1. 1. 11 Toxicological -Agents By: Prof. Helen C. Santos JFSM-UPHSD
2. 2. 22 Common Toxicological Agents: - Drugs - Toxic household products - Environmental and occupational solvents Heavy metals Air pollutants Solvents Insecticides Microorganisms
3. 3. 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
4. 4. 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
5. 5. 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
6. 6. 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
7. 7. 77 - Normal nonsmoking adults COHb level 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%
8. 8. 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
9. 9. 99 * Other s x s of CO poisoning: - Delayed neuropsychiatric impairment - Slow resolution of behavioral consequences
10. 10. 1010 * Variability of individual responses to different COHb levels: - 60% - death may ensue * Aggravating Factors for CO Clinical Effects: - Heavy labor - High altitudes - High ambient temperature
11. 11. 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
12. 12. 1212 Treatment of Carbon Monoxide Poisoning: * Acute intoxication- > Removal of the individual from the exposure source > Maintenance of respiration i.e. aim. Of O2specific antagonist to CO 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.
13. 13. 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
14. 14. 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
15. 15. 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
16. 16. 1616 Treatment for SO2 Poisoning: - no specific treatment - depends on therapeutic maneuvers used in respiratory tract irritation
17. 17. 1717 NITROGEN OXIDES * NO2 brownish irritant gas associated w/ fires - formed from fresh silage - common exposures of farmers - can lead to silo-fillers disease - TLV-TWA = 3ppm; TLV-STEL =5ppm -> Mech. Of Action: NO2 is a deep lung irritant producing pulmonary edema
18. 18. 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
19. 19. 1919 Clinical Effects of NO2 Exposure: 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.
20. 20. 2020 -- Drug Therapy for NO2 Intoxication: Bronchodilators Sedatives Antibiotics
21. 21. 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
22. 22. 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
23. 23. 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
24. 24. 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
25. 25. 2525 HEAVY METALS
26. 26. 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
27. 27. 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 safeonce 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
28. 28. 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
29. 29. 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
30. 30. 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
31. 31. 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
32. 32. 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
33. 33. 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
34. 34. 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
35. 35. 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
36. 36. 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
37. 37. 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
38. 38. 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 leads toxic-> most sensitive target organ for leads toxic effect = developing nervous system:effect = developing nervous system: * fetus* fetus * young child* young child -> young children-> young children - blood lead concentrations adults - less sensitive to CNS lead effects- less sensitive to CNS lead effects - blood lead concentration >30mcg/dl- blood 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
39. 40. 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/dl- blood lead concentrations >100mcg/dl lead encephalopathylead encephalopathy increased intracraneal pressureincreased intracraneal pressure => ataxia => convulsions=> ataxia => convulsions => stupor => death=> stupor => death => coma=> coma
40. 41. 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
41. 42. 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
42. 43. 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
43. 44. 4444 of lead inhibition of the enzyme 35-of lead inhibition of the enzyme 35- 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.
44. 45. 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
45. 46. 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
46. 47. 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
47. 48. 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
48. 49. 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
49. 50. 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
50. 51. 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
51. 52. 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
52. 53. 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
53. 54. 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
54. 55. 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
55. 56. 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
56. 57. 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 naphthenatestill usedstill used - organolead = well absorbed through:- organolead = well absorbed through: * respiratory tract* respiratory tract * skin* skin volatilityvolatility lipid solubilitylipid solubility
57. 58. 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
58. 59. 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
59. 60. 6060 Treatment for lead poisoning - inorganicTreatment for lead poisoning - inorganic * parenteral chelation=> limited* parenteral chelation=> limited 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
60. 61. 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
61. 62. 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
62. 63. 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
63. 64. 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
64. 65. 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
65. 66. 6666 * component pharmaceuticals for man ..Fowlers 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
66. 67. 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
67. 68. 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
68. 69. 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
69. 70. 7070 keratinized tissues after exposure nails skin contain elevated level of arsenic (indistinguishable from that absorbed internally) urine level = normal
70. 71. 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-
71. 72. 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
72. 73. 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
73. 74. 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
74. 75. 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
75. 76. 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
76. 77. 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
77. 78. 7878 * confirmation of dx determination of inorganic arsenic level and its metabolites in the urine range = several thousand 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
78. 79. 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
79. 80. 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
80. 81. 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
81. 82. 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
82. 83. 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
83. 84. 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
84. 85. 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 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
85. 87. 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
86. 88. 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
87. 89. 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
88. 90. 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
89. 91. 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
90. 92. 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
91. 93. 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
92. 94. 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
93. 95. 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.
94. 96. 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
95. 97. 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
96. 98. 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
97. 99. 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)
98. 100. 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
99. 101. 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
100. 102. 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
101. 103. 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
102. 104. 104104 end-of-work wk whole blood Hg 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
103. 105. 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
104. 106. 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
105. 107. 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
106. 108. 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
107. 109. 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) soln of Na2 salt of EDTA the Na+ & H+ ions = chemically and biologically available b) soln of CaNa2 edetate calcium is bound by coordinate covalent bonds with nitrogens as well as by the usual ionic bonds
108. 110. 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
109. 111. 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
110. 112. 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 kidneyincrease nephrotoxicity negate therapeutic value for Cd chelation - capacity of chelating agent in preventing toxic effect of metals greatest if administered very soon after exposure
111. 113. 113113 Most commonly use chelating agents: Dimercaprol (2,3 Dimercaptopropanol, BAL) - aqueous soln of dimercaprol is unstable and readily oxidizedispensed 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
112. 114. 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
113. 115. 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 =>
114. 116. 116116 * not advocated for chronic intoxication treatment * replaced by : > unithiol water analogs of > succimer BAL = higher therapeutic indices
115. 117. 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
116. 118. 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
117. 119. 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
118. 120. 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 vomiting patients > diarrhea * rashes may require discontinuation of the medication > intracellular ions EDTA penetrates cell membranes relatively poorly - EDTA = highly polar limits its oral absorption - oral adm. may increase Pb absorption from the gut
119. 122. 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
120. 123. 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 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
121. 125. 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 Wilsons disease => hepatolenticular degeneration * occassionally use to tx severe
122. 126. 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
123. 127. 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 CNS depressant > injury of liver, kidney and heart > carcinogenicity due to CCl4, CCl3, trichloethylene and tetrachloroethylene
124. 132. 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
125. 133. 133133 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: No specific treatment Management depends on the organ system
126. 134. 134134 AROMATIC HYDROCARBONS * Benzene Uses : -- as solvent -- intermediate in the synthesis of other chemicals -- TLV-TWA = 0.5ppm; TLV-STEL = 2.5ppm Acute Toxic Effect of Benzene: -- Depression of the CNS
127. 135. 135135 * Exposure to 7500ppm for 30 mins. = fatal * >3000ppm causes: - Euphoria - Nausea - Locomotor problems - Coma 250 500ppm.= vertigo, drowsiness, headache and nausea
128. 136. 136136 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
129. 137. 137137 * Early symptoms of benzene intoxication: -- headache -- fatigue -- loss of appetite Treatment for acute benzene intoxication- no specific treatment recommended
130. 138. 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
131. 139. 139139 INSECTICIDES
132. 140. 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
133. 141. 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
134. 142. 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
135. 143. 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
136. 144. 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
137. 145. 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
138. 146. 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
139. 147. 147147 > Human : neurotoxicity particularly observed w/ the used of triortho-cresyl phosphate such as: .. dichlorvos .. mipalox .. trichlorfon .. leptophos .. methamidophos .. trichloronat
140. 148. 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
141. 149. 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
142. 150. 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
143. 151. 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
144. 152. 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,
145. 153. 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 xs Cholinesterase regenerator compounds involves: regeneration of active enzyme from the organophosphorus-cholinesterase complex to form oxime agents (=NOH)
146. 154. 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.
147. 155. 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
148. 156. 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
149. 157. 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
150. 158. 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
151. 159. 159159 BOTANICAL INSECTICIDES Derived from natural sources It includes the ff.: * Nicotine from Nicotiana tabacum N rustica * Rotenone * Pyrethrum
152. 160. 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
153. 161. 161161 the mucous membrane --->Toxic doses cause stimulation rapidly followed by blockade of transmission Treatment: > Maintenance of vital sign > Suppression of convulsion
154. 162. 162162 Effects of oral ingestion: > GIT irritation > Pharyngitis > Conjunctivitis > Rhinitis Treatment: > symptomatic
155. 163. 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
156. 164. 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 > Peripheraltype benzodiazepine receptor
157. 165. 165165 Treatment for Pyrethrum Intoxication: > symptomatic treatment is employed > anticonvulsants = not consistently effective > chloride channel agonist: * ivermectin * pentobarbital * mephenesin
158. 166. 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
159. 167. 167167 Human Toxicity Effects: > 2,4-D coma muscle hypotonia > 2,4,5-T coma muscular dysfunction occupational exposure=> associated w/ increased risk of Non-Hodgkins lymphoma
160. 168. 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)
161. 169. 169169 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
162. 170. 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
163. 171. 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
164. 172. 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
165. 173. 173173 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
166. 174. 174174 = 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
167. 175. 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
168. 176. 176176 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
169. 177. 177177 Thank You