Tox agent-12

11
Toxicological -Agents
By: Prof. Helen C. Santos
JFSM-UPHSD

22
Common Toxicological Agents:
- Drugs
- Toxic household products
- Environmental and occupational solvents
● Heavy metals
● Air pollutants
● Solvents
● Insecticides
● Microorganisms

33
Drugs;
● Acetaminophen
- commonly involve in:
▪ suicide attempts as sole agent or in
▪ accidental poisoning combination with
other drugs
- ingestion of > 150 – 200 mg/kg => children
>7=g total => adults
i.e. highly toxic metabolite=> produced in
the liver
S x S: initially=> asymptomatic or GIT upset
=> nausea and vomiting
after 24-36hrs. s x s=> evidence of
liver injury appears, i.e

44
5 Major Air Pollutants:
- CO = 52% NO = 14%
- SO = 14%
- Hydrocarbons = 14%
- Particulate matter = 4%
Sources:
- Transportation - space heating
- Industry - refuse disposal
- Generation of electric power

55
CARBON MONOXIDE:
> Colorless, tasteless, odorless, and non-
irritating gas
> by-product of incomplete combustion
> ave. conc. in atmosphere = 0.1 ppm
heavy traffic >100.0 ppm
> TLV-TWA = 25.0 ppm
TLV-TWA = conc. for a normal 8hr.workday or 40
workweek to w/c workers may be repeatedly
exposed w/o adverse effects

66
Mechanism of action how CO exert its toxic
effect: CO + Hb COHb
CO has 220x affinity to Hb compare to O2
therefore:
* O2 cannot be transported to the whole part
of the body
* COHb interferes w/ the dissociation of O2
from the remaining OHb  reducing the
the transfer of O2 to tissues
* CO has also a direct damaging effect on the
body cells
- Brain and heart are the most sensitive
organs on CO effects

77
- Normal nonsmoking adults COHb level <1%
saturation (1% of total Hb is in the form of
COHb)
- 1% saturation=> endogenous formation of
CO from heme catabolism
- Smokers = 5-10% saturation (depending on
their smoking habits)
- Individual breathing 0.1% CO (1000ppm)
≈ COHb level of about 50%

88
Clinical Effects of CO Exposure:
* Principal S x S:
- Hypoxia w/c progress into:
> psychomotor impairment
> headache and tightness in the
temporal area
> confusion and loss of visual acuity
> tachycardia, tachypnia, syncope
> deep coma, convulsions, shock and
respiratory failure

99
* Other s x s of CO poisoning:
- Delayed neuropsychiatric impairment
- Slow resolution of behavioral consequences

1010
* Variability of individual responses to
different COHb levels:
- <15% -rarely produce symptom
- around 40% collapse and syncope
- >60% - death may ensue
* Aggravating Factors for CO Clinical Effects:
- Heavy labor
- High altitudes
- High ambient temperature

1111
- presence of cardiovascular diseases –
increase risk w/ CO exposure
- pregnancy-fetus=>susceptible to CO effects
- smoking – CO poisoning= chronic among
cigarette smokers
e.g. of effect: atherosclerotic coronary
disease

1212
Treatment of Carbon Monoxide Poisoning:
* Acute intoxication-
> Removal of the individual from the
exposure source
> Maintenance of respiration
i.e. aim. Of O2–specific antagonist to CO
ö Elimination of Halftime of CO:
-- room air at 1 atm. =320 mins.
-- w/ 100% O2 = 80 mins.
-- w/ hyperbaric O2 at 2-3 atm.=20mins.

1313
SULFUR DIOXIDE
- Colorless
- Irritant gas
- TLV-TWA = 2ppm; TLV-STEL= 5 ppm
* TLV-STEL = Threshold Limit Value-Short
Term Exposure Limit
= max. conc. that should not be
exceeded at anytime during a 15 min.
exposure period
- Commonly Affected:
> elderly
> w/ preexisting cardiac or respiratory
disease

1414
• Mechanism of Action How SO2 Exerts its
Effect:
- On contact with moist membranes, SO2
forms sulfurous acid w/c is responsible for
its severe irritant effects on the eyes,
mucous membranes and skin
• Absorption of SO2:
- Absorbed thru the upper respiratory tract
- 90% of the inhaled is absorbed

1515
Clinical Effects of SO2 Poisoning:
* irritation of the eyes, nose and throat
* reflex bronchoconstriction
* delayed onset of pulmonary edema –
severe exposure
* chronic exposure= associated w/
aggravation of chronic
cardiopulmonary disease

1616
Treatment for SO2 Poisoning:
- no specific treatment
- depends on therapeutic maneuvers
used in respiratory tract irritation

1717
NITROGEN OXIDES
* NO2 – brownish irritant gas associated w/
fires
- formed from fresh silage
- common exposures of farmers
- can lead to silo-filler’s disease
- TLV-TWA = 3ppm; TLV-STEL =5ppm
-> Mech. Of Action: NO2 is a deep lung
irritant producing pulmonary edema

1818
Effects on Exposure to NO2:
> 25ppm – irritating to some individuals
> 50ppm – moderately irritating to the eyes
and nose
> 1hr to 50ppm – pulmonary edema and
perhaps subacute or chronic pulmonary
lesions
> 100ppm – pulmonary edema to death
> On acute exposure type I cells are affected

1919
Clinical Effects of NO2 Exposure:
ö Acute
- Irritation of eyes and nose
- Cough
- Mucoid or frothy sputum
- Dyspnea and chest pain
- Pulmonary edema w/in 1-2hrs.
- s x s may subside in about 2 wks.

2020
-- Drug Therapy for NO2 Intoxication:
Bronchodilators
Sedatives
Antibiotics

2121
OZONE
O3 – bluish irritant gas
- normally occurs in the atmosphere
- it is an important absorbent of UV light
- source in a workplace:
* High-voltage electrical equipment
* Ozone-producing devices use for air and
water purification
* urban-polluted air
* TLV-TWA = 0.05; TLV-STEL = NA

2222
Clinical Effects of Ozone:
* Mild exposure=upper respiratory tract
irritation
* Severe exposure = deep lung irritation w/
pulmonary edema
* S X S :
- formation of reactive free radicals
- gas causes: shallow rapid breathing
: decrease in pulmonary compliance
- enhanced sensitivity of the lungs to
bronchoconstrictors

2323
- exposure to 0.1ppm for 10-30 mins.=>
irritation and dryness of the throat
- >0.1ppm. = changes in visual acuity
- substernal pain
- dyspnea
- >0.8ppm= pulmonary function is impaired
- human = airway hyper responsiveness
= airway inflammation

2424
Clinical Treatment of Ozone Toxicity:
- no specific treatment for acute O3
intoxication
- Management depends on therapeutic
measures utilized for:
* deep lung irritation
* noncardiogenic pulmonary edema

2626
LeadLead
• Possible sources of exposuresPossible sources of exposures::
> Commercial application of lead-> Commercial application of lead-
- production and storage of batteries- production and storage of batteries
- metal alloys- metal alloys
- solder- solder
- glass- glass
- ceramics- ceramics
> Exposure to air, water, and food – due> Exposure to air, water, and food – due
to contamination of gasolineto contamination of gasoline
> Workplace> Workplace

2727
• Concern over the effects of low-level leadConcern over the effects of low-level lead
exposure:exposure:
> neurocognitive function> neurocognitive function
> blood pressure at blood lead concentration> blood pressure at blood lead concentration
once considered ”normal” or “safe”once considered ”normal” or “safe”
-> lead serves no useful purpose in the-> lead serves no useful purpose in the
human bodyhuman body
-> in key target organs e.g. the developing-> in key target organs e.g. the developing
CNSCNS no safe threshold of leadno safe threshold of lead
exposureexposure

2828
PharmacokineticsPharmacokinetics of Leadof Lead
AbsorptionAbsorption
Factors that affect absorption:Factors that affect absorption:
 Form of leadForm of lead
• Inorganic lead – absorbed through the :Inorganic lead – absorbed through the :
▪▪ respiratory tractrespiratory tract
▪▪ GITGIT
▪▪ skin = absorbed poorlyskin = absorbed poorly
• Organic lead– well absorbed through the skinOrganic lead– well absorbed through the skin
- lead dust =>absorbed through the respiratory tract- lead dust =>absorbed through the respiratory tract
=> most common cause of industrial=> most common cause of industrial
poisoningpoisoning
- leaded antiknock gasoline => well absorbed- leaded antiknock gasoline => well absorbed
through the skinthrough the skin

2929
AbsorptionAbsorption
Route of entryRoute of entry
-> intestinal tract - 1-> intestinal tract - 1oo
route of entry inroute of entry in
nonindustrial lead exposurenonindustrial lead exposure
-> GIT - absorption depends upon the nature-> GIT - absorption depends upon the nature
of lead compoundof lead compound
- generally: adults absorb = 10-15%- generally: adults absorb = 10-15%
of the ingested amountof the ingested amount
young = up to 50% of ingestedyoung = up to 50% of ingested
 low dietary calcium associated withlow dietary calcium associated with
 iron deficiency increased leadiron deficiency increased lead
 ingestion on an empty stomach absorptioningestion on an empty stomach absorption

3030
Distribution of LeadDistribution of Lead
• Absorbed lead- from respiratory tract and GITAbsorbed lead- from respiratory tract and GIT
bind to erythrocytesbind to erythrocytes
bone brain kidney liver muscle gonadsbone brain kidney liver muscle gonads
marrowmarrow
subperiosteal surface of bonesubperiosteal surface of bone
bone matrixbone matrix
- crosses the placenta- crosses the placenta poses a potentialposes a potential
hhazard to the fetusazard to the fetus

3131
Elimination of LeadElimination of Lead
• Lead clearance = multicompartment modelLead clearance = multicompartment model
composed of:composed of:
-> blood-> blood
-> soft tissues – half-life = 1-2 mos.-> soft tissues – half-life = 1-2 mos.
-> skeleton – half-life = years-decades-> skeleton – half-life = years-decades
• Eliminated lead ~70%Eliminated lead ~70%  urineurine
- lesser amount excreted through:- lesser amount excreted through:
* bile * nails* bile * nails
* skin * sweat* skin * sweat
* hair * breast milk* hair * breast milk

3232
Elimination of leadElimination of lead
- fraction not undergoing prompt excretion- fraction not undergoing prompt excretion
~ half of the absorbed lead~ half of the absorbed lead incorporatedincorporated
into the skeletoninto the skeleton  repository of morerepository of more
than 90% of the body lead burden inthan 90% of the body lead burden in
most adultsmost adults
* patients = high body lead burdens:* patients = high body lead burdens:
-> slow release from the skeleton-> slow release from the skeleton 
elevate blood lead concentrationselevate blood lead concentrations
for yrs. => after exposure ceasesfor yrs. => after exposure ceases

3333
Elimination of leadElimination of lead
-> pathologic high bone turnover states-> pathologic high bone turnover states
e.g. hyperthyroidisme.g. hyperthyroidism
or prolonged immobilizationor prolonged immobilization frank leadfrank lead
intoxicationintoxication
* quantitation of lead burden in bone* quantitation of lead burden in bone
-> noninvasive x-ray fluorescence = best-> noninvasive x-ray fluorescence = best
measure of long-term cumulative leadmeasure of long-term cumulative lead
absorptionabsorption

3434
Toxicology of LeadToxicology of Lead
•• Form entering the bodyForm entering the body
-> inorganic = lead oxides-> inorganic = lead oxides
lead saltslead salts
-> organic = tetraethyl lead-> organic = tetraethyl lead
•• Major route of absorptionMajor route of absorption
-> inorganic = GIT-> inorganic = GIT
respiratoryrespiratory
-> organic = skin-> organic = skin
GITGIT
respiratoryrespiratory

3535
•• DistributionDistribution
-> inorganic = soft tissues-> inorganic = soft tissues skeleton i.e.skeleton i.e.
>90% of adult body burden>90% of adult body burden
-> organic = soft tissues – especially: liver-> organic = soft tissues – especially: liver
: CNS: CNS
* Major clinical effects of lead intoxication:* Major clinical effects of lead intoxication:
-> inorganic-> inorganic
▪▪ CNS deficits ▪ hypertensionCNS deficits ▪ hypertension
▪▪ peripheral neuropathy ▪ reproductiveperipheral neuropathy ▪ reproductive
▪▪ anemia toxicityanemia toxicity
▪▪nephropathynephropathy

3636
* Major clinical effects* Major clinical effects
-> organic = encephalopathy-> organic = encephalopathy
* Mechanism of action* Mechanism of action
-> inorganic = inhibits enzymes-> inorganic = inhibits enzymes
= interferes w/ essential cations= interferes w/ essential cations
such as: calcium, iron & zincsuch as: calcium, iron & zinc
= disturbs cellular redox status= disturbs cellular redox status
= alters membrane structures &receptors= alters membrane structures &receptors
-> organic = hepatic dealkylation (fast)-> organic = hepatic dealkylation (fast)
trialkymetabolitestrialkymetabolites
(slow)(slow)  dissociation to leaddissociation to lead

3737
* Metabolism and elimination* Metabolism and elimination
-> inorganic = renal => major-> inorganic = renal => major
= feces minor= feces minor
breast milkbreast milk
-> organic = urine major-> organic = urine major
fecesfeces
= sweat => minor= sweat => minor

3838
Effect of lead on the different body organ systemEffect of lead on the different body organ system
• Nervous systemNervous system
-> most sensitive target organ for lead’s toxic-> most sensitive target organ for lead’s toxic
effect = developing nervous system:effect = developing nervous system:
* fetus* fetus
* young child* young child
-> young children-> young children
- blood lead concentrations<5mcg/dlblood lead concentrations<5mcg/dl
 subclinical deficits in neurocognitive fxnsubclinical deficits in neurocognitive fxn
* no demonstrable threshold for a* no demonstrable threshold for a
““ no effect” levelno effect” level
 hearing acuity may diminishedhearing acuity may diminished

3939
Effects of lead on body organs system – CNSEffects of lead on body organs system – CNS
-> adults-> adults
- less sensitive to CNS lead effects- less sensitive to CNS lead effects
- blood lead concentration >30mcg/dlblood lead concentration >30mcg/dl
* behavioral* behavioral
* neurocognitive effects* neurocognitive effects
 sign & symptoms:sign & symptoms:
.. irritability .. fatigue.. irritability .. fatigue
.. sleep disturbance .. anorexia.. sleep disturbance .. anorexia
.. decreased libido.. decreased libido
.. impaired visual-motor coordination.. impaired visual-motor coordination
.. slowed reaction time.. slowed reaction time

4040
Effects of lead on body organ system- CNSEffects of lead on body organ system- CNS
 other frequent complaints:other frequent complaints:
.. headache .. myalgias.. headache .. myalgias
.. arthralgias.. arthralgias
 tremors = less commontremors = less common
- blood lead concentrations >100mcg/dlblood lead concentrations >100mcg/dl
 lead encephalopathylead encephalopathy
 increased intracraneal pressureincreased intracraneal pressure
=> ataxia => convulsions=> ataxia => convulsions
=> stupor => death=> stupor => death
=> coma=> coma

4141
Effect of lead on body organ system - CNSEffect of lead on body organ system - CNS
- accentuate an age-related decline in cognitive- accentuate an age-related decline in cognitive
function in older adultsfunction in older adults
- chronic high-dose exposure = following- chronic high-dose exposure = following
mos.-yrs. of blood lead concs. >100mcg/dlmos.-yrs. of blood lead concs. >100mcg/dl
 peripheral neuropathy => clinicallyperipheral neuropathy => clinically
.. painless weakness of the extensors.. painless weakness of the extensors
particularly in the upper extremityparticularly in the upper extremity
--> wrist-drop--> wrist-drop
.. detectable by electrodiagnostic testing.. detectable by electrodiagnostic testing

4242
Lead effects on body organ systemLead effects on body organ system
• Blood - anemiaBlood - anemia
-> lead interferes w/ heme synthesis by:-> lead interferes w/ heme synthesis by:
* blocking the incorporation of iron into* blocking the incorporation of iron into
protoporphyrin IXprotoporphyrin IX
* inhibiting the function of enzymes in the* inhibiting the function of enzymes in the
heme synthesis pathway includingheme synthesis pathway including
.. aminolevulinic acid dehydratase.. aminolevulinic acid dehydratase
.. ferrochelatase.. ferrochelatase
 elevation of blood lead concentrationelevation of blood lead concentration
=> 2 – 8 wks.=> 2 – 8 wks. >> 30 – 50mcg/dl30 – 50mcg/dl 

4343
Lead effect on body organ system - BloodLead effect on body organ system - Blood
 increased of heme precursors detectableincreased of heme precursors detectable
in the whole blood:in the whole blood:
.. free erythrocyte protoporphyrin.. free erythrocyte protoporphyrin
.. zinc chelate – zinc protoporphyrin.. zinc chelate – zinc protoporphyrin
-> increases erythrocyte fragility-> increases erythrocyte fragility  decreaseddecreased
red cell survival time => anemiared cell survival time => anemia
- frank hemolysis- frank hemolysis
-> occur w/ high exposure-> occur w/ high exposure
-> presence of basophilic stippling on-> presence of basophilic stippling on
peripheral blood smear = consequenceperipheral blood smear = consequence

4444
of lead inhibition of the enzyme 3’5’-of lead inhibition of the enzyme 3’5’-
pyrimidine nucleotidasepyrimidine nucleotidase  diagnostic cluediagnostic clue
for lead intoxicationfor lead intoxication
• KidneyKidney
- renal interstitial fibrosis- renal interstitial fibrosis
- nephrosclerosis- nephrosclerosis
 chronic high-dose of lead exposure =>chronic high-dose of lead exposure =>
mos. – yrs. of blood lead conc.mos. – yrs. of blood lead conc.
>> 80mcg/dl80mcg/dl
- lead nephropathy- lead nephropathy  latency period of yrs.latency period of yrs.

4545
- altered uric acid excretion by the kidney- altered uric acid excretion by the kidney 
recurrent bouts of gouty arthritisrecurrent bouts of gouty arthritis
=>“saturnine gout”=>“saturnine gout”
- transient azotemia- transient azotemia  acute high-dose leadacute high-dose lead
exposureexposure  intrarenal vasoconstrictionintrarenal vasoconstriction
• Reproductive organsReproductive organs
- high-dose lead exposure = recognized risk- high-dose lead exposure = recognized risk
factor for:factor for:
* stillbirth* stillbirth
* spontaneous abortion* spontaneous abortion

4646
- impact of low-level lead exposure on the- impact of low-level lead exposure on the
reproductive organ:reproductive organ:
-> female-> female
* low birth weight* low birth weight
* preterm delivery* preterm delivery
* spontaneous abortion – detected odds ratio* spontaneous abortion – detected odds ratio
= 1.8 : 5mcg/dl increase in maternal= 1.8 : 5mcg/dl increase in maternal
blood lead across ~ range 5-20mcg/dlblood lead across ~ range 5-20mcg/dl
-> male- blood lead conc. > 40mcg/dl-> male- blood lead conc. > 40mcg/dl 
diminished or aberrant spermdiminished or aberrant sperm
productionproduction

4747
Effect of lead on body organ systemEffect of lead on body organ system
• GITGIT
- moderate lead poisoning- moderate lead poisoning 
* loss of appetite* loss of appetite
* constipation* constipation
* diarrhea – less commonly* diarrhea – less commonly
- high dosage- high dosage  intermittent bouts of severeintermittent bouts of severe
colicky abdominal pain => lead coliccolicky abdominal pain => lead colic
 spasmodic contraction of the smoothspasmodic contraction of the smooth
muscle of the intestinal wallmuscle of the intestinal wall

4848
-- heavily exposed individuals to lead w/ poorheavily exposed individuals to lead w/ poor
dental hygienedental hygiene
circulating lead + sulfur (released by microbes)circulating lead + sulfur (released by microbes)
dark deposits of PbSdark deposits of PbS
 ““gingival lead lines” i.e. at the gingivalgingival lead lines” i.e. at the gingival
marginmargin
• Cardiovascular systemCardiovascular system
- relatively low-level of lead exposure by the- relatively low-level of lead exposure by the
general publicgeneral public  independent risk factorindependent risk factor
for HPNfor HPN
- lead increases BP in animals- lead increases BP in animals interaction w/interaction w/
calcium mediated contraction of vascular smoothcalcium mediated contraction of vascular smooth
musclemuscle

4949
Major forms of lead intoxicationMajor forms of lead intoxication
• Inorganic lead poisoningInorganic lead poisoning
-> acute – industrial inhalation of large-> acute – industrial inhalation of large
quantities of lead oxide fumesquantities of lead oxide fumes
- ingestion by small children of- ingestion by small children of
large dose of lead in:large dose of lead in:
.. lead based paints.. lead based paints
.. contaminated food or drink.. contaminated food or drink
- S x S: severe- S x S: severe  occur afteroccur after
several days or weeks ofseveral days or weeks of
recurrent exposurerecurrent exposure

5050
Forms of lead intoxicationForms of lead intoxication
- S x S of acute inorganic intoxication:- S x S of acute inorganic intoxication:
* encephalopathy* encephalopathy
* colic* colic
* hemolytic anemia or anemia w/* hemolytic anemia or anemia w/
basophilic stippling if exposure isbasophilic stippling if exposure is
subacutesubacute
* elevated aminotransferases* elevated aminotransferases
- dx = difficult- dx = difficult
= mistaken for: appendicitis, peptic ulcer,= mistaken for: appendicitis, peptic ulcer,
pancreatitis or infectious meningitispancreatitis or infectious meningitis

5151
= subacute cases S x S:= subacute cases S x S:
* headache* headache
* fatigue* fatigue
* intermittent abdominal cramps* intermittent abdominal cramps
* myalgias* myalgias
* arthralgias* arthralgias
 mistaken for a flu-like viral illnessmistaken for a flu-like viral illness  maymay
not come to medical attentionnot come to medical attention
= radiopacities= radiopacities  visible on abdominalvisible on abdominal
radiographs upon ingestion of: paintradiographs upon ingestion of: paint
chips, glazes or weightschips, glazes or weights

5252
Forms of lead intoxicationForms of lead intoxication
-> chronic inorganic lead poisoning-> chronic inorganic lead poisoning
- multisystemic findings:- multisystemic findings:
* constitutional complaints* constitutional complaints
.. anorexia.. anorexia
.. fatigue.. fatigue
.. malaise.. malaise
* neurologic complaints* neurologic complaints
.. headache.. headache
.. difficulty in concentrating.. difficulty in concentrating
.. irritability.. irritability
.. depressed mood.. depressed mood

5353
* weakness* weakness
arthralgiasarthralgias
miyalgiasmiyalgias
* GIT symptoms* GIT symptoms
 lead poisoning => strongly suspectedlead poisoning => strongly suspected
* headache * anemia* headache * anemia
* abdominal pain* abdominal pain
=> less commonly w/=> less commonly w/
* motor neuropathy * gout* motor neuropathy * gout
* renal insufficiency* renal insufficiency

5454
=> chronic lead intoxication = considered in=> chronic lead intoxication = considered in
child w/:child w/:
* neurocognitive deficits* neurocognitive deficits
* growth retardation* growth retardation
* developmental delay* developmental delay
 dx = best confirmed by lead concentrationdx = best confirmed by lead concentration
determination from whole blooddetermination from whole blood
.. test reflects lead currently circulating.. test reflects lead currently circulating
in blood and soft tissuesin blood and soft tissues
.. not a reliable marker of either recent.. not a reliable marker of either recent
or cumulative lead exposureor cumulative lead exposure

5555
= concentration of lead in bone= concentration of lead in bone  noninvasivenoninvasive
K x-ray fluorescence measurement of leadK x-ray fluorescence measurement of lead
in bone:in bone:
* correlated w/ long-term cumulative lead* correlated w/ long-term cumulative lead
exposureexposure
* its relationship to numerous lead-related* its relationship to numerous lead-related
disordersdisorders
= measurement of lead excretion in the urine= measurement of lead excretion in the urine
following a single dose of a chelating agentfollowing a single dose of a chelating agent
=> “chelation challenge test”=> “chelation challenge test”
1100
reflects the lead content of soft tissuesreflects the lead content of soft tissues

5656
* may not be a reliable marker of:* may not be a reliable marker of:
.. long-term lead exposure.. long-term lead exposure
.. remote past exposure.. remote past exposure
.. skeletal lead burden.. skeletal lead burden

5757
Forms of lead poisoningForms of lead poisoning
• Organolead poisoning – now very rareOrganolead poisoning – now very rare 
tetraethyl and tetramethyl lead = phased-outtetraethyl and tetramethyl lead = phased-out
- lead stearate or lead naphthenate- lead stearate or lead naphthenatestill usedstill used
- organolead = well absorbed through:- organolead = well absorbed through:
* respiratory tract* respiratory tract
* skin* skin
 volatilityvolatility
 lipid solubilitylipid solubility

5858
- organolead = main target => CNS- organolead = main target => CNS 
produces dose-dependent effects such as:produces dose-dependent effects such as:
* neurocognitive deficits* neurocognitive deficits
* insomnia* insomnia
* delirium* delirium
* hallucination* hallucination
* tremor* tremor
* convulsion* convulsion
* death* death

5959
Treatment for lead poisoningTreatment for lead poisoning
• Inorganic lead poisoningInorganic lead poisoning
- termination of exposure- termination of exposure
- supportive care- supportive care
- judicious use of chelation therapy- judicious use of chelation therapy
-> lead encephalopathy-> lead encephalopathy  medicalmedical
emergency=>intensive supportive careemergency=>intensive supportive care
 some clinicians advocate:some clinicians advocate:
* initiated w/ I.M.dimercaprol* initiated w/ I.M.dimercaprol
* followed in 4 hrs.=> by concurrent* followed in 4 hrs.=> by concurrent
adm. of dimercaprol and EDTAadm. of dimercaprol and EDTA

6060
Treatment for lead poisoning - inorganicTreatment for lead poisoning - inorganic
* parenteral chelation=> limited* parenteral chelation=> limited << 5days5days
 oral chelator succimer => institutedoral chelator succimer => instituted
-> cerebral edema-> cerebral edema  corticosteroids andcorticosteroids and
mannitolmannitol
-> seizures-> seizures  anticonvulsantanticonvulsant
-> radiopacities on abdominal radiographs-> radiopacities on abdominal radiographs 
presence of retained lead objectspresence of retained lead objects  GITGIT
decontaminationdecontamination
 adequate urine flow=> maintainedadequate urine flow=> maintained
overhydration => avoidedoverhydration => avoided

6161
Treatment of lead poisoning - inorganicTreatment of lead poisoning - inorganic
 edetate calcium disodium(CaNa2EDTA)edetate calcium disodium(CaNa2EDTA)
=> I.V. administered; 1000 1500mg/m=> I.V. administered; 1000 1500mg/m22
/d/d
~ 30-50mg/kg/d by continuous~ 30-50mg/kg/d by continuous
infusion for 5daysinfusion for 5days
-> symptomatic lead intoxication w/o-> symptomatic lead intoxication w/o
encephalopathyencephalopathy initiated w/ succimerinitiated w/ succimer
 end point of chelation:end point of chelation:
= resolution of symptoms= resolution of symptoms
= return of lead concentration to pre-= return of lead concentration to pre-
morbid rangemorbid range

6262
Treatment of lead poisoning-inorganicTreatment of lead poisoning-inorganic
-> patients w/ chronic exposure-> patients w/ chronic exposure  cessationcessation
of chelationof chelation upward rebound in bloodupward rebound in blood
lead concentration => lead reequilibrateslead concentration => lead reequilibrates
from bone lead storesfrom bone lead stores
-> for all children w/ blood lead concentration-> for all children w/ blood lead concentration
>> 45mcg/dl45mcg/dl  chelation is recommendedchelation is recommended
-> clinical trial of succimer in children w/-> clinical trial of succimer in children w/
blood lead conc. between 25 & 44mcg/dlblood lead conc. between 25 & 44mcg/dl
 no benefit on neurocognitive fxn orno benefit on neurocognitive fxn or
long-term blood lead reductionlong-term blood lead reduction

6363
Treatment of lead poisoning
• Inorganic
-> prophylactic use of chelating agents in the
workplace = never a substitute for:
* reduction of excessive
* prevention exposure
• Organic
-> initial treatment = decontaminating the skin
= prevent further exposure
-> seizures = appropriate anticonvulsants
-> high blood lead conc. present = chelation

6464
Arsenic
- naturally occurring earth element
-> ground water = contains high arsenic level
 leached from natural mineral deposits
- use as:
* constituent of commercial and industrial
products
.. use in the manufacture of semiconductors
-> arsine gas = manufactured for use in
semiconductor industry

6565
= generated accidentally when
arsenic-containing ores come in
contact w/ acidic solutions
 w/ potent hemolytic effect
.. wood preservatives for industrial
applications e.g. marine timbers, utility poles
.. nonferrous alloys
.. glass
.. gel-based insecticidal ant baits
.. veterinary pharmaceuticals

6666
* component pharmaceuticals for man
..Fowler’s solution – contains 1% potassium
arsenite = widely use medicine in 18th-
20th century
.. Organic arsenicals = 1st pharmaceutical
antibiotics  replaced by penicillin and
other effective and less toxic agents
.. Lewisite (dichloro [2-chlorovinyl]arsine) =
organoarsenicals developed as chemical
warfare agents

6767
.. Arsenic trioxide = reintroduced in US
pharmacopoeia in 2000 orphan drug
for the tx of:
--> relapsed acute promyelocytic
leukemia
--> use in experimental cancer tx
protocols
.. Melarsoprol = trivalent arsenical  tx
advance African trypanosomiasis
* agent of deliberate poisoning

6868
Pharmacokinetics of arsenic
- soluble arsenic compounds = well absorbed
* respiratory
* GIT
* percutaneous  limited  clinically
significant after heavy exposure to
concentrated arsenic reagents
arsonic acid and dimethylarsenic acid
excreted along with the residual arsenic
in the urine

6969
Pharmacokinetics of arsenic
- chronic daily absorption : < 1000mcg of
soluble inorganic arsenic  ~ 2/3 of
absorbed dose => urine
- after massive ingestion elimination half-life
=> prolonged
- inhalation of arsenic compounds of low
solubility  prolonged retention in the lung
 may not be reflected by urinary arsenic
excretion

7070
keratinized tissues
after exposure nails
skin
contain elevated level of arsenic
(indistinguishable from that absorbed internally)
 urine level = normal

7171
Pharmacodynamics of arsenic
- inorganic trivalent arsenic = As3+
; arsenite
 2-10x more acutely toxic than inorganic
pentavalent arsenic = As5+
; arsenate
- recent studies trivalent form of methylated
metabolite e.g. monomethylarsonous acid
(MMAIII
)>toxic than the inorganic parent cpd.
- action how arsenic exerts its toxic effect :
• interference with enzymatic function =>
As3+
+ sulfhydryl group or substitution
for PO4
3-

7272
• inorganic arsenic or its metabolites may
-> induce oxidative stress
-> alter gene expression
-> interfere w/ cell signal transduction
• arsine gas  oxidized in vivo
 exerts a potent hemolytic effect
= associated w/ alteration of ion flux
across the erythrocyte membrane
= disruption of cellular respiration in
other tissues

7373
Pharmacodynamics of arsenic
- arsenic => recognized human carcinogen
=> associated w/ cancer:
.. lung .. bladder
.. skin
- marine organisms=>contain large amounts of
.. trimethylated organoarsenic
.. arsenobetain- no known toxic effect in
mammals excreted in urine unchanged
.. variety of arsenosugars partially
metabolized to dimethylarsenic acid

7474
Major forms of arsenic intoxication
• Acute inorganic arsenic poisoning
-> exposure to high doses = tens -100 of mgs.
of soluble inorganic compounds
 GIT S x S w/c include:
.. nausea .. diarrhea
.. vomiting .. abdominal pain
 diffuse capillary leak + GIT fluid loss
hypotension - shock - death

7575
 cardiopulmonary toxicity => includes:
.. congestive cardiomyopathy
.. cardiogenic & noncardiogenic
pulmonary edema
.. ventricular arrhythmias – occur promptly
or after a delay of several days
 pancytopenia – usually develops w/in a
wk.
 basophilic stippling of erythrocytes – may
be present soon after

7676
 CNS effects:
* delirium occur w/in first
* encephalopathy few days of
* coma intoxication
* ascending sensorimotor peripheral
neuropathy – develop after a delay of
2-6wks.
- ultimately involve the proximal
musculature ---> neuromuscular
respiratory failure

7777
* transverse white striae = Aldrich-Mees
lines  visible in the nails, months after
an episode of acute poisoning
-> Dx and tx of acute inorganic arsenic
poisoning:
- Dx : individuals presenting
initially => abrupt onset of gastroenteritis
+ hypotension + metabolic acidosis
* followed by=> cardiac dysfunction,
pancytopenia and peripheral neuropathy

7878
* confirmation of dx  determination of
inorganic arsenic level and its
metabolites in the urine
 range = several thousand µ in the first
2-3 days following acute
symptomatic poisoning
 blood – not used for dx purposes
=> arsenic disappears rapidly from
the blood except in anuric patients

7979
- tx  based on:
* appropriate gut decontamination
* intensive supportive care
* prompt chelation w/:
.. unithiol 3-5 mg/kg I.V. every 4-6hrs.
.. or dimercaprol, 3-5 mg/kg, I.M.
every 4-6 hrs
 in animal studies:
* efficacy of chelation = highest if
administered w/in minutes – hours
after arsenic exposure

8080
 succimer – effective in animal models
- has a higher therapeutic index than
dimercaprol
- available only for oral administration
=> use = not advisable in the initial tx
of acute arsenic poisoning
= severe gastroenteritis and
splanchnic edema may
limit absorption by oral
route

8181
• Chronic inorganic arsenic poisoning
-> appearance of symptoms vary with:
* dose
* interindividual tolerance
- chronic absorption > 500-1000mcg/d
 evidence of overt noncarcinogenic
effects such as:
.. constitutional symptoms of:
* fatigue * weakness
* weight loss

8282
.. anemia
.. nonspecific gastrointestinal complaints
.. sensorimotor peripheral neuropathy
 stocking glove pattern of dysesthesia
 skin changes – most characteristic
effects develop after years of
exposure w/c include:
* “raindrop” pattern of
hyperpigmentation
* hyperkeratoses involving the palms

8383
.. peripheral vascular disease and noncirrhotic
portal hypertension possible link to:
* hypertension
* diabetes
* chronic nonmalignant respiratory
disease
- years after exposure to not high enough
doses to elicit acute or chronic effects
 cancer of:
* lungs * bladder
* skin * other sites

8484
- in cancer chemotherapy : arsenite dose
= 10-20mg/day for wks-few months 
associated w/ prolongation of the QT
interval on the ECG occasionally
resulted in malignant ventricular
arrhythmias such as torsade de pointes
-> dx of chronic arsenic poisoning:
- integration of clinical findings w/
confirmation of exposure
- urinary levels of total arsenic < 30 mcg/L

8585
- or 50 mcg/24 hr. in general population 
return to normal w/in days-wks after
exposure ceases
 seafood should be avoided 3days prior
to submission of urine sample
.. contains large amount of nontoxic
organoarsenic
- arsenic content of hair and nails <1ppm
 may reveal past elevated exposure
 result should be cautiously interpreted in
view for external contamination

8686
• Arsine gas poisoning
-> intoxication dominated by profound
hemolytic effects
- after a latent period = 2-24hrs. post-
inhalation=> depending on the
magnitude of exposure:
* massive intravascular hemolysis S x S:
.. malaise .. nausea .. hemogobinuria
.. headache .. vomiting
.. dyspnea .. abdominal pain
.. weakness .. jaundice

8787
 oliguric renal failure => consequence of
Hb deposition in the renal tubules
.. appears w/in 3days
 massive exposures => lethal effects on
cellular respiration may occur before
renal failure develops
=>urinary arsenic levels = elevated
.. seldom available to confirm dx

8888
-> tx for arsine poisoning:
=> intensive supportive care – including:
* exchange transfusion
* vigorous hydration
* hemodialysis – mainstay of therapy in
case of renal failure
=> chelating agents – not yet demonstrated
of clinical value

8989
Mercury
-> metallic mercury- known as “quicksilver”
 the only metal that is liquid under
ordinary condition
->1950s mercury = determined cause of :
* birth defect Minamata
* neurologic diseases Japan
 causative agent = methyl mercury in
contaminated seafood => traced to
industrial charges from a nearby factory

9090
-> forms of mercury causing clinical toxicity:
* elemental mercury
* alkylmercury – e.g. methylmercury
* inorganic mercury salts
* aryl mercury compounds
-> mercury = mined predominantly as HgS
in cinnabar ore  variety of forms for
different applications  sources of
exposure

9191
-> industrial and commercial application of
mercury:
* electrolytic production of chlorine and
caustic soda
* manufacture of electrical equipment,
thermometers and other instruments
* fluorescent lamps
* dental amalgam
* artisanal gold production

9292
 pharmaceutical use and use in biocides
– declined significantly
- occasional use in antiseptics and
folk medicines
 environmental mercury
– burning fossil fuels
- bioaccumulation of methylmercury in
fish
 low-level exposure to mercury – released
from dental amalgam fillings => systemic
toxicity – established

9393
Pharmacokinetics of Mercury
- absorption depends on the chemical form
-> elemental mercury – quite volatile 
may be absorbed from the lungs
 poorly absorbed from the intact
GIT
-> inhaled mercury = 10
source of
occupational exposure
-> organic short-chain alkylmercury cpds.
- volatile  potentially harmful by
inhalation and ingestion

9494
-> percutaneous absorption of metallic and
inorganic mercury – clinical concern ff.
massive acute or long-term chronic
exposure
-> alkylmercury compounds – well absorbed
through the skin
-> acute contact w/ few drops of dimethylHg
 severe delayed toxicity
- distribution of Hg:
absorbed Hg few hrs. tissues  highest in the
kidney

9595
- excretion of hg:
-> inorganic Hg
 excreted through the urine and feces
 excretion follows multicomponent
model =>most excreted w/in wks.-
mos.
=> fraction.. retained in the
kidneys and brain for years
-> elemental Hg =>inhaled urinary Hg level
decline w/ ~ half-life = 1-3mos.

9696
-> methylHg =>blood and whole body half-life
~ 50days  biliary excretion and
enterohepatic circulation
 >2/3 excreted in the feces
-> Hg + sulfhydryl groups in keratinized
tissue as in Pb2+
, As3+
hair and
nails

9797
Major forms of mercury intoxication
- Hg interacts w/ sulfhydryl groups in vivo
 inhibits enzymes
 alters cell membranes
- factors that affect pattern of clinical
intoxication from Hg:
* chemical form of the metal
* route of exposure
* severity of exposure

9898
 acute intoxication
- inhalation of elemental Hg vapor causes:
* chemical pneumonitis
* noncardiogenic pulmonary edema
* acute gingivostomatitis
* neurologic sequelae
- ingestion of inorganic Hg salts e.g. HgCl2
 corrosive, potentially life threatening
hemorrhagic gastroenteritis
 followed w/in hrs.- days by: acute
tubular necrosis and oliguric renal failure

9999
 chronic intoxication
- inhalation of Hg vapor results in:
* classic triad of tremor = hands
= face
= choreiform movements of the limbs
* neuropsychiatric manifestations
= memory loss = fatigue
= insomnia = anorexia
= change in mood -> shyness
-> w/drawal
-> depression along w/ explosive
anger or blushing (erethism)

100100
= low-dose exposure -> produce subclinical
neurologic effects
* gingivostomatitis -> high-dose exposure to
Hg
-> sometimes accompanied by loosening
of teeth
* overt peripheral neuropathy = rare
= peripheral nerve damage -> detected by
electrodiagnostic testing
* acrodynia - uncommon idiosyncratic reaction
to subacute or chronic Hg exposure
- occurs mainly in children

101101
- acrodynia is characterized by:
-> painful erythema of the extremities
associated w/:
.. HPN .. insomnia
.. diaphoresis .. irritability or apathy
.. anorexia .. miliarial rash
 methyl Hg intoxication – affects mainly the
CNS and results in:
-> paresthesias -> dysarthria
-> ataxia -> progressive
-> hearing impairment constriction of
the visual fields

102102
- S x S -> appear several wks. or mos. After
exposure begins
-> methyl Hg= reproductive toxin
= high dose prenatal exposure
 mental retardation offspring
 cerebral palsy-like syndrome
= low-level prenatal exposures  assoc.
w/ a risk of subclinical
neurodevelopment deficits
- dimethyl Hg -> rarely encountered
-> extremely neurotoxic = lethal in small
quantities

103103
- dx of Hg intoxication=> integration of :
* history
* physical findings
* laboratory –> confirmatory test
-> w/o occupational exposure
..urine Hg concentration < 5mcg/L
..whole blood Hg < 5mcg/L
-> 1990 => Biological Exposure Index
(BEI) committee recommended :
..workplace exposures urine conc.
< 35mcg/g of creatinine

104104
 end-of-work wk whole blood Hg<15mcg/L
-> to minimize risk from methyl Hg:
 avoid consumption of fish w/ high Hg
levels e.g. swordfish
 limit consumption of fish w/ lower levels
of Hg => to no more than 12ounces =
340g. or two average meals/wk.
..to minimize risk should be in particular
among: * pregnant women
* women who might become pregnant
* nursing mothers
* young children

105105
- treatment of Hg poisoning:
 acute poisoning
* intensive supportive care
* prompt chelation w/:
-> oral or intravenous unithiol
-> I.M. dimercaprol
-> oral succimer -of value in diminishing
nephrotoxicity after acute exposure
to inorganic Hg salts
* vigorous hydration- help to maintain
urine output

106106
* days or weeks of hemodialysis or
hemodiafilration in conjunction w/
chelation - necessary if acute renal failure
occurs
- tx should not be delayed until
the onset of uliguria or other
major systemic effects

107107
 chronic exposure
-> unithiol and succimer increase urine Hg
excretion  after acute or chronic
inhalation of elemental Hg
 impact on clinical outcome = ?
-> succimer, unithiol and N-acetyl-
L- cysteine (NAC)  enhance body
clearance of methyl Hg
-> dimercaprol  redistribute Hg to the
CNS from other tissues
 brain = target organ not used to tx
exposure to elemental or organic Hg

108108
Chelators
- drugs used to:
* prevent or reverse toxic effects of heavy
metals on enzymes or other cellular target
* accelerate the elimination of the metal
from the body
- chelating agents are flexible molecules
two or more electronegative groups
 form stable coordinate –covalent bond
w/ a cation metal atom

109109
e.g. succimer
parent compound in vivo biotransformation active
complexing agent  excreted by the body
↓
Salt and chelate formation with edetate
(ethylenediaminetetraacetate, EDTA) i.e.
a) sol’n of Na2 salt of EDTA – the Na+
& H+
ions = chemically and biologically
available
b) sol’n of CaNa2 edetate – calcium is
bound by coordinate – covalent bonds
with nitrogens as well as by the usual
ionic bonds

110110
c) in the lead chelate – lead is incorporated
into five heterocyclic rings
- efficiency of chelator may be determined by:
▪ number of ligand groups on the molecule
available for metal binding
– more ligand groups → more stable the
metal-chelator complex
→ complex may be referred to as
* mono depending on the
* bi # of metal-ligand
* poly dentate bonds

111111
Effects of metal binding of chelating agents:
● Prevents interaction of the metal with similar
functional groups of:
▪ enzymes
▪ coenzymes
▪ cellular neutrophiles
▪ membranes
● May enhance the excretion of essential
cations such as zinc or copper a side
effect which is seldom of clinical significance
 due to limited time of chelation course
e.g. Ca EDTA in lead intoxication

112112
● Metal-mobilizing effect of a therapeutic
chelating agent  redistribute some of the
metal to other vital organs
e.g.* dimercaprol - redistributes Hg & As to
the brain
- enhances urinary Hg &
As excretion
* other chelating agent – redistribute Cd
to the kidneyincrease nephrotoxicity
 negate therapeutic value for Cd
chelation
- capacity of chelating agent in preventing toxic
effect of metals greatest if administered
very soon after exposure

113113
Most commonly use chelating agents:
● Dimercaprol (2,3 – Dimercaptopropanol, BAL)
- aqueous sol’n of dimercaprol is unstable and
readily oxidizedispensed in 10% peanut oil
 must be adm. I.M.painful
- action of dimercaprol:
* animal models – prevents and reverses
arsenic induced inhibition of sulfhydyl
containing enzymes if BAL is given
soon after exposure, lethal effects of
inorganic & organic arsenicals may be
prevented
* human – increases excretion of As & Pb
 therapeutic benefit for As, Pb & Hg
intoxication

114114
Indications of BAL
- used as a single-agent treatment for acute
poisoning by:
▪ arsenic
▪ inorganic mercury▪
▪ severe lead poisoning when used ih
conjunction with edetate calcium disodium
- in human:
▪ adm. = I.M.
▪ readily absorbed
▪ metabolized and excreted by the kidney
within 4-8hrs
▪ bIliary excretion = uncertain
- animal models => biliary excretion is indicated

115115
- adverse effects of BAL:
▪ therapeutic dose
* HPN
* tachycardia
* vomiting
* lacrimation
* salivation
* fever – particularly in children
* pain in the injection site
* I.M. adm. risk of hematoma formation
♦ thrombocytopenia
♦ increase prothrombin time
▪ in acutely intoxicated animals  BAL may
redistribute As & Hg to the CNS =>

116116
* not advocated for chronic intoxication
treatment
* replaced by : > unithiol water analogs of
> succimer BAL = higher
therapeutic
indices

117117
● Succimer (Dimercaptosuccinic Acidd, DMSA)
♦ therapeutic use:
* in animals - protect acute lethal effects of
arsenic poisoning  succimer prevents
and reverse metal induced inhibition of
sulfhydryl-containing enzymes
* in human– increase urinary lead excretion
- decrease in blood lead concentration
- decrease the Hg content of the kidney
=> key target organ of inorganic Hg
salts
- U.S. => only oral formulation
- all others=> I.V. formulation =
successfully used

118118
- absorbed rapidly but variably after oral
adminiatration
- peak blood level ~ 3hrs.
i.e. succimer + cysteine 1:1 & 1:2
mixed disulfides in the kidney
↓
active chelating moieties
↓
elimination half-time = 2-4 hrs.
♦ indication & toxicity of succimer
- use for the treatment of Pb poisoning:
* children with Pb conc. >45mcg/ml.
* adults Pb poisoning
 usual dosage =10mg/kg orally 3x/day

119119
succimer indications & toxicity
 oral administration of succimer:
> comparable to parenteral EDTA in
reducing blood lead concentration
> supplanted EDTA in outpatient tx of
patients capable of absorbing the drug
- treat As & Hg poisoning:
* has a protective effect against As in
animals
* has the ability to mobilize Hg from the
kidney
* limited clinical trials showed DMSA =
well tolerated

120120
* negligible impact on body stores of calcium,
iron and magnesium
* induces a mild increase in urinary zinc 
minor or no clinical significance
- toxicity of DMSA:
* gastrointestinal disturbances
> anorexia
> nausea most common <10% of
> vomiting patients
> diarrhea
* rashes – may require discontinuation of the
medication <5% of patients
* mild, reversible increases in liver
aminotransferases 6 – 10% of patients

121121
● Edetate Calcium Disodium (EDTA)
- efficient chelator of many divalent and
trivalent metal in vitro
- administered only as calcium disodium salt
 to prevent potentially life-threatening
depletion of calcium
- chelates extracellular metal ions >>
intracellular ions  EDTA penetrates
cell membranes relatively poorly
- EDTA = highly polar  limits its oral
absorption
- oral adm. may increase Pb absorption
from the gut

122122
- EDTA rapidly excreted by glomerular
filtration in normal renal fxn
 50% of injected is in the urine in 1hr.
 mobilizes lead from soft tissues
=> marked increase in urinary lead
excretion
=> decline in blood lead concentration
- indication of EDTA:
▪ chelator of:
* lead
* zinc
* manganese
* certain heavy radionuclides like uranium
plutonium, americium and curium

123123
 analogs of EDTA used to remove uranium
and certain transuranic radioisotopes:
> calcium disodium salts of diethylene-
> zinc triaminepentaacetic acid
(DTPA), pentetate
▪ contraindicated in anuric patients  low
doses of EDTA + hemodialysis or
hemofiltration = used
▪ toxicity of EDTA:
* nephrotoxicity – prevented by:
> adequate urine flow
> avoidance of excessive doses
> limitation of treatment course to <5 days

124124
● Unithiol (Dimercaptopropanesulfonic acid,
DMPS)
- water-soluble analog of dimercaprol
- administered orally and intravenously
- oral route : bioavailability = 50%
peak blood level= 3.7hrs
- I.V. : >80% of dose => excreted in the urine
mainly as cyclic DMPS sulfides
- elimination half-time of total unithiol
administered ~ 20hrs
- in animal models: exhibits protective
effects against Hg & As toxic action
- in human: increase excretion of Hg, As &
Pb

125125
● Penicillamine (D-Dimethylcysteine)
- white crystalline
- water-soluble derivative of penicillamine
- D-Penicillamine < L-Penicillamine in toxicity
 more preferred therapeutic form
- readily absorb from the gut
- resistant tometabolic degradation
- chiefly used :
* for the treatment of copper poisoning
* prevent copper accumulation Wilson’s
disease => hepatolenticular
degeneration
* occassionally use to tx severe

126126
* increases urinary excretion of Pb & Hg 
may be used to treat intoxication by these
metals  now replaced by succcimer
- toxicity :
* hypersensitivity
* nephrotoxicity with proteinuria
* pancytopenia – associated with prolonged
drug intake
● Deferoxamine
● Deferasirox

127127
● Prussian Blue (Ferric Hexacyanoferrate)
- has high affinity for univalent cations such
as: cesium
thallium
- used as an oral drug
- insoluble form undergoes minimal GIT
absorption <1%
- elimination of the chelator is enhanced by:
* nonabsorbability of the complexes it
forms with cesium & thallium oral adm.
of chelator diminishes intistinal
absorption or interrupts enterohepatic
and enteroenteric circulation of the ions

129129
HALOGENATED ALIPHATIC
HYDROCARBONS
• Uses
* Industrial solvents
* Degreasing agents
* Cleaning agent

130130
• Included w/ these Hydrocarbons:
* CCl4 –TLV-TWA = 5ppm; TLV-STEL =10ppm
* CCl3 - =10ppm; = NA
* Trichloroethylene=50ppm; = 100ppm
* Tetrachloroethylene (perchloroethylene) –
TLV-TWA = 25ppm; TLV-STEL = 100ppm
* 1,1,1 trichloroethane (Methylchloroform) –
TLV-TWA = 350ppm; TLV-STEL =450ppm

131131
Toxicity Effects of Halogenated Aliphatic H-C:
* Animals –
> CNS depressant
> injury of liver, kidney and heart
> carcinogenicity – due to CCl4, CCl3,
trichloethylene and tetrachloroethylene

132132
* Human – CNS depressant
. CCl3 – most potent
- widely used as anesthetic agent
. Tetrachloethylene – chronic exposure
- impaired memory
- peripheral neuropathy
. 1,1,1 trichloroethane – depressing agent
. CCl4 –most potent hepatotoxic agent
. CCl4, CCl3 & trichloroethylene
- nephrotoxicity

133133
ö Carcinogenicity – effects of low-level long
term exposure
-Trichloroethylene– environmental exposure
- CCl3 – household exposure very large
margin of safety for human
Treatment for Acute Intoxication of Halogenated
Aliphatic H-C:
ö No specific treatment
ö Management depends on the organ system
ö

134134
AROMATIC HYDROCARBONS
* Benzene
ö Uses :
-- as solvent
-- intermediate in the synthesis of other
chemicals
-- TLV-TWA = 0.5ppm; TLV-STEL = 2.5ppm
ö Acute Toxic Effect of Benzene:
-- Depression of the CNS

135135
* Exposure to 7500ppm for 30 mins. = fatal
* >3000ppm – causes:
- Euphoria
- Nausea
- Locomotor problems
- Coma
250 – 500ppm.= vertigo, drowsiness,
headache and nausea

136136
ö Chronic Exposure to Benzene:
-- insidious to unpredictable injury of the
bone marrow
-- aplastic anemia
-- leukopenia
-- pancytopenia
-- thrombocytopenia
-- leukemia
* Bone marrow cells in early development
stage = most sensitive to benzene

137137
* Early symptoms of benzene intoxication:
-- headache
-- fatigue
-- loss of appetite
ö Treatment for acute benzene intoxication- no
specific treatment recommended

138138
* Toluene - Methylbenzene
- CNS depressant
- Difference from that of benzene
-> No myelotoxic properties as that of
benzene
-> Not associated with leukemia
- TLV-TWA = 50ppm.; TLV-STEL = NA
- Acute Exposure Effect:
-> 800ppm =severe fatigue and ataxia
-> 10,000ppm. = rapid loss of consciousness

140140
Organochlorine Insecticide include the ff:
> DDT (Chlorophenothane) and analogs –
poorly absorbed in the skin
> Benzene hexachlorides –
> Cyclodienes – e.g. dielderin very efficiently
absorbed in the skin
> Toxaphenes

141141
Mechanism Action of Organochlorine:
> Organochlorine interfere w/ inactivation
of the sodium channel in excitable
membranes
 cause rapid repetitive firing in most
neurons
 Calcium ion transport is inhibited
 affect repolarization and enhance the
excitability of neurons
 major effect = CNS stimulation

142142
S X S of Organochlorine intoxication:
• W/ DDT = tremor
= Convulsions
• W/ other compounds
convulsion =first sign of intoxication
Treatment of Organochlorine Intoxication:
- No specific treatment had yet been establish
for acute organochlorine poisoning

143143
Environmental Toxicology of Organochlorine:
* persistent chemicals
* degradation - quite slow
* bioaccumulate - particularly in aquatic eco-
systems
* mobility in soil
-> presence of organic matter – favors
adsorption onto the soil
-> sandy soils – adsorption is poor
- once adsorbed –> do not readily
desorbed

144144
Organophosphorus Insecticide
• Dangerous to human and highly effective as
insecticide
• Biotransformation = rapid
• Less stable than carbamates when dissolved
in water thus have limited half-life in the
environment compared to halogenated
hydrocarbons

145145
• Absorption of Organophosphorus Except
Echothiophate:
* Skin * Conjunctiva
* Respiratory tract * CNS
* GIT
• Human Toxicology of Orgonophosphorus:
* Mechanism of action – inhibition of acetyl-
cholinesterase through phosphorylation of
the esteratic site- known to be
cholinesterase inhibitors

146146
• S X S for acute intoxication of
Organophosphorus:
> accumulation of acetylcholine
> some of the agents possess direct
cholinergic activity
> altered neurologic and cognitive function
> psychological symptoms caused by
exposure to high concentration
> Organophosphorus ester-induced delayed
polyneuropathy (OPIDP – particularly
sensitive are hens

147147
> Human : neurotoxicity – particularly
observed w/ the used of triortho-cresyl
phosphate such as:
.. dichlorvos .. mipalox
.. trichlorfon .. leptophos
.. methamidophos .. trichloronat

148148
Thiophosphates are quite lipid-soluble
- Absorbed by all routes
- Activated in the body by conversion to the
oxygen analogs- occurs both in insects and
vertebrate
-- Parathion and a few other
organophosphate insecticides – rapidly
metabolized by other pathways to inactive
products in birds and mammals but not
insects

149149
 safe enough for sale in gen. public
- not detoxified by fish
-- Parathion- not detoxified effectively in
vertebrates
- more dangerous than malathion to
human and livestocks and is not
available for public use

150150
Organophosphates - cholinesterase inhibitors
- initial signs of acute intoxication manifest
those of muscarinic excess
* meiosis * salivation
* sweating * bronchial constriction
* vomiting * diarrhea
> CNS involvement accompanied by
peripheral nicotinic effect especially
depolarizing neuromuscular blockade

151151
Therapy of Organophosphate Acute Intoxication:
• Maintenance of vital signs – respiration in
particular may be impaired
• Decontamination – to prevent further
absorption
> remove all clothing
> washing of the skin in cases of exposure
to dust and sprays
• Atropine –parenterally administered in large
dose given as required to control signs
of muscarinic excess

152152
Treatment: Severe Organophosphate Poisoning:
• Tertiary amine e.g atropine  must be used
– treats both the CNS and peripheral
effects of organophosphate inhibitors
- dose
* Parathion & chemical warfare “nerve gases
= 1 – 2 mg. of atropine sulfate; given
intravenously every 5 – 15 mins. Until
signs of effects such as: dry mouth,

153153
.. atropine administration – may have to be
repeated many times  acute effects of
cholinesterase agents may last for 24 – 48
hrs. or longer
.. 1 gm. of atropine/day  given for as long
as 1 mo. to fully control muscarinic x’s
• Cholinesterase regenerator compounds
– involves: regeneration of active enzyme
from the organophosphorus-cholinesterase
complex to form oxime agents (=NOH)

154154
* Pralidoxime (PAM) – most studied in human
- only one available for clinical use in U.S.A.
- most effective in regenerating the
cholinesterase associated w/ skeletal
muscle neuromuscular junctions
- ineffective in reversing the central effect of
organophosphate poisoning its positive
charge prevents entry into the CNS
- administered by I.V. , 1-2gms. given over
15-30 mins.

155155
- excessive doses of PAM can induce the ff.:
> neuromuscular weakness
> other adverse effects observed
- not recommended to reverse inhibition of
cholinesterase by carbamate inhibitors
Diacetylmonoxime (DAM) – crosses the blood-
brain barrier
- in animals – can regenerate some of the
central CNS cholinesterase

156156
• Pretreatment w/ reversible enzyme inhibitors
– to prevent binding of irreversible
organophosphate inhibitor
e.g. pyridostigmine
pysostigmine
=> reserved only wherein lethal poisoning is
anticipated e.g chemical warfare
=> simultaneous use of atropine is required
to control muscarinic excess

157157
Carbamate Insecticides
- inhibit acetylcholinesterase by carbamoylation
of the esteratic site
- non-persistent pesticides => small impact on
the environment
- Clinical effects:
> similar to organophosphate but of shorter
duration
> the range between doses causing
intoxication and lethality is larger in
carbamates than w/ organophosphates

158158
> compared to organophosphate reactivation
of cholinesterase is more rapid after
inhibition by carbamates
> carbamates are referred to as reversible
cholinesterase inhibitors organophosphates
– irreversible cholinesterase inhibitors
- Treatment of Carbamate Poisoning:
> Similar to that of organophosphate
poisoning but PAM is not recommended

159159
BOTANICAL INSECTICIDES
Derived from natural sources
It includes the ff.:
* Nicotine – from Nicotiana tabacum
N rustica
* Rotenone
* Pyrethrum

160160
NICOTINE
• Absorption:
> Free alkaloid but not the salt – readily
absorbed from the skin
• Mechanism of action:
> Nicotine reacts w/ acetylcholine receptor of
the postsynaptic membrane i.e. sympathetic
and parasympathetic ganglia, neuromuscular
junction---> depolarization of………………

161161
the mucous membrane
--->Toxic doses cause stimulation rapidly
followed by blockade of transmission
• Treatment:
> Maintenance of vital sign
> Suppression of convulsion

162162
Effects of oral ingestion:
> GIT irritation > Pharyngitis
> Conjunctivitis > Rhinitis
• Treatment:
> symptomatic

163163
PYRETHRUM
• Includes:
> Pyrethrin I > Cinerin II
> Pyrethrin II > Jasmolin I
> Cinerin I > Jasmolin I
• Esters are extensively biotransformed
• Highly toxic to mammals
• Major site of toxic action = CNS
• Absorption = ingestion, inhalation and skin –not
significant

164164
> Excitation > contact dermatitis
> Tetanus paralysis >cutaneous paresthesias
> Convulsions
• Targets of Pyrethrum:
> Voltage gated sodium channel
• Toxic Effects of Pyrethrum Insecticides:
> Voltage gated calcium channel
> Voltage gated chloride channel
> Peripheral–type benzodiazepine receptor

165165
• Treatment for Pyrethrum Intoxication:
> symptomatic treatment is employed
> anticonvulsants = not consistently
effective
> chloride channel agonist:
* ivermectin
* pentobarbital
* mephenesin

166166
HERBICIDES
1. Chlorophenoxy Herbicides –
> 2,4 Dichlorophenoxyacetic acid (2,4-D)
* toxicity rating=4
* human lethal dose = 50 – 500 mg/kg BW
> 2,4,5 Trichlorophenoxyacetic acid (2,4,5-T)
* toxicity rating = 3
* human lethal dose =500– 5000mg/kg BW
> Salts and esters of 2,4-D & 2,4,5-T

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Human Toxicity Effects:
> 2,4-D
 coma
 muscle hypotonia
> 2,4,5-T
 coma
 muscular dysfunction
 occupational exposure=> associated
w/ increased risk of Non-Hodgkin’s
lymphoma

168168
 Soft tissue sarcoma = equivocally suspected
Pls. note:
- Care in establishing toxicological profile
especially 2,4,5-T => intoxication can be
caused by contaminants most important of
w/c is Tetrachlorodibenzo-p-dioxin (TCDD)

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2. Bipyridyl Herbicides
* Paraquat – most important agent of
bipyridyl herbicides
.. mechanism of action:
> involves single electron reduction of
the herbicide to free radical species
.. toxicity rating = 4
Human lethal dose = 50- 500 mg/kg

170170
• Toxicity Effects of Paraquat:
- Accumulates slowly in the lungs by an active
process causing:
> lung edema
> alveolitis
> progressive fibrosis
- S X S in human:
> after oral ingestion
.. GIT irritation=> hematemesis, bloody

171171
> Delayed Toxicity:
.. Respiratory distress
.. Congestive hemorrhagic pulmonary edema
.. Cellular proliferation
.. Hepatic, renal or cardiac involvement
.. Death – several weeks after ingestion
• Treatment of Paraquat Intoxication:
> Prompt removal of paraquat from GIT by:
.. Use of gastric lavage
.. Use of cathartics

172172
.. Use of adsorvent
.. Oxygen should be used cautiously to
combat dyspnea or cyanosis- may
aggravate the pulmonary lessions
.. Patients should be observed longer –
proliferation phase begins 1-2 weeks
after ingestion

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Polychlorinated dibenzo-p-dioxin(PCDDs) or
dioxins= group of congeners of PCBs
* 2,3,7,8-tetrachlorodibenzo-p-dioxins(TCDD)
most important congener
* Polychlorinated dibenzofurans (PCDFs)
* Coplanar biphenyls dioxin-like cpds.
.. TCDDs and PCDFs:
- like PCBs = very stable
= highly lipophilic

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= poorly metabolized
= very resistant to environmental degradation
.. TCDDs effect in lab animals:
- wasting syndrome
- thymic atrophy
- epidermal changes
- hepatotoxicity
- effects on reproduction and development
- teratogenicity
- carcinogenicity

175175
> effects observed in animals are not
observed in human
> workers involved in manufacturing:
.. 2,4,5-T perhaps exposed to TCDD
- contact dermatitis
- chloracne
.. Severely TCDD-intoxicated patients =
discrete chloracne
> presence of TCDD in 2,4,5-T =
responsible for other human toxicities

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2. Endocrine Disruptors:
- chemicals that mimic or enhance or inhibit
a hormonal action
- included are:
* plant constituents – phytoestrogen
* mycoestrogens
* persistent organochlorine- DDT, PCBs
* brominated flame returdants
- Properties: bioaccumulation
* potent toxicant
* increasing contamination of the
environment

Tox agent-12

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