Severe manifestations of peripheral vascular

involvement have not been observed in
occupationally exposed persons, but slight
changes with Raynaud’s phenomenon.
• An increased prevalence of low peripheral
blood pressure on cooling have been found in
workers exposed for a long time to airborne
inorganic arsenic.
EFFECTS ON HUMANS

Chronic Toxicity: Vascular System

• Peripheral Gangrene (Black Foot

Disease)

• “In a large study conducted in Taiwan, China,

There was a clear dose–response relationship
between exposure to arsenic and the frequency of
dermal lesions, “blackfoot disease” (a peripheral
vascular disorder) and skin cancer.” (Lu,1990)
EFFECTS ON HUMANS

Chronic Toxicity: Dermatologic disorders

• In occupational exposure to mainly airborne
arsenic, skin lesions may result from local
irritation.
• Two types of dermatological disorders:
• an eczematous type with erythema, swelling and
papules or vesicles
• a follicular type with erythema and follicular
swelling or follicular pustules.
EFFECTS ON HUMANS

Chronic Toxicity:
• Dermatitis
• face, back of the neck,
forearms, wrists and
hands, the scrotum,
the inner surfaces of
the thighs, the upper
chest and back, the
lower legs and
around the ankles.
EFFECTS ON HUMANS
Chronic Toxicity:
• Dermatologic disorders:
• Melanosis - upper and
lower eyelids, around the
temples, on the neck, on
the areolae of the nipples
and in the folds of the
axillae.
• Arsenomelanosis -
abdomen, chest, back and
scrotum
• Hyperkeratosis
EFFECTS ON HUMANS

Chronic Toxicity:
• - Dermatologic disorders:
• Warts
• Raindrop Pigmentation
- Depigmentation (i.e.,
leukoderma), especially
on the pigmented areas
• may develop into pre-
cancerous and
cancerous lesions
• Mee’ s lines
EFFECTS ON HUMANS

Chronic Toxicity:Respiratory System

• Perforation of the nasal septum

• mucous membrane irritation : nose, larynx,
trachea, bronchi
EFFECTS ON HUMANS

Chronic Toxicity:
Peripheral Nervous System

• motor dysfunction
• paresthesia
• Less severe cases: Sensory Unilateral
Neuropathy
• Lower extremity > Upper Extremity
• Wallerian Degeneration
EFFECTS ON HUMANS
Chronic Toxicity:
• - Carcinogenicity
• -classified by the
International
Agency for
Research on Cancer
(IARC) as lung
and skin
carcinogens.
• - Angiosarcoma of
the liver
• - stomach cancer
EFFECTS ON HUMANS
Chronic Toxicity:Carcinogenicity

• Cancer of the Respiratory Tract

• workers engaged in the production of insecticides
containing lead arsenate and calcium arsenate
• in vine-growers spraying insecticides containing
inorganic copper and arsenic compounds
• in smelter workers exposed to inorganic compounds of
arsenic and a number of other metals.
EFFECTS ON HUMANS
Cancer
“there is overwhelming evidence that
consumption of elevated levels of arsenic
through drinking-water is causally related to the
development of cancer at several sites,
particularly skin, bladder and lung.”

(USNRC, 1999, 2001; ATSDR, 2000; IPCS, 2001).

EFFECTS ON HUMANS
• Cancer
“Long-term exposure to arsenic in drinking-water
is causally related to increased risks of cancer in
the skin, lungs, bladder and kidney, as well as
other skin changes such as hyperkeratosis and
pigmentation changes.”

IPCS (2001)
EFFECTS ON HUMANS
• Cancer

“Inorganic arsenic is classified as a Class A

Carcinogen, or Human Carcinogen, by the U.S.
Environmental Protection Agency when
exposure is ingestion or inhalation.”

(U.S. Environmental Protection Agency 1998)

EFFECTS ON HUMANS
Chronic Toxicity: Teratogenic Effects
• No firm evidence that arsenic compounds
cause malformations under industrial
conditions.
• Some evidence suggests such an effect in
workers in a smelting environment who were
exposed simultaneously also to a number of
other metals as well as other compounds
EFFECTS ON HUMANS
Diabetes Mellitus
“There was an exposure–response relationship
between cumulative arsenic exposure and the
prevalence of diabetes mellitus. A similar
exposure–response pattern was observed in a
study in Bangladesh, where prevalence of
keratosis was used as a surrogate for arsenic
exposure’’
(USNRC, 1999, 2001; IPCS, 2001).
EFFECTS ON HUMANS
• Arsenicosis

“Arsenicosis–or arsenic poison-ing–occurs after

chronic or long term exposure to arsenic
contaminated drinking water. Naturally occurring
arsenic compounds appear in much of the world‘s
water supply in small amounts. Higher
concentrations of arsenic compounds in
groundwater do appear in various countries in-
cluding the USA, Thailand, China, India, Argentina,
Nepal and Bangladesh.”
(World Health Organization 2008)
EFFECTS ON HUMANS
“ The main adverse effects reported to be
associated with long-term ingestion of inorganic
arsenic by humans are cancer, skin lesions,
developmental effects, cardiovascular disease,
neurotoxicity and diabetes.”

- Joint FAO/WHO Expert Committee on Food

Additives (JECFA), 2011
ROUTE OF EXPOSURE & TARGET ORGAN

ROUTE OF
TARGET ORGAN EFFECTS
EXPOSURE

discolorations and
lesions
Skin
Local redness and
irritation
Dermal
nausea, diarrhea
Gastrointestinal
and abdominal
Tract
pain
ROUTE OF EXPOSURE & TARGET ORGAN
ROUTE OF
TARGET ORGAN EFFECTS
EXPOSURE

Irritation of
Respiratory mucous
Inhalation
System membranes and
Lung Cancer

“Exposure of this kind can be occupational, such as refinery workers

and farmers. Exposure of greater than .75 mg/m3 is associated with a
greater risk of lung cancer.”
(World Health Organization, 2001) (ASTDR 2007)
 ROUTE OF EXPOSURE & TARGET ORGAN
ROUTE OF EXPOSURE TARGET ORGAN EFFECTS

discolorations and
lesions
Skin
Local redness and
irritation
nausea, diarrhea and
Ingestion Gastrointestinal Tract
abdominal pain
Decreased RBC’s and
Hematopoeitic System
WBC’s
Fatigue and abnormal
cardiac rhythm
Cardiovascular Blood vessel damage
resulting to bruising
Impaired nerve function
SAFETY AND CONTROL MEASURES
SAFETY AND CONTROL MEASURE

Best means
of
Prevention:
• To keep
exposure below
the accepted
exposure limits
SAFETY AND CONTROL MEASURE
Biological monitoring
of urine samples

Protective clothing and

Boots for workers

Respiratory Protective
Equipment

High standard of
sanitary facilities
SAFETY AND CONTROL MEASURES
Smoking, eating and drinking at the
workplace should not be allowed.

Pre-employment medical
examinations should be carried out.

Periodic medical examinations of all

arsenic-exposed employees should
be performed with special attention
to possible arsenic-related
symptoms.
TREATMENT

Immediate removal of the individual from

the contaminated environment and
prompt medical attention are required.

Impaired renal function: total

replacement blood transfusion associated
with artificial dialysis; forced diuresis
TREATMENT
Treatment with 2,3-dimercapto-1-propanol
or British anti-lewisite (BAL, dimercaprol) -
to obtain maximal benefit such treatment
should be given within 4 hours of poisoning.

Minimizing absorption from the

gastrointestinal tract by gastric lavage and
administration by gastric tube of chelating
agents or charcoal.
TREATMENT

maintenance of respiration and circulation

maintenance of water and electrolyte balance

control of nervous system effects

elimination of absorbed poison through

haemodialysis and exchange transfusion
References
• Aitio, A. et al (2001). Environmental Health Criteria 224 Arsenic
and Arsenic Compounds, 2nd ed. World Health Organization,
Geneva, Switzerland.
• Fowler, B. et al (2007). Handbook on the Toxicology of Metals, 3rd
ed. Elsevier, USA.
• Hughes, M (2011). Arsenic Exposure and Toxicology: A Historical
Perspective. Toxicological Sciences, 123(2), 305–332.
• Klaasen, C. (2008). Casarett and Doull’s Toxicology The Basic
Science of Poisons, 7th ed. Mc Graw Hill, USA.
• Nordberg, G (1998). Arsenic. International Labor Organization
Encyclopedia of Occupational Health and Safety. Geneva,
Switzerland. From
http://www.ilo.org/safework_bookshelf/english?d&nd=170000102
&nh=0
• National Toxicology Program (2011). Arsenic Group Review. From
http://ntp.niehs.nih.gov/ntp/ohat/diabetesobesity/Wkshp/Arsenic
GroupReviewV3formatted.pdf