American College of Medical Toxicology 2012 www.acmt.net

ACMT Medical Toxicology Board Review Course

ARE YOU PREPARED? Astor Crowne Plaza Hotel New Orleans, LA September 8-10, 2012 SYLLABUS

Day Two - 3 slides per page

Sponsored by the University of Alabama School of Medicine Division of Continuing Medical Education American College of Medical Toxicology Medical Toxicology Board Review Course September 8-10, 2012 - New Orleans, LA

Day 1 - Saturday, September 8, 2012 7:00-7:50am Breakfast & Stimulus Room 7:50-8:20am Welcome & Introductions 8:20-9:10am Pharmacokinetics/Toxicokinetics Howard A. Greller, MD, FACMT 9:10-10:00am Molecular Mechanisms William P. “Russ” Kerns II, MD, FACMT 10:00-10:20am Break 10:20-11:10am Analytical/Forensics Evan S. Schwarz, MD 11:10-12:00pm Autonomics/Neurotransmitters G. Patrick Daubert, MD 12:00-1:30pm Lunch –n-Learn: Mushrooms & Fish-borne Howard A. Greller, MD, FACMT 1:30-2:20pm Psychotropics G. Patrick Daubert, MD 2:30-3:20pm Cardiovascular Toxins Trevonne M. Thompson, MD 3:20-3:40pm Break 3:40-4:05pm Hydrocarbons Trevonne M. Thompson, MD 4:05-4:30pm Pharmaceutical Additives G. Patrick Daubert, MD 4:30-4:55pm Endocrine Trevonne M. Thompson, MD 6:00-7:30pm Welcome Reception - Napoleon House, 500 Chartres Street in the French Quarter

Day 2 - Sunday, September 9, 2012 7:00-8:00AM Breakfast & Stimulus Room 8:00-8:50am Pesticides J. Dave Barry, MD, FACMT 8:50-9:15am Terrorism Hazmat J. Dave Barry, MD, FACMT 9:15-9:40am Antimicrobials Michael Policastro, MD 9:40-10:00am Break 10:00-10:50am GI/Heme Michael Policastro, MD 10:50-11:15am Chemotherapeutics Michael Policastro, MD 11:15-12:05pm Plants Thomas C. Arnold, MD, FACMT 12:05-1:30pm Lunch-n-Learn: Historical Outbreaks Stephen W. Munday, MD, MPH FACMT 1:30-2:20pm Envenomations Thomas C. Arnold, MD, FACMT 2:20-3:10pm Carcinogens Stephen W. Munday, MD, MPH, FACMT 3:10-3:30pm Break 3:30-4:20pm Misc Toxins 1 Brandon K. Wills, DO, FACMT 4:20-4:45pm Misc Toxins 2 Brandon K. Wills, DO, FACMT

Day 3 - Monday, September 10, 2012 7:00-8:00am Breakfast & Stimulus Room 8:00-8:50am Anesthetics; Drugs of Abuse & Withdrawal Kurt C. Kleinschmidt, MD, FACMT 8:50-9:15am Herbal/Supplemental Tox Kurt C. Kleinschmidt, MD, FACMT 9:15-10:05am Industrial Poisons Jefrey Brent, MD, PhD, FACMT 10:05-10:25am Break 10:25-11:15am Assessment/Population Health/Risk Jefrey Brent, MD, PhD, FACMT 11:15-12:05pm Metals/Metalloids 1 Cyrus Rangan, MD 12:05-12:30pm Metals/Metalloids 2 Cyrus Rangan, MD John G. Benitez, MD, MPH, FACMT 12:30-3:00pm Stimulus Room Russ Kerns, MD, FACMT Pesticides

ACMT Board Review Course

J. Dave Barry Naval Medical Center Portsmouth Portsmouth, VA

2

Pesticides

 Insecticides  Fungicides

 Rodenticides  Fumigants

 Herbicides  Others

3

1 Pesticides

Insecticides

 Cholinesterase Inhibitors  Organophosphates  Carbamates  Organochlorines  Pyrethrins/Pyrethroids  Newer Insecticides

4

Insecticides Cholinesterase Inhibitors

O  Carbamates R1  Ordeal (Calabar) Bean R-O C N (or S) R2 Carbamates

 Organophosphates O (or S)  Synthesized R2 P R1 X Organophosphates 5

Insecticides Cholinesterase Inhibitors

6 Goldfrank’s Toxicologic Emergencies – 8th Ed (2006)

2 Pesticides

sympathetic Autonomic Nervous System parasympathetic

N M M C

N T ne

N ne L

N M S

N 7

Sympathetic Parasympathetic (cholinergic)

agit N M Sz M C sec mio

N T sec rr ne

sec vasoconstr hr N hr ne L

mot N M S sec Fasic N 8 paraly mict

Insecticides Organophosphates Delayed Syndromes  Intermediate Syndrome  Weakness 1-4d after exposure  peripheral NMJ dysfunction  ineffective AChE reactivation

 OPIDN  Neuropathy target esterase (NTE)  Lysophospholipase (lysoPLA)  TOCP (tri-ortho cresyl phosphate)  Jamaican ginger paralysis (1930’s)  Cooking oils (1950’s) 9

3 Pesticides

Insecticides Organophosphates Diagnosis  RBC Cholinesterase  Butyrylcholinesterase (pseudocholinesterase)  Better reflection of  Falls first synaptic inhibition  Recovers rapidly (few days)  Regenerates more  Wide daily variation slowly than neuronal  in other disorders AchE  Liver dysfunction  Wide variations  Malnutrition  in RBC disorders  Drugs  Pregnancy 10  Genetic deficiency

Insecticides Cholinesterase Inhibitor Treatment  Decontamination  Protect Providers  Glove  Bag  Skin  Triple wash – soap/water  Shave scalp?  GI  Gastric?  AC?

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Insecticides Cholinesterase Inhibitor Treatment  Decontamination  Antimuscarinic Agents  Atropine  Infusion 0.02 – 0.08 mg/kg/hr  Bolus 2mg q 2-15 min / double dose  Glycopyrrolate  Scopolamine

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4 Pesticides

Insecticides Cholinesterase Inhibitor Treatment  Decontamination  Antimuscarinic Agents  Benzodiazepine  Diazepam

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Insecticides Cholinesterase Inhibitor Treatment  Decontamination  Antimuscarinic Agents  Benzodiazepine

(Organophosphates)  Oximes  Pralidoxime Bolus: 600mg q ?4hr Infusion: 1-2g load f/b  Obidoxime, HI-6 500mg/hr

 ?carbaryl? 14

Insecticides Organophosphates

 Aging & Oximes

R

“Aging”

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5 Pesticides

Insecticides Organochlorines

 Large family of neuroexcitatory toxins  DDT and analogues

 Cyclodienes

 Hexachlorocyclohexane (lindane)

 Mirex and chlordecone

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Insecticides Organochlorines

 Large family of neuroexcitatory toxins  DDT and analogues  Most banned from industrialized countries  Na Ch Blockade  Neuroexcitation

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Insecticides Organochlorines

 Large family of neuroexcitatory toxins

 DDT and analogues  Cyclodienes  Most banned from industrialized countries  GABA Antagonists  neuroexcitation

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6 Pesticides

Insecticides Organochlorines

 Large family of neuroexcitatory toxins

 DDT and analogues

 Cyclodienes  Hexachlorocyclohexane (lindane)  Scabicide  GABA Antagonist  Seizures, neuroexcitation

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Insecticides Organochlorines

 Large family of neuroexcitatory toxins

 DDT and analogues

 Cyclodienes

 Hexachlorocyclohexane (lindane)  Mirex and chlordecone  Hopewell Epidemic (1974)  “Kepone Shakes”

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Insecticides Pyrethrins/Pyrethroids

 Pyrethrins  Naturally occuring  NaCh openers  Rapidly decompose

 Pyrethroids  Synthetic derivatives  More persistent, potent  Piperonyl butoxide

 P450 inhibitor 21

7 Pesticides

Insecticides Pyrethrins/Pyrethroids

 Toxicity  Pyrethrins  Allergic

 Pyrethroids  Type 1  Type II  Non-CN  -CN  “T” Syndrome  More potent  Tremor  “CS” Syndrome  Low tox in humans  Choreoathetosis, salivation  GI (saliv, n/v/d), pulmonary neuroexcitation 22

Insecticides Pyrethrins/Pyrethroids

 Treatment  Supportive  Decontamination  Skin  GI - AC

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Insecticides Others

 Boric Acid  Ant/cockroach killer  Mechanism unclear  Symptoms  GI (blue-green emesis/diarrhea)  Kidney  CNS/Neuro  Derm (boiled lobster rash)

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8 Pesticides

Insecticides Others

 Amitraz  2-agonism  Treatment  Fipronil  supportive  GABA antagonist  Insect:Human 1000:1  Imidacloprid  Nicotinic  Avermectins (abamectin, ivermectin)  Fermentation of Streptomyces avermitilis

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Rodenticides

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Rodenticides Compound 1080/1081

 Sodium Monofluoroacetate (SMFA)  Compound 1080  Flouroacetamide  Compound 1081

 Inhibit aconitase in Krebs cycle  “lethal synthesis”

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9 Pesticides

Compound 1080/1081

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Rodenticides Compound 1080/1081

 Symptoms  apprehension  dysrhythmias, seizures, coma, ↓ Ca  Not flouride toxicity

 Treatment  Unknown

 Ethanol, Glycerol 29 monoacetate,

Rodenticides PNU (Vacor)

 n-3-pyridylmethyl-N-p-nitrophenyl urea  Interferes with nicotinamide activity in pancreas, brain, liver

 Rapid development of  Diabetes mellitus (DKA)  Orthostatic hypotension  CNS toxicity  GI perforation 30

10 Pesticides

Rodenticides PNU (Vacor)

 Treatment  Aggressive Decontamination

 Nicotinamide

 Niacin

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Rodenticides Phosphine

 Rodenticide (Zinc Phosphide)  Fumigant (Aluminum Phosphide)

 Phosphine gas  Cellular poison  Inhibits cytochrome oxidase and ETC  Rotten fish / garlic-like odor

32

Rodenticides Phosphene

 Symptoms

 Low level exposure  Pulmonary edema (delayed)

 High level exposure  Multisystem failure  N/V, coma, seizures, hypertension, pulmonary edema

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11 Pesticides

Rodenticides Phosphene

 Treatment  Inhalation – supportive

 Ingestion  Intubation  lavage/suction  diluted HCO3 solution, milk  Supportive  NAC, Mg

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Rodenticides Strychnine

 Strychnos nux vomica  Glycine inhibition  Involuntary generalized muscular contractions  Opisthotonos, trismus, risus sardonicus  Treatment  Benzodiazepines  NM Blockade

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Rodenticides ATNU

 α-naphthyl-thiourea

 Acute pulmonary edema

 Mechanism unknown

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12 Pesticides

 History

 ‘superwarfarins’  Longer T1/2  100X more potent  Same mechanism

37

Warfarins Exogenous Vitamin K Vit K (phytonadione) Quinone

Vit Ki (inactive) Vit Ka (active) Vit K 2,3 epoxide hydroquinone FFP

Factors II,VII,IX,X Factors Iia,VIIa,Ixa,Xa (active)38

 Diagnosis & Treatment  Child/unintentional  none

 Suicidal/other  Labs

 Vit K1 (phytonadione) IV, PO, IM  FFP

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13 Pesticides

 Bromethalin  Uncouples oxidative phosphorylation  AMS, myoclonus, seizures, coma

 Norbormide (dicarboximide)  Norway rat selective smooth muscle constriction  Death from profound vasoconstriction  Other rats, rodents, humans don’t have the same receptor or transporter

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Herbicides

 Bipyridyl herbicides  Paraquat  Diquat  Chlorphenoxy herbicides  2,4-D, 2,4,5-T and Agent Orange  Glyphosate  Anilide derivatives

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 Paraquat/Diquat

 Redox cycling

 1 – depletion of NADPH  2 – superoxide formation  3 – lipid peroxidation cascade  4 – glutathione & NADPH depletion 42

14 Pesticides

 Paraquat

 Active transport into Type I & II alveolar epithelial cells

 Surfactant depletion, destruction of

alveoli 43

 Symptoms

 Dependant on amount ingested  May be delayed, especially with dilute products

 Caustic (Skin, GI Mucosa)

 Renal Toxicity/Failure  ARDS

 Paraquat – pulmonary fibrosis  CNS (somnolence, coma, sz, etc)  Diquat – predilection for pontine hemorrhage?

44

 Treatment  Skin Decon  Lavage (N/V usually occur though)  AC, Fuller’s earth, bentonite, garden clay  Hemodialysis, hemoperfusion, hemofiltration

 ?No O2 until PaO2 < 50mm Hg

45

15 Pesticides

 chemical analogs of auxins (a plant growth hormone)  Uncontrolled and lethal growth

46

 Corrosive, cell membrane damage  form Acetyl Co-A analogues, uncouple oxid phos?

 Symptoms  Treatment  GI  supportive  N/V, abdominal pain, diarrhea  CV  hypotension, nonspecific ECG abnormalities  CNS  coma, hypertonia, hyperreflexia,

Ukrainian opposition 47 presidential candidate Viktor Yushchenko

 Plant mechanism –  amino acid analogue  Human mechanism – unclear,  difficult to separate the toxicity of glyphosate from surfactants and other additives

 Symptoms  Treatment  GI/caustic  supportive  Pulmonary (?aspiration)  CV, renal, CNS toxicity 48

16 Pesticides

acetochlor amide propanil

 Symptoms  Treatment  methemoglobinemia  Methylene blue

49

Fungicides

 Metallic/organo-metallic  Ba, Cu, Cd, Sb, Hg  Substituted Aromatics  Chlorothalonil, pentachlorophenol, hexachlorobenzene  Thiabendazoles  Benomyl, terrazole, thiabendazole

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Fungicides Dithiocarbamates

51

17 Pesticides

Fumigants

 Phosphene – see rodenticides

 Methyl bromide

 Sulfuryl flouride

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Fumigants Methyl Bromide

 Heavier than air  Chloropicrin additive  Phased out (oxone-depleting agent)

 Skin  Treatment  irritation, blistering  supportive  Pulmonary  dyspnea, NCPE  CNS  visual disturbances, tremor, sz, coma 53

Fumigants Sulfuryl Fluoride (Vikane)

 Heavier than air  Chloropicrin  Suspected flouride poisoning mechanism

 Mucus membranes (skin, GI, resp)  irritation, blistering  Treatment  CNS  Supportive  paresthesias, tremor, sz, coma  monitor Ca  CV  Shock, cardiac dysrhythmias 54

18 Pesticides

Pesticides Others

 Moth balls

 DEET

 Molluscicides

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Others Moth Balls

Salt H2O XR Sx Tx water Camphor float float luc CNS/Sz support

faint metHb meth Napthalene sink float op Hemolysis blue Paradichloro N/V, HA, sink sink op support -benzene CNS

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Others DEET

 N,N-diethyl-3-methylbenzamide  Wide safety margin

 Primarily CNS toxicity  Only after high doses

57

19 Pesticides

Others Molluscicides

 quaternary ammonium compounds  carbamates  metals

 Metaldehyde  acetaldehyde?  GI – N/V/D, abdominal pain  CNS – seizures, coma, hyperthermia

58

Pesticides

 Insecticides  Fungicides

 Rodenticides  Fumigants

 Herbicides  Others

59

20 Terrorism / Hazmat

2012 ACMT Toxicology Board Review Course

Warfare, Terrorism and Other

J. Dave Barry Naval Medical Center Portsmouth Portsmouth VA

The Core Content of Medical Toxicology

Warfare, Terrorism and Other

 Chemical  Nuclear  Biological  Hazardous Materials

1 Terrorism / Hazmat

Chemical Agents

 Nerve agents  Blister agents  Incapacitating agents  Riot control agents  Pulmonary agents  Blood Agents (cyanogens)

Chemical Agents Nerve Agents  History  1930’s – Nazi’s synthesize “G” agents during WWII  Never used in battle  Tested in concentration camps  1940’s – Soviet Union begins production after capturing German munitions  1950’s – US begins production  1990’s – Aum Shinrikyo Matsumoto ‘94, Tokyo ‘95  Iraq against Kurds

Chemical Agents Nerve Agents

Goldfrank’s Toxicologic Emergencies – 8th Ed (2006)

2 Terrorism / Hazmat

Sympathetic Parasympathetic (cholinergic)

agit N M Sz M C sec mio

N T sec rr ne

sec vasoconstr hr N hr ne L

mot N M S sec N Fasic paraly mict

Aging Half-Life >14h 3h 2-6 min 48h

Chemical Agents Nerve Agents

 Personal Protection  Respiratory  Skin

 Decontamination  Alkaline solutions  Diluted sodium hypochlorite soln  Soap & water

3 Terrorism / Hazmat

Chemical Agents Nerve Agents

 Treatment  Atropine – combat excess muscarinic Ach  Goal – dry respiratory secretions  Diazepam – combat excess nicotinic Ach  Oximes (Pralidoxime) – combat “aging”

Aging >14h 3h 2-6 min 48h Half-Time

Chemical Agents Nerve Agents

 Pretreatment  Pyridostigmine  Carbamate (reversible)  Protect a small % of AchE from irreversible OP aging

4 Terrorism / Hazmat

Chemical Agents Blister Agents

 Mustards  Sulfur Mustard (HD)  Nitrogen Mustard (HN)  Lewisite (L)  Phosgene Oxime (CX)

Chemical Agents Blister Agents  History  1917 WWI, Ypres  1930’s Italians vs. Ethiopia  1940’s WWII  Japanese vs. Chinese  German/Japanese concentration camps  1960’s Egypt vs. Yemen (alleged)  1980’s Iraq vs. Iran

High casualty rate, low mortality (>20:1)

Chemical Agents Blister Agents

Sulfur Liquid Pale Garlic, Hours Immediate Fluid 2 weeks – Mustard yellow to onion or later , but filled 3 years (HD dark mustard effects brown delayed til hours later

Lewisite Liquid Colorless Geranium immediate Seconds Fluid Days (L) to amber -like smell to minutes filled or black

Phosgene Solid colorless Irritating Immediate Seconds Solid 2 hours oxime or as solid, wheal (CX) liquid yellow- brown as liquid

5 Terrorism / Hazmat

Chemical Agents Mustard  Mechanism  Alkylating agent  “Cyclization” reactive sulfonium ion  Alkylates sulfhydryl (-SH) and amino (-NH2) groups

 Depletes glutathione  Increased oxidative stress

Chemical Agents Mustard  Clinical Effects  Vapor or liquid exposure  Cellular damage w/i 1-2 min  Clinical effects 2-48hrs (usually 4-8hrs)  Skin  Erythema vesicles blisters/bullae  Eye  Range: Mild severe conjunctivitis  ‘legal’ blindness possible  Airways  Bronchospasm, pulmonary edema  Obstruction, hemorrhage in severe cases

Chemical Agents Mustard  Clinical Effects  Skin  Eye  Airways  GI  N/V, GI bleed  Systemic  BM suppression/immunosuppression  With high doses  IARC Group I – respiratory cancer

6 Terrorism / Hazmat

Chemical Agents Mustard  Diagnosis  M8, M9 paper, etc  Thiodiglycol  Urine, blood

 Treatment  Decontamination  Supportive/symptomatic care  No antidote

Chemical Agents Mustard  Decontamination  Remove large globs or liquid  Soap and water, diluted hypochlorite  Military self decon kits

Chemical Agents Lewisite  History  less persistent alternative to mustard agents  No confirmed battlefield use

 Mechanism  Unclear  similar to other arsenicals?  Inhibition of pyruvate dehydrogenase  Inhibition of other lipoamide enzymes

7 Terrorism / Hazmat

Chemical Agents Lewisite  Clinical Effects  Immediate effects (unlike mustard)  Similar to mustard  Skin – erythema, vesicles, blisters  Eyes - conjunctivitis  Airways – MM irritation, pulmonary edema  Treatment  Same as mustard  BAL (British Anti-Lewisite) (dimercaprol)  Topical / systemic

Chemical Agents Phosgene Oxime  Background  No battlefield use  Penetrates garments more quickly than other agents  Rapid onset severe and prolonged effects

 Mechanism  Unclear  Not a true vesicant  Irritant or “nettle” agent

Chemical Agents Phosgene Oxime  Clinical Effects  Immediate severe tissue damage  Skin – erythema, wheals, urticaria  Eyes – conjunctivitis  Airways – pulmonary edema  Treatment  Supportive  No antidote

8 Terrorism / Hazmat

Chemical Agents Incapacitating Agents

 US experimented with multiple agents

 Antimuscarinics felt to be most promising  BZ (3-quinuclidinyl benzilate)  Physostigmine is potential antidote

 Opioids  Kolokol-1 (fentanyl analogue)  2002 Chechen Moscow Theatre Siege

Chemical Agents Riot Control Agents

 CN (chloracetophenone) Mace®  CS (o-chlorobenzilidene malenonitrile)  Capsaicin (“pepper spray”)

 Chloropicrin (trichloronitromethane)  DM (adamsite)(vomiting agent)

Chemical Agents Riot Control Agents  OC - Capsaicin (“pepper spray”)  better safety margin / more potent  Release of Substance P - “neurogenic inflammation”  depletion

9 Terrorism / Hazmat

Chemical Agents Pulmonary Agents

 Phosgene (CG)  Diphosgene (DP)  Chlorine (Cl)

 Nitrogen Oxides (NOx)  Perfluoroisobutylene (PFIB)

Chemical Agents Pulmonary Agents

Chlorine (Cl) Yellow-green Gas, with Strong bleach Intermediate Immediate pressure and irritation, cooling can be pulmonary liquid edema 2-24hrs later Phosgene Colorless or Gas, with Freshly mown Poor Delayed up to (CG) white to pale- pressure and hay, green corn 48hrs (usually yellow cloud cooling can be 2-6 hrs) liquid Diphosgene Colorless gas Freshly mown Poor Delayed up to (DP) hay, green corn 48hrs (usually 2-6 hrs)

Nuclear/Radiological

 Atomic Radiation Primer  Measurement  Acute Radiation Syndrome/Dosimetry  Treatment of Radiation Injuries  Scenarios  Specific Radionuclides

10 Terrorism / Hazmat

Nuclear/Radiological Atomic Radiation Primer

 Nonionizing radiation  Doesn’t have enough energy to disrupt atoms or molecules

 Ionizing radiation  Radiation with enough energy to disrupt an atom or molecule that it hits

Nuclear/Radiological Atomic Radiation Primer

 Ionizing Radiation Effects  DNA effects  Repairable Damage  Mutations  Cell Death

Nuclear/Radiological Atomic Radiation Primer

 Ionizing Radiation Effects  DNA effects  Repairable Damage  Mutations  Cell Death  Free Radical Formation  Hydroxyl free radicals

11 Terrorism / Hazmat

Nuclear/Radiological Atomic Radiation Primer

 Ionizing Radiation Effects

 Dose absorbed depends on:  Time  Distance (1/R2)  Shielding

Nuclear/Radiological Atomic Radiation Primer

Nuclear/Radiological Measurement

Geiger Counter

Gamma Spectroscopy

12 Terrorism / Hazmat

Nuclear/Radiological Acute Radiation Syndrome

Nuclear/Radiological Acute Radiation Syndrome

0.7-10 Gy 70-1000 Rads

10-50 Gy 1000-5000 Rads

>50 Gy >5000 Rads

 CXR – 0.25 mRem  Abd CT – 5-60 mRem  Whole body dose limit – 5 Rem/yr

Nuclear/Radiological Dosimetry

 Nonspecific/GI symptoms (time to vomit)  <0.7Gy (70Rads): no effects  1-2Gy (100-200Rads): vomiting in 50% w/i 6hrs

 3Gy (300Rads): vomiting w/i 4hrs LD50/60 without medical care  8Gy (800Rads): early, severe vomiting

13 Terrorism / Hazmat

Nuclear/Radiological Dosimetry

 Lymphocyte reduction  Drop in lymphocytes q6hrs  Dose rate of decline of lymphocytes

Nuclear/Radiological Dosimetry

 Chromosomal cytogenetics  # abberations dose

Nuclear/Radiological Treatment

 Treat conventional (lifethreatening) injuries first!

 Decontaminate (if necessary)  External decon (remove clothes, decontaminate wounds first)  Internal decon

 Dosimetry screen  Cbc w diff q6  Absolute lymphocyte count (ALC)

14 Terrorism / Hazmat

Nuclear/Radiological Treatment

 Internal decontamination  Antacid (decrease absorption)  Precipitate to insoluble salt  Saturate critical organ with stable isotope  KI (I131)  Chelation  DTPA (239Pu), prussian blue (137Cs), BAL, etc.  Catharsis (decrease residence time)

Nuclear/Radiological Treatment

 Supportive care  Antimicrobials, antiemetics, anxiolytics, antidiarrheals, fluids, electrolytes, analgesics, burn therapy, psychosocial care  Surgical intervention in first 36hrs  Stimulation of the hematopoetic system  cytokines, colony stimulating factors

Nuclear/Radiological Sources/Scenarios

 Simple Radiological Device  RED: radiological emitting device  Radiological Dispersal Device

 Reactor Accident - ’meltdown’ (criticality)  Improvised Nuclear Device  Nuclear Weapon

15 Terrorism / Hazmat

Nuclear/Radiological Specific Radionuclides

Radioactive elements act the same in the body as regular elements, they just give off radiation.

 131I  Radon  Depleted Uranium

Nuclear/Radiological Specific Radionuclides

 Iodine (131I)  T1/2 = 8.03 days, emits beta/gamma radiation  Low levels in hospital nuclear medicine departments  Nuclear reactor accidental releases / nuclear bombs

 Accumulates in thyroid tissue  if incorporated – thyroid damage

 Prophylactic treatment with Potassium Iodide (KI)

Nuclear/Radiological Specific Radionuclides  Radon (222Rn)  Heaviest noble gas, alpha/gamma emissions  Product of the natural decay of uranium in soil, concentrated indoors  Largest component of background radiation

16 Terrorism / Hazmat

Nuclear/Radiological Specific Radionuclides

 Radon (222Rn)  incidence of lung cancer (IARC I) (EPA estimates 21,000 deaths/yr)  Avoidance: enclosed space ventilation, detectors, don’t smoke

Nuclear/Radiological Specific Radionuclides  Depleted Uranium (238U)  Natural uranium is mixture of 235U (0.7%) and 238U (99.3%). Reactors and weapons require the more radioactive 235U

 After enrichment, 238U is left  0.7 X as radioactive as natural uranium

 T1/2 45billion years (very little decay)  Alpha, beta, gamma emmitter

Nuclear/Radiological Specific Radionuclides  Depleted Uranium (238U)  Low risk radiation hazard  internal contamination (inhalation) is controversial.

 Primarily a chemical toxicity (renal toxicity)

17 Terrorism / Hazmat

Biological Warfare

 Toxins  Bacteria  Viruses

Biological Warfare Toxins

 Botulinum Toxins  Ricin  Staphylococcal Enterotoxin B (SEB)  T-2 Mycotoxins

Biological Warfare Botulinum Toxins  Produced by Clostridium Botulinum  7 antigenic types: A-G  Military relevance  Most potent toxins known  Easily produced  Weaponized by several countries  Soviet Union, Iran, Iraq, North Korea, Syria  1960’s US – Agent X  Terrorists – Aum Shinriky (1990-1995)

18 Terrorism / Hazmat

Biological Warfare Botulinum Toxins  Inhibits Ach release at peripheral NMJ  Heavy chain binds to cell membrane, endocytosis allows entry to cell  Light chain cleaves specific sites of SNARE proteins, inhibiting exocytosis and Ach release  Doesn’t cross BBB

JAMA. 2001;285:1059-1070

Biological Warfare Botulinum Toxins

 Foodborne: toxin ingestion after production by bacteria in (canned) food  Infant: intestinal colonization  Wound: colonization  Inhalational: weaponized agents

 All have similar clinical picture:  Progressive descending flaccid paralysis  Always starts with cranial nerves/bulbar involvement

Biological Warfare Botulinum Toxins

 Diagnosis  Mouse neutralization assay  ELISA  Wound or stool Culture

JAMA. 2001;285:1059-1070

19 Terrorism / Hazmat

Biological Warfare Botulinum Toxins  Treatment  Supportive care  Antitoxin (equine)  Bivalent (A,B)  Type E

 Immune Globulins (BIG)  BIG (BabyBIG)

 Heptavalent (A-G) (dBIG)(Fab2 fragment)

Biological Warfare Botulinum Toxins

 Vaccine  Pentavalent (A-E) (IND)

Biological Warfare Ricin

 Ricinus Communis (castor Bean)  attractive as a biological weapon since it’s widely available, cheap and has a heat stable toxin  History  Compound W (WWII)  Georgi Markov (1978)

20 Terrorism / Hazmat

Biological Warfare Ricin  Mechanism  Inhibits protein synthesis  B Chain  Binds to cell surface, undergoes endocytosis to enter cell  A Chain  Binds and inhibits 60S ribosome, inhibiting protein synthesis

Biological Warfare Ricin

 Symptoms vary based on route of exposure  In general: Local tissue irritation regional lymph node necrosis multi-organ failure  PO  N/V/D, vascular collapse, shock  IM  Local pain, regional painful swollen lymph nodes, multi- organ failure  Inhalational  Pulmonary edema, pneumonia, mediastinal lymphadenitis, multi-organ failure

Biological Warfare Ricin  Diagnosis  ELISA assay of nasal swab, blood or other fluids  Treatment  Supportive care  AC may bind orally ingested toxin  No antidote

 Prophylaxis  None, vaccine being investigated

21 Terrorism / Hazmat

Biological Warfare Staphylococcal Enterotoxin B

 Military relevance  potent compared to chemical agents  Incapacitating (usually not lethal)  Studied by US in 1960’s as a biological incapacitant (PG)

Biological Warfare Staphylococcal Enterotoxin B

 “superantigens”  Profound activation of the immune system  Bind monocytes (MHC Class II molecules) - stimulation of helper T-cells - massive release of cytokines (interferon gamma, interleukin-6, TNF-) - intense inflammatory response

Biological Warfare Staphylococcal Enterotoxin B  GI Syndrome  Identical to staph food poisoning  Pulmonary Syndrome  inhalation of weaponized toxin

22 Terrorism / Hazmat

Biological Warfare Bacteria

 Anthrax  Plague  Tularemia  Brucellosis  Q Fever

Biological Warfare Anthrax  Bacillus anthracis  Gram +, capsulated, spore-forming bacillus  Virulence factors  Antiphagocytic capsule  Lethal toxin  Edema toxin

Biological Warfare Anthrax  Virulence factors  Antiphagocytic capsule  No virulence without this capsule  Lethal toxin  Zinc metalloprotease  Stimulates macrophages to release TNF and IL-6  Edema toxin  Calmodulin-dependent adenylate cyclase  cAMP leads to massive edema and impaired neutrophil function

23 Terrorism / Hazmat

Biological Warfare Anthrax  General Pathophysiology  Spores exist worldwide in the soil  Spores enter the body, are ingested by macrophages and germinate  Incubation period 1-6 days  Bacteria multiply in local lymph nodes leading to: edema, hemorrhage tissue necrosis

Biological Warfare Anthrax

 Cutaneous  Inhalational  GI

Biological Warfare Anthrax  Cutaneous  95% of cases, 2000 annually worldwide  Vesicle – painless necrotic ulcer – lymphadenitis – black eschar – scar  Septicemia is rare.

24 Terrorism / Hazmat

Biological Warfare Anthrax  Cutaneous  Inhalational  Woolsorters disease  Aerosol release from Biological weapons  Fever, malaise, myalgia, fatigue chest pain, respiratory distress cyanosis, shock, death  Wide mediastinum  Hemorrhagic meningitis is common  Anticipated mortality essentially 100%

Biological Warfare Anthrax

 Cutaneous  Inhalational  GI  Rare, but high mortality 25-60%  Ingestion of poorly cooked, contaminated meat  N/V/D, abdominal pain ascites, hematemesis - toxemia, shock, death

Biological Warfare Anthrax

Med Sci Monit. 2003;9(11):RA276-283

25 Terrorism / Hazmat

Biological Warfare Anthrax  Immunization  Cell free vaccine  attenuated, unencapsulated strain  Main ingredient is ‘protective antigen’  FDA approved for “at risk” populations

Biological Warfare Anthrax  Immunization  Prophylaxis

Med Sci Monit. 2003;9(11):RA276-283

Biological Warfare Plague

 Biologic Warfare History  Crimean port city of Caffa 1346-1347  First attempt at biologic warfare

26 Terrorism / Hazmat

Biological Warfare Plague

 Biologic Warfare History  Crimean port city of Caffa 1346-1347  First attempt at biologic warfare  WWII Japanese Unit 731  Suspected use against the Chinese

Biological Warfare Plague

 Biologic Warfare History  Crimean port city of Caffa 1346-1347  First attempt at biologic warfare  WWII Japanese Unit 731  Suspected use against Chinese  Soviet Union 1970’s-1980’s  Reported to have genetically engineered, dry, antibiotic resistant form of plague

Biological Warfare Plague  Yersinia pestis  Gram -, nonsporulating, anaerobic bacillus  More deaths than any other infectious agent in history  Virulence Factors  Antiphagocytic fraction, pH 6 antigen, Yop H, Yop E, Yop M, V antigen, plasminogen activator  environmental signals within the host (pH, temp, etc) induce the synthesis and activity of these factors, contributing to virulence.

27 Terrorism / Hazmat

Biological Warfare Plague

Biological Warfare Plague  General Pathophysiology  Introduction by flea, ingestion or inhalation  Initially susceptible to phagocytisis but induction and synthesis of virulence factors leads to resistance  Spread to regional lymph nodes (1-8d incubation)  Septicemia and multi-organ involvement if untreated

Biological Warfare Plague

 Bubonic  Pneumonic

28 Terrorism / Hazmat

Biological Warfare Plague  Bubonic  Bubo  Painful lymphadenopathy (90% inguinal or femoral)  Constitutional symptoms (F/C, HA, etc)  5-15% develop 2o pneumonic plague

Biological Warfare Plague  Bubonic  Pneumonic  1o: inhalation of aerosols  human-human or weaponized  2o: hematogenous spread  Productive cough with blood-tinged sputum  Bilateral alveolar infiltrates

Biological Warfare Plague

JAMA. 2000; 283:2281-2290

29 Terrorism / Hazmat

Biological Warfare Plague

JAMA. 2000; 283:2281-2290

Biological Warfare Plague

 Vaccination  Killed whole cell vaccine  Not effective against pneumonic plague

 Other vaccine development underway

Biological Warfare Viruses

 Smallpox  Equine Encephalitis  Viral Hemorrhagic Fevers (VHF)

30 Terrorism / Hazmat

Biological Warfare Smallpox

 Variola a poxvirus  large enveloped DNA virus  Certified by WHO as eradicated in 1977

 Military Relevance  Infectious as aerosol  Increasingly naive population (not immunized)  Easy large scale production, stable virus

Biological Warfare Smallpox

 Incubation – not contagious, 7-17 days

 Prodrome – viral syndrome, 2-4 days

 Rash – centrifugal, highly contagious  Vesicular - pustular - umbilicated - scab Scabs form 10-14d after onset of rash  Recovery – immunity  not contagious once all scabs separate 14-28 d after rash onset

Smallpox Day 3 of Day 5 of Day 7 of Rash rash rash rash

 Centrifugal  Hands/face  Synchronous  All in same stage

 Highly contagious by aerosol  30% mortality in unvaccinated population

31 Terrorism / Hazmat

Biological Warfare Smallpox  Complications  Bronchitis, pulmonary edema  Arthritis, osteomyelitis  Encephalitis  Keratitis, corneal ulcer  Infection in pregnancy  High perinatal fatality

Biological Warfare Smallpox

Biological Warfare Smallpox  Lab Diagnosis –  virus isolation from pharyngeal swab or scab material (PCR, ELISA)  Treatment  Supportive care  Isolation (and vaccination) of patient and all contacts for 17 days  Vaccination (w/i 4 days)  VIG (w/i 1 week)  Cidofovir

32 Terrorism / Hazmat

Biological Warfare Smallpox  Vaccination  Vaccinia – a poxvirus related to cowpox  Scarification with a bifurcated needle  Contraindicated in:  Immunosuppresed  HIV  Eczema  other skin diseases  Pregnancy  Children < 18mo

Hazardous Materials

 Treaties  Incident Command System, Site Safety  National Pharmaceutical Stockpile  Regulatory/Legal Acts

end

Hazardous Materials Control Zones

Hot Zone WarmZone Cold Zone

33 Terrorism / Hazmat

flammability

health instability

special

Warfare, Terrorism and Other

 Chemical  Nuclear  Biological  Hazardous Materials

34 Anmicrobials

Anmicrobials

Michael Policastro, MD Director, Medical Toxicology, QESI Clinical Assistant Professor, WSU

Overview

• Anmicrobials • Anmycobacterials • Anvirals • Disinfectants • Anfungals • Anparasics • Adverse Effects by Systems

Anbiocs

• Cell Wall (β- lactams, Glycopepdes- Vanc) • Cell membrane (Polymyxin B) • Protein synthesis (Aminoglycosides,Tetracycline, Linezolid Macrolides, Chloramphenical) • Nucleic Acids (Fluoroquinolones, Metronidazole, Rifampin) • An-metabolites (Sulfonamides,Trimethoprim)

1 Anmicrobials

Β-lactam

• Penicillins: - Anaphylaxsis, SZ ( Picrotoxin binding site GABA), ↑K – Hoigne Syndrome: males, fear/illusion, apprehension – Jarisch-Herxheimer: fever, chills, rash; lysed bacteria • Cephalosporins: nMTT side chain • ( moxalactam, cefazolin, cefoperazone, cefmetazole, cefmandole, cefotetan) • hypothrombinemia, Vit. K epoxide reductase inhibion, • disulfiram rxn • Cefaclor = serum sickness • Imipenem: Seizures, Picrotoxin binding site • No PNC cross reacvity with Impenem, Aztreonam

Disulfiram reacons

• Metronidazole • Cephalosporins with NMTT side chain: - cefoperazone, cefamandole, moxalactam, cefotetan, cefmetazole • Chloramphenical • Nitrofurantoin • Trimethoprim-sulfamethoxazole • Griseofulvin • OSHA: chlorpropamide, tolbutamide • Mushrooms: Coprinus,Clitocybe,Tricholoma

Clinical Environmental Health and Toxic Exposures .Sullivan and Kreiger.2001 . Table 18-4. P.238

Vancomycin

• Inhibits cell wall synthesis binding D-alanyl-D- alanine cell wall precursors • Tox: Red Man syndrome, ototoxicity, nephrotoxicity

2 Anmicrobials

Aminoglycosides

• Inhibits 30s ribosomal subunit • Nephrotoxicity, Ototoxicity, Vebulotoxicity • NMB: inhibit presynapc release of ACH

Chloramphenical

• Inhibits 50s ribosomal subunit • Metabolism: glucuronyl transferase • limited conjugate in children • “Grey baby”-voming,anorexia, ash color, met acidosis • Aplasc anemia, peripheral neuropathy , opc neuris , metabolic acidosis, cardiovascular collapse

Drugs that undergo primary Synthec Phase II Biotransformaon that you may forget

• Glucuronidaon : Valproic acid, lamotrigine, opioids, APAP, irinotecan, 5-FU, chloramphenical

• Acetylaon: INH, hydrazines, Sulfonamide, Dapsone, amonafidine

3 Anmicrobials

Macrolides/Ketolides/Licosamides

• Inhibit 50s ribosomal subunit • Eythromycin,azithromycin,clarithromycin, Clindamycin • Inhibit 3A4 except azithromycin, ↑QT • Inhibit PGP intesnal = Digoxin • Chronic cholestac hepas, sensory neural hearing loss • Telithromycin: carbamate side chain; cholinergic crisis in Myasthenia pts • Clindamycin: C.diff, Stevens-Johnson, NMB, dysrhythmias

Tetracycline

• Inhibits 30s/50s ribosomal subunit • Teratogen- Teeth discoloraon, hypoplasc enamel, seen aer 4th month • Benign intracranial hypertension • Phototoxicity, pneumonis, drug-induced Lupus • Minocycline: Lupus like syndrome, Diabetes Insipidus ( DI) • Democycline: nephrogenic DI

Linezolid

• Inhibits N-formylmethionyl- tRNA • HA, thrombocytopenia • Brown discoloraon tongue • Weak MAO inhibitor • Serotonin syndrome with SSRIs

4 Anmicrobials

Nitrofurantoin

• Pulmonary: dyspnea/cough, intersal fibrosis • Rash, Lupus like syndrome • Neuropathy peripheral • Disulfiram reacons

Fluoroquinolones

• Inhibit DNA gyrase/topoisomerase • Binds Caons, esp. Mg2+ • Seizures: Binds Mg2+, + NMDA, (-) GABA • QTc= sequestraon Mg2+ • Carlage/Tendon damage • Hepatoxicty • Psychosis, serum sickness

Metronidazole

• Metallic taste • Peripheral neuropathy • Disulfiram reacon

5 Anmicrobials

Sulfonamides

• Inhibit para-amino acid/para-amino acid glutamic acid • Folate synthesis inhibitor • Hypersensivity Rxns • MetHgb, hemolysis • Pneumonis, hepatotoxicity- cholestasis, asepc menigis

Folate Inhibitors- Anmetabolites

• MTX • Sulfasalazine • Proguanil • Aminopterin • Pyrimethane • 5-FU • Dapsone • Atovaquone • Sulfonamides • Trimethoprim • Triamterene

Anmycobacterials- TB Drugs

• INH • Rifampin • Ethambutol • Pyrazinamide – niconamide analog, hepas, gout • Cycloserine • Para-Aminosalicylic acid- hepas, hypersensivity reacon, thrombocytopenia • Capreomycin

6 Anmicrobials

INH

• OD: Seizures, coma, metabolic acidosis • INH Tox : opc neuris, pancreas, hepas • TOX: +/-slow acetylators, 2E1 • TX: Pyridoxone

Goldfrank’s Toxicologic Emergencies. 6th edion. 2006. Figure 55-3 p.863

B6 ( Pyridoxine)

• Tx: hydrazines, ethylene glycol • Dose: INH- gram/gram • OD: sensory neuronal neuropathy, ataxia

Hydrazines

• INH • Non-selecve MAO A/B Inhibitors: -Phenelzine, Isocarboxazid, Procarbazine • Hydrazine ( Diamine) • Monomethyhydrazine • Gyromitra • Ginkgo Biloba seeds ( 4-Methoxypyridoxine)

7 Anmicrobials

Rifampin

• Binds B units DNA dependent RNA polymerase • * 3A4 inducer • Red/orange body fluids • False negave PPD • TOX: hepas, Lupus like syndrome, ARF, thrombocytopenia, hemolyc anemia, eosinophilic colis

Ethambutol

• 1st line in pregnancy • Chelates metal • ** Zn chelaon = opc neuris • ** shi wavelength discriminaon • ** loss red/green discriminaon

Cycloserine

• Analog of alanine • Neuro dysfuncon • Sz, psychosis • Contraindicated in Seizure Paents • Safe in breast feeding

8 Anmicrobials

Capreomycin

• * Hearing loss, nnitus • Preonuria, electrolyte loss • Sterile abscess at injecon sites

Anmalarial

• Quinine • Chloroquine/Hydroxychloroquine/Amodiaquine • Primaquine- MetHgb, Contraindicated Pregnancy • Mefloquine: Neuropysch- Sz, psychosis • Proguanil/Pyimethamine/Suldoxine • Atovaquone • Dapsone • Artemisinin: very safe, sz

Chloroquine Quinine • Cardiac: Class Ia effect, neg • Cinchoa tree ( Rubiacea) ionotropy, VT, VF • Cinchoism: auditory, GI, sweang, HA, vasodilaon • Hypokalemia • Cardiac: Class Ia affect, • Sz, transient blindness myocardial depression, phase 0 • TX: AC, Hypokalemia depression, vasodilaon protecve Do NOT treat • Heme: thrombocytopenia, aggressive, diazepam pupura, hemolysis • CNS: Blindness, Tinnitus/ deafness • Hypoglycemia- sulfonyurea like • TX: MDAC, Bicarb, ?Octreode

9 Anmicrobials

Anmalarials:Folate Inhibitors

• Atovaquone: Rash, erythema mulformae • Proguanil: GI, megaloblasc anemia, rash • Pyrimethamine: N/V, SZ, megaloblasc anemia • Dapsone

Dapsone

• Bacteriostac synthec sulfone, inhibits folic acid synthesis, binds dihydropterate synthase • Oxidizer, MetHgb, Hemolysis, also Sulemoglobin • “Sulfone Syndrome” delayed hypersensivity syndrome = fever, eosinophilic pneumonia, dermas, hepac necrosis • Also: thrombocytopenia, neutropenia, neuropathy • TX: MDAC, Methylene Blue, Exchange transfusion

HIV Drugs

Nucleoside Reverse Non-Nucleoside Reverse Nucleode Analogue Transcriptase Inhibitors (NRTI) Transcriptase Inhibitors tenofovir DF/Viread (TDF) zidovudine/Retrovir (AZT, ZDV) (Non- NRTI ) Adefovir/Hepsera didanosine/Videx, Videx EC (ddI) nevirapine/Viramune Emtricitabine/Emtriva zalcitabine/HIVID (ddC) delavirdine/Rescriptor stavudine/Zerit (d4T) efavirenz/Susva lamivudine/Epivir (3TC) Fusion (entry) inhibitors abacavir/Ziagen (ABC) Protease Inhibitors (PI) Enfuvirde/ Fuzeon indinavir/Crixivan ritonavir/Norvir saquinavir/Invirase,Fortovase nelfinavir/Viracept amprenavir/Agenerase lopinavir/ritonavir, Kaletra Atazanavir/Reyataz

10 Anmicrobials

HIV Drug Toxicies

NRTI • Protease Inhibitors -lacc acidosis, impaired -Dyslipidemias, Hyperglycemia β –oxidaon *ritanovir- hepatotoxicity, PGP TX: L-carnine inhibitor -peripheral neuropathy *Indinavir-nephrolithiasis -Lipodystrophy syndrome

NNRTI - Skin rashes ( Stevens- Johnson, TEN, Eosinophilic systemic) * nevirapine - Hepatotoxicity, pancreas - * Efavirenz- neurotox

Side effects of anretroviral medicaons Side Effect Drugs

Lactic acidosis Nucleoside reverse transcriptase inhibitors, especially didanosine, stavudine

Hypersensitivity reaction Abacavir, nevirapine

Liver toxicity Saquinavir, ritonavir, nelfinavir, tenofovir, nevirapine, efavirenz, atazanavir

Pancreatitis Didanosine, stavudine, zalcitabine, lopinavir/ritonavir

Nephrolithiasis Indinavir

Acute tubular necrosis Tenofovir

Acute interstitial Indinavir, ritonavir nephritis

Myelosuppression Zidovudine

Myopathy Zidovudine

Neuropathy Stavudine, didanosine, zalcitabine

AnVirals

• Fusion Inhibitors- • M2 protein Blockers Guanosine Analogs - Amantadine, Rimantadine -Acyclovir • Neurominidase Inhibtors -Famciclovir -Oseltamivir -Ganciclovir • Other -Valacyclovir - Ribavirin -Valganciclovir - Cidofovir • Pyrofosfate Analog - Palivizumab - Foscarnet

11 Anmicrobials

Anvirals

• Amantadine: pre-synapc DA blockade; TOX: Hyperthermia,↑QT, ? Ancholinergic • Oseltamivir: GI • Acyclovir: Neurotox/Nephrotox- crystal formaon • Ganciclovir: Renal tox • Valacyclovir: TTP • Foscarnet: *chelates divalet metals: Ca, Mg, Fe, Zn, Nephrotox • Cidofovir: Nephrotox, OD TX: * Probenicid decreases renal clearance/renal failure • Ribavirin: teratogen,sperm morphology

Ansepcs, Disinfectants, Sterilants

• Ansepc: Agent applied to living ssue to kill/ inhibit microorganism

• Disinfectant: Agent applied to inanimate objects to kill microorganisms.

• Sterilant : Agent applied to inanimate objects to kill all microorganisms and spores

Disinfectants

• Formalin: 37 % Formaldehyde + 15 % methanol, Formaldehyde IARC 1 classificaon

• Phenol ( carbolic acid ) : severe burns skin /oral white ulcers, sz, met acidosis, rabbit syndrome (↓DA) -TX: PEG ,Isoproponal – skin burns

• Benzalkonium chloride: quarternary ammonium- occasional paralysis, NMJ- ACHE inhibion, occ. asthma

12 Anmicrobials

Ansepcs

• Chlorhexidine: vaporized converts p-chloraniline, MetHgb

• Hydrogen peroxide: Conc. dependent, possible air emboli, local injury

- • Iodophors: (I2 ) elemental iodine, (I ) iodide: ingeson, blue- purple emesis with starch, false posive Hematest (orthotoluidine), causc, GI bleed psuedohyperchloremia. TX: Covert Iodine to Iodide with milk/starches, thiosulfate

• Potassium Permanganate: oxidizer, reacts with H20 to form manganese dioxide ( stains areas brown-black), potassium hydroxide and molecular oxygen. -Acute : local injury, MetHGB. - Chronic: possible Manganese poisoning- ams, parkinsonism, behavior d/o. -TX: Skin stains- dilute oxalic acids, NAC

Sterilants

• Ethylene Oxide: spontaneous aborons,Oligiospermia mutagenic, Possible carcinogenic- leukemia, gastric CA, motor/ sensory neuropathies • Glutaraldehyde: vapor- cp, palpitaons, mucosal irritant

Anfungals

• Amphotericin • Imidazoles -Liposome B complex to reduce ( ketaconazole, clotrimazole, econazole, nephrotox miconazole) -Inhibit fungal cell walls -Nephrotox • 3A4 Inhibitors, ↑QT with -Fever, chills due to PGE2 disrupon terfenadine,cisapride,astemizole -↓ K, Mg, WBC, Plts • Ketoconazole: Alopecia, gynecomasa, adrenal suppression, - Tinnitus androgen suppression, hepas

• Triazole (fluconazole, itraconazole, terconazole, voriconazole) -Inhibits ergosterol synthesis, ↑LFTs - Inhibits * 3A4

13 Anmicrobials

Anhelmincs

• Mebenazole: teratogenic,rash • Thiabendazole: GI, cholestasis,leukopenia,Hypersensivity rxn • Levamisole: ↓Plts, encephalopathy, TEN • Niridazole: Sz • Piperazine: Angioedema, sz • Metrofonate: inhibits ACHE, cholinergic crisis • Hyocanthone:mutagenic, carcinogenic • Ivermecn: Facial edema, bullous skin • Suramin: Renal/adrenal insufficency, TEN • Anmony ( 3+/5+): GI, dermas; TX:BAL

Neurologic Adverse effects

• AMS: Ethambutol, PNC, Chloramphenical, Mefloquine, Efavirenz • Intracranial Hypertension: Tetracyclines, Albendazole • Seizures: PNC, Cephalosporins, Rifampin, Sulfonamides, Fluoroquinolones, INH, Ethylene oxide, Imipenim • Neuromuscular blockade: Polymyxin B, Fluoroquinolones,colismethate Aminoglycosides, Clindamycin, Vancomycin, Benzalkonium chloride • Myosis: Chloroquine, PNC, Rifampin, Sulfonamides, Zidovudine • Peripheral Neuropathy: Chloramphenical, Flagyl, Ritanovir, Didanosine, Zalcitabine,Stavuidine, amprenavir • Movement Disorder: Potassium Permanganate, Phenol • Ototoxicity: Vancomycin, Chloroquine/Quinine, Aminoglycosides, erythromycin • Opc neuris: Ethambutol, Chloramphenical, Cidofovir, Gancyclovir • Renal Blindness: Quinine, Hydroxychloroquine

Skin Rash Adverse Effects

• “Red Man”- Vancomycin • “Grey baby”- Chloramphenical • Blue ( MetHgb): Sulfonamides,Dapsone, Primaquine, chloroquine, nitrofurans, • Stevens-Johnson: PNC, Cephalosporins, Sulfa, nevirapine • TEN: PNC, Sulfas, nevirapine • Vesiculobullous: PNC, Rifampin, Sulfonamides, Griseofulvin • Vasculis: Levamisole • Acute Hypersensivity Syndrome: Sulfas, Bacitracin, Clindamycin, Lincomycin, Nitrofurazone, nevirapine • Alopecia: Selenium Sulfide

14 Anmicrobials

Renal/GU Adverse Effects

• Acute Tubular Necrosis: Aminoglycosides, Acyclovir, Amphotericin,Pentamidine, Polymyxins, Fluroquinolones,Foscarnet, Ritonavir, Tenovir, Phenazopyridine • Acute Intersal Nephris: PNC,Ampicillin,Rifampin,Sulfonamides, Vancomycin • Nephrolithiasis/Obstrucon: Indanavir, Sulfonamides ( crystal deposits), Acyclovir • Tubular dysfuncon: Aminoglycosides, Amphotericin, Tetracycline, Griseofulvin • Decrease Sperm: Ethylene oxide , Nitrofurantoin, Ribavirin • Aborons: Ethylene Oxide

Electrolyte Adverse Effects

• Diabetes Insipidus: Amphotericin, Foscarnet, Minocycline, Rifampin, Streptozotocin • Hypokalemia ( ↑ QT): Aminoglycosides, Amphotericin, Chloroquine • Hyperkalemia: PNC, Triamterene, Trimethoprim • Hypocalcemia (↑QT): Aminoglycosides, Neomycin • Hypomagnesium ( ↑QT): Aminoglycosides, Foscarnet, Fluroquinolones

Teratogens

• Fluconazole: Abnormal facies, cardiac, femoral bowing • Quinine: Hypoplasia 8th CN • Streptomycin: Hearing loss • Tetracycline: Teeth discoloraon, hypoplasc enamel, seen aer 4th month • Trimethoprim: NTD, hypospadias • *See Folate inhibitor list*

15 Anmicrobials

Hematologic/Immune

• Type I: IgE: PNC, tetracyclines, Sulfonamides, Nitrofurantoin,Streptomycin • Type II: Anbody IgG/IgM- cytopenias: Amoxicillin, Sulfonamide • Type III: Immune Complex IgG/IGM- Serum Sickness: Cefaclor • Type IV: T- lympocyte- contact dermas: Topical PNC • Oxidave Hemolysis/MetHgb: Dapsone, Nitrofurantoin, Phenol, Sulfonamides, Novobiocin • Agranulocytosis: B-lactams, Cephalosporins, Chloramphenical, Dapsone, Ganicyclovir, Rifampicin, Sulfonamides, Vancomycin • Thrombocytopenia: Amphotericin, Indinavir, Levamisole, Quinine, Rifampin, Trimethoprim-sulfamethoxazole, Vancomycin • TTP: Valacyclovir

16 GI / HEME

Gastrointesnal/Hematologic Toxicology Board Review

Michael Policastro, MD Director, Medical Toxicology, QESI Clinical Assistant Professor, WSU

1

Overview

GI Heme • Oral/Anal • Anplatelet • Hepac • Ancoagulants • Pancreas • Procoagulants • Anmolity • Thrombolyc • Inflammatory Bowel Meds • Iron • Anulcer • Erythropoien • Promolity

2

Oral Discoloraon

Tongue • Brown • Bromine, bismuth, arsenic, phenolpthalein, doxrubicin, quinacrine, tobacco • Green • Vanadium

• Black, Hairy • Cefoxin, corcosteroids,lansoprazole, penicillin, sodium perborate, sodium • White peroxide, tetracycline • Chlorhexidine, phenol, causc acids, hydrogen peroxide • Blue • Methylene blue • Blue Gray Gums • Bismuth, lead, mercury, copper salts, thallium, zinc

3

1 GI / HEME

Fecal Discoloraon

• Acetazolamide, aluminum hydroxide, • Black aminophylline,amphotericin b,barium, benzene,bismuth, bromides, charcoal,chloramphenical,chlorpropamide,clindamycin,c orcosteroids,cyclophosphamide,digitalis,feroous salts,fluoruracil,formaldehyde,halides,halothane, metals (Ag,As, Cu,Hg,Mn,Pb,Tl),hydralazine,methotrexetae,methylene blue, nitrates,NSAIDs, tetracycline,theophylline,warfarin

• Blue • Boric acid, chloramphenical, maganese dioxide, methylene blue • Yellow-green • Mercurous chloride, yellow phosphorus • Orange-red • Phenazopyridine, rifampin • Pink • Manganese dioxide, phenolthalein

4

Secreons and Muscarinic Receptors

• M 1,3,5 = Phospholipase C • M2,4 = Adenylate cyclase • M3 = sphincter of oddi, ciliary body • M4 =agonism =Clozapine sialorrhea • Also unusual drooling: Aminopyridine ( CCB treatment)

5

Selecve IgA deficiency- Drug Associated

• Captopril • Penacillamine • phenytoin

6

2 GI / HEME

Drugs that undergo primary Synthec Phase II Biotransformaon that you may forget

• Glucuronidaon : Valproic acid, lamotrigine, opioids, APAP, irinotecan, 5-FU, chloramphenical

• Acetylaon: INH, hydrazines, Sulfonamide, Dapsone, amonafidine

7

Hepatotoxin Classificaon Scheme

Clinical Environmental Health and Toxic Exposures .Sullivan and Kreiger.2001 .Figure18.3.pg 236. 8

Hepac Toxophysiology

• Ingested toxins: enter via portal blood • Inhaled,dermal: enter via hepac artery Zone 1 (periportal): highest O2,highest glycogen, highest mitochondria concentraon, Krebs cycle, more protein synthesis Zone 2 (intermediate)

Zone 3 (Centrilobar or peripheral): Lowest O2 tension, Glycogen storage, fat formaon, Cyp 450

Clinical Environmental Health and Toxic Exposures.Sullivan and Kreiger.2001.Figure18.1.pg 234. 9

3 GI / HEME

Zonal hepatotoxicity

• Zone 1 (periportal): Phosphorus, Iron, Allyl formate, P. Vulgarus endotoxin

• Zone 2 (intermediate or midzonal): Beryllium, Ngaione

• Zone 3 (Centrilobar or peripheral): Bromobenzene, halothane carbon tetrachloride, ethanol, APAP, paraquat,chlorinated hydrocarbons - *Think 2E1 metabolites *

10

Steatosis

• Macrovesicular: Nucleus displace by intracellular fat accumulaon - Ethanol, Amiodarone - Amiodarone has lamellated intralysomal phospholipid inclusion bodies, ethanol doesn’t • Microvesicular: No nuclear displacement by fat; *failed β oxidaon, more severe

11

Microvesicular steatosis

• Tetracycline • Margosa oil • VPA • Nucleoside inhibitors • Hypoglycin • Cerulide • Aflatoxin

12

4 GI / HEME

Hepac Veno-Oclussive Disease

• Radiaon, Anneoplascs ( Cyclophophamide) • Pyrrolinizide alkaloid plants -Symphytum species (Comfrey tea) - Heliotropium, Senecio (Ragwart) -Crotalaria ( Bush teas)

13

Buzzword Hepas

• Peliosis Hepas: Sinusoidal dilaon, large blood filled cavies : Androgenic Steroids • Vitamin A Toxicity :Increased fat content of sinusoidal Ito cells with increased collagen formaon

14

Xenobioc Autoimmune Liver injury

• Covalent binding of reacve electrophile with hepatocellular protein creates an Adduct • APAP, minocycline, halothane, dihydrazine, phenytoin, germander

15

5 GI / HEME

Toxin-Hepas Immunomarkers

• Halothane : an-trifluoroacetylated proteins • Iproniaziad : an-mitochiondrial type 6 autoanbody ( an-M6) • Tienilic acid: An-liver kidney type 2 autoanbody (an-LKM2) autoanbody • Dihydralazine: anliver microsomal assay • Immunoallergic drug hepas: Lymphocyte proliferaon assay

16

Drug Hypersensivity Hepas

• Halothane hepas • trimethoprim-sulfamethazole • Anconvulsants • Allopurinol

17

Drug induced Cholestasis Without Hepas • Estrogens/OCPs • Anabolic Steroids • Cyclosporin • 4,4’-methylenedianiline ( Epping Jaundice) • Rapeseed oil aniline ( Spanish toxic oil syndrome) • Alpha-napthyl-isothiocyanate ( ANIT) –acute cholangis with PMN infiltraon

18

6 GI / HEME

Drug Hypersensivity Cholestasis

• Chlorpromazine • Erythromycin • Penicillin • Rifampin • Sulfonamides

19

Occupaonal chemical cholestasis

• Toleune diisocyanate • Methylenediamine • paraquat

20

Hepac Tumors

• Angiosarcoma: Vinyl chloride (chlorethane), arsenic, copper sulfate, Thoratrast, cadmium ? • Adenoma: Oral contracepves ( OCP), androgens • Carcinoma: OCP, anabolic steroids, thoratrast, anabolic steroids • Hepatocellular carcinoma: aflatoxin, dimethylnitrosamine, ethanol • Focal Nodular Hyperplasia: OCP • Peritoneal Mesothelioma: asebetos amphibole fibers, eronite, thoratrast,

21

7 GI / HEME

Liver Carcinogens

• Aflatoxin ( Aspergillus flavus/parasicus) • Mycotoxins • Pyrrolizidine alkaloids • Nitrosamides,Nitrosamines • Heterocyclic aromac amines • Ethanol • OCP • Androgens, anabolic steroids • Azo dyes • Thoratrast- alpha radiaon

22

Retroperitoneal fibrosis

• Methylsergide • Stephania tetrandra • Magnolia officinalis • Bromocripne • LSD

23

Exocrine Pancreas

24

8 GI / HEME

Exocrine Pancreas

* Tityus trinitas

25

Xenobioc Endocrine Pancreas

• Alpha: Cobalt, biguanide,diguanide • Beta: Aflatoxin, Androgens, cyclizine,Cyproheptadine,Diazoxide,Glucagon, Epinephrine, Growth Hormone,Pentamidine, Streptozocin,sulfonamides, Vacor, Zinc Chelators

26

Pancrelipase ( Pancrease)

• Indicaon: malabsorpon syndrome • Chronic use in Cysc Fibrosis * Fibrosing Colonopathy: abd pain, distension, conspaons

27

9 GI / HEME

Andiarrheal Agents

• AnMolity:Opioids: Diphenoxylate, Loperamide, Paregoric/Laudanum • Intraluminal Agents: Silicates, Bulk-forming fibers, Microfloral altering agents • Ansecretory : Somatostan, Octreode

28

Diphenoxylate

• Derived from meperidine • Metabolite: diphenoxylic acid ( 5x more acve, 2x ½ life) • Combined with atropine =Lomol Meperidine • Onset: 4.5 hrs ( 1- 8 hrs) • Toxicity: delayed opioid

29

Loperamide

• Derived from diphenoxylate • 40 % absorpon, <1% absorpon • Poor CNS penetraon, • Rare respiratory • Large safety profile

30

10 GI / HEME

Opioids

• Paregoric • Laudanum • Camphorated ncture of • Deodorized Tincture of opium opium • Morphine (0.4 mg/ml) • Morphine (10 mg/ml) • Other components: • Use in Neonatal Absnence essenal oil, Benzoic Acid, Syndrome /Neonatal Ethanol ( 45 %), glycerol Withdraw syndrome

31

Inflammatory Bowel Meds

• Mesalamine, Sulfasalazine • Immunomodulators ( Azathioprine,6-MP, infliximab) • Steroids • Anbiocs

32

Mesalamine

• Salicylate based • Metabolism: acetylaon = n-acetyl- 5-ASA • Topical bowel an-inflammatory • AE: HA/Diarrhea • OD: low likelyhood salicylate toxicity

33

11 GI / HEME

Sulfasalazine

• Sulfa + salicylate ( 5-ASA) • Colonic bacteria split sulfa to free 5-ASA • 5-ASA Not absorbed in colon • AE: due to sulfapyridine *** decreased ferlity, abnormal sperm *** folate inhibitor Other AE: HA,n/v/d, rashes

34

Azathioprine and 6-MP

6-thioguanine (6-TG)

hypoxanthine–guanine phosphoribosyltransferase

thiopurine S- methyltransferase thiopurine S- xanthine methyltransferase oxidase

Nature Reviews Cancer 8, 24-36 (January 2008) 35

Azathioprine/6MP Adverse effects • Infecon • Myelosuppression, Leukemia • GI: diarrhea,mucosis • Pregnancy D, NOT OK in Breaseeding • congenital anomalies: including polydactyly, plagiocephaly, congenital heart disease, hypospadias, and bilateral talipes equinovarus have occurred. • Monitoring: CBC and Thiopurine methyltransferase (TPMT) acvity

36

12 GI / HEME

Anulcer

• Antacids • H2 blockers • Proton pump inhibitors • Misoprostol

37

Antacids

• Salts of: aluminum,magnesium,calcium, sodium hydroxide • Increase gastric pH • Toxicity with renal failure • Al = “dilaysis demena”, encephalopathy, conspaon • Mg =diarrhea, weakness, ↓Hr,reflexes,BP • Milk-Alkali (headache, occasional nausea and voming, muscle ache, weakness and malaise) ( stones, bones, moans, groans) – seen with both calcium, sodium binders + milk/vitamin D − Hypercalcemia with suppressed PTH

38

H2 Blockers

• Cimedine, ranidine, famodine, roxadine, nizadine,endine • Inhibitors: 3A4, 2D6, 1A2, 2C9, 2E1 • AE: AMS, fague, possible thrombocytopenia, vasculis, movement disorders • Cimedine: Anandrogen ( Gynecomasa ) • Ranidine: hepas

Cimedine

39

13 GI / HEME

Proton pump inhibitors

• Rabeprazole,Lansoprazole,Omeprazole,Esmeprazole Pantoprazole • Block the gastric acid pump, H+/K+ (ATPase) • interacon 2C19, 3A4 • Alkali stomach may alter absorpon: griseofulvin, ketaconazole, iron • AE: diarrhea

40

Misprostol

• PGE1 antagonist (↓acid, ↑uterine contracon, mucous,bicarbonate, dilate blood vessels ) • Pregnancy X • AE: aborfacient, HA, diarrhea

41

Laxaves

[Epsom Salts]

phenolphthalein

42

14 GI / HEME

Laxave Overdose

ACUTE CHRONIC • Osmoc: • Osmoc: -Magnesium: CNS, + aldosterone = hypoK respiratory↓ - Catharc colon = -Phosphate: atrophy,atony hypocalcemia,QT↑ • Smulant • Smulant -psuedomembranosis -Phenolthalein: pulm edema, coli=macrophage pigment shock, met acidosis uptake,melanosis coli, harmless * Phenolpthalein = carcinogen, fixed drug erupon

43

Prokinecs

• Metoclopramide: 5HT3 antagonist, DA antagonist; AE: EPS, NMS, * MetHgb, neutropenia • Cisapride: 5HT4 agonist, 3A4 inhibitor, Ikr blockade, QT ↑ • Tegasarod (Zelnorm): paral 5HT4 agonist, 5HT1B agonist =↑vasoconstricon, MI, CVA

44

Hemostasis Pediatric Emergency Medicine Reports V14 N3 March 2009

45

15 GI / HEME

Anplatelets

Pharmacology Corner Flavio Guzmán, M.D. on 9/24/09 46

ADP Inhibitors

Ticlopidine Clopidogrel • 3-5 days onset • 2 hrs onset • 2C19 • 2C19, 3A, B6 and CYP1A2 • AE: rash, neutropenia, TTP • SS: 3-7 days • Severe OD: reversal with • AE: bleeding, rash platelet transfusion • 1 case report of HSP, TTP • Severe OD: reversal with platelet transfusion

47

Drug Induced Thrombocytopenia

48

16 GI / HEME

Occupaonal Isolated Toxic Thrombocytopenia • Immune: Toluene diisocyanate • Megakaryocyte hypoplasia: Dieldrin,Pyrethrin, Lindane,DDT

49

50

Indirect Thrombin Inhibitors

• Heparin: UFH ,LMWH (3,000-30,000 daltons) • Factor XA Inhibitors: Indirect/Direct • Vitamin K antagonist: Warfarin

51

17 GI / HEME

Heparin

Increased ATIII-thrombin (IIA) Rx 100-1000 fold

Thrombin

Most sensive to inhibion of ATIII/Heparin complex 52

Protamine Sulfate

• Derived male salmon gonads • Binds heparin, ↓interacon with AT III • 1mg/unit heparin • Heparin rebound • Contraindicaon: Allergy ( DM with AB due to protamine containing insulin)

53

Heparin Induced Thrombocytopenia

• Type I =Platelets ↓ • Type II = Anplatelet IgG anbodies Platelet 4 protein, paradoxical thrombosis, thrombocytopenia, 1 wk aer RX • Primarily UFH, possible but less likely with LMWH • All UFH/LMWH contraindicated in future,must use direct thrombin

54

18 GI / HEME

LMWH

Choices Mechanism • Ardeparin (Normiflo): • An thrombin III mediated • Daltaparen (Fragmin): Selecve inhibion Xa and to a • Enoxaparen (Lovenox): lesser extent IIa • Tinzoparin (Innohep):

55

56

Factor XA Inhibitors

• Fondaparinux ( Arixtra): Indirect, synthec pentasaccharide, selecve Factor Xa inhibitor • Rivaroxaban (Xarelto):Direct,oral,Selecve factor Xa inhibitor • Apaxiban ( Eliquis):Direct, oral, Selecve factor Xa Inhibitor

57

19 GI / HEME

Warfarin

Vitamin K(H2) Quinol Reduced Vitamin K epoxide reductase C1 (Acve)

Mayo Clinic Proceedings July 2010 85 (10) 58

Warfarin

Acve Inacve

Reduced

59

Warfarin Skin Necrosis

Skin necrosis • 0.01-0.1 % of pts • Female> male • High fat area • Rapid protein C loss

60

20 GI / HEME

Fetal Warfarin Syndrome

• Pregnancy X • Crosses placenta • Nasal/midface hypoplasia • Bone sppling of epiphyses on plain x- ray (chrondrodysplasia punc) • Opc atrophy • Metal retardaon

61

Warfarin purple toe syndrome

• 3- 8 wks of therapy • Cholesterol microemboli

62

Vitamin K1 (Phytonadione)

• ½ life : 2 hrs • Oral:mephyton • IV: AquaMephyton • IV: only if lifethreat • ( < 1mg/min) • AE: photosensavity, anaphylaxsis

63

21 GI / HEME

64

65

Direct Thrombin Inhibitors

• Hirudin( Refludan): Bivalent : Exosite 1, acve site binding • Bivalirudin: ( Angiomax,Hirulog):Bivalent: Exosite 1, acve site dinding • Argatroban: Univalent: Acve Site Only binding, N2-derivave of arginine • Dabigatran( Pradaxa): Univalent: Acve Site ONLY binding

66

22 GI / HEME

67

Thrombolycs

Thrombin specific fibrinolysis Non specific fibrinolysis • Alteplase • Streptokinase • Reteplase • urokinase • tenectaplase Side effect: -Allergy rxn if re-exposure

68

Aminocaproic Acid

• Reversal of fibrinolycs • analogue of the amino acid lysine • Inhibits plasminogen acvators • Renal eliminaon • AE: hypotension,rhabdomyolysis

69

23 GI / HEME

Iron

Ionic Nonionic- low toxicity • Ferrous gluconate 12 % • Iron polysaccaride 46% • Ferrous lactate 19% • Carbonyl iron 98 % • Ferrous sulfate 20 % • Ferrous chloride 28 % • Ferrous fumarate 33%

70

Iron

• Fe 2+ (Ferrous) absorbed in duod/jejun, bound to Ferrin • Changed to Fe 3+ (ferric), bound to transferrin • Free iron ( Fe 3+) released • 4-5 Stages: GI,Latent,Shock/Met Acidosis,Hepac failure,Gut Stricture

71

Iron

• >60mg/kg elemental iron ( Be able to calculate) likely tox • 4 hr serum Fe level >500mcg/dl + symptoms • Obtain radiographs • NOT Useful: WBC >15 K,Glc>150mg/dl,TIBC • Pregancy: ? placental receptor mediated endocytosis • Deferoxamine therapy

72

24 GI / HEME

Deferoxamine

• Derived from streptomyces pilosus • Indicaons: serum Fe>350-500mcg/dl, symptoms • Goals: resoluon acidosis,shock, trate dose • AE: GI- Yersina enterocolica, Pulm ? 24 hrs PE

73

Erythropoien

• Smulate stem cells to mature RBCs • Side effects:↑Hct ↑plt acvity, ↑systolic HTN -Hyperviscosity,HTN, Thromboembolism Chronic OD: Plethora, Black toes

74

25 Chemotherapeucs

Chemotherapeucs

Michael Policastro, MD Director, Medical Toxicology, QESI Clinical Assistant Professor, WSU

1

2

Cancer treatment strategy

• Cell surface receptor • Intracellular signal pathway • Cell maintenance process

3

1 Chemotherapeucs

Classificaon Chemotherapeucs

• Alkylang Agents: • Anmetabolite:- Methotrexate, Busulfan,Dacarbazine, Melphalan, fludarabine, mercaptopurine, Mustards (Chloramphenical pentostain,thioguanine, cyctaarabine, Cyclophosphamide, ifosfamide, Fluorouracil ( 5-FU) Mechlorethamine) Nitrosureas ( carmusne) Planoids (cisplan,carboplan), • Anmitoc:Vinblasne, Procarbazine ( hydrazine) Vincrisine,Paclitaxel, etoposide, teniposide • Anbioc: • Biologics Anthracyclin (Danorubicin, Doxorubicin, Idarubicin,) • Radionuclides Mitoxantrone, Bleomycin, Mithramycin,Mitomycin, Mitoxantrone

4

Targeted Sites Of Acon

Interphase: All phases except mitosis

DNA duplicaon

5

Adverse effects

• Alkylang Agents: • Anmetabolites: mucosis, Transamanis, pulm fibrosis, renal failure, n,v, transaminis, pancreas, sz hyperuricemia,myelosuppression, *Cylophosphamide- hemorrhagic cyss due renal failure to ACROLEIN *carmusne-toxic encephalopathy, * 5 FU –Cardiomyopathy, CHF *Cisplan- ototoxicity,renal tox, renal failure, *carmusne-hypersensavity, skin ↓ lytes reacons, BM suppression

• Anbioc:Mucosis, myelosuppression, dysrhythmias, • Anmitocs: Autonomic cardimyopathy dysfuncon, dysrhythmias, *Bleomycin- Pulm fibrosis, BOOP myelosupression, SZ, Peripheral * Mitomycin C- Hemolyc uremic syndrome neuropathy, SIADH * Taxol- GI perforaon

6

2 Chemotherapeucs

Methotrexate (MTX)

MTX Inhibits *Dihydro folate reductase (DHFR) * Thymidylate synthetase (TYMS)

N5-formyl FH4 (Leucovorin)

7

Methotrexate

• Inhibits DHFR, TYMS • Tri-phasic clearance, ( 2nd phase- renal clearance, 3rd phase ssue redistribuon into plasma) • Acidosis, renal failure, doses 100-1000mg/m2 associated with toxicity, folate deficiency • Toxicity primarily dependent on DURATION of exposure • Toxicity: Mucosis,hepas,renal failure, pancytopenia, seizures, hemiparesis,alopecia,olgiospermia,hypersensavity pneumonis

8

Treatment of MTX Toxicity

• Leucovorin 15mg/m2 • q 6 hrs x 2- 3 days unl MTX <5 x 10-8 • IVFS • Urinary Alkalinizaon • Hemodialysis • Thymidylate IV, carboxypepdase • Intrathecal MTX: CSF drainage/exchange

9

3 Chemotherapeucs

Neurologic Adverse Effects

• AMS/SZ: MTX, Vincrisne, Mustards (Chloramphenical Cyclophosphamide, ifosfamide, mechlorethamine,carmusne) • SZ: Chlorambucil/Ifosfamide- toxin (chloroacetaldehyde) • Cerebellar ataxia: 5-FU • Peripheral Neuropathies: vinca alkaloids , cisplan -( vincrisne>vinblasne; sensory + motor and ascending) - taxol- primarily sensory • Cranial N ( 3-7, 10): vinca alkaloids • Tinnitus, hearing loss, renopathy: cisplan

10

An-Microtubules

• Colchicine: Colchicum autumnale, • Paclitaxel: Taxus brevifola Gloriosa superba • Podophyllotoxin : Podophyllum - Meta-phase ( M) arrest peltatum - 3 phases tox: GI, Muli-organ failure, - derivates: etoposide, teniposide alopecia, Diabetes insipidus - Podophyllin more tox than - TX: MDAC, G- CSF derivates, similar tox colchicine - Podophyllin- M- phase • Vinca Alkaloids: Catharanus roseus

- Vincrisne most reported chemo OD in - Etoposide- inter-phase, lit. , - Severity: Vincrisne>vinblasne topoisomerase II inhibitor - Vincrisne: Crical Neuro , SIADH - No specific andote ( sensory/motor, ascending) - Vinblasne: bone marrow - TX: Glutamic acid- neuro, Hyaluronidase- extravasaon injuries

11

Renal/Electrolyte Adverse Effects

• SIADH: Vincrisne • Diabetes Insipidus(DI) : Colchicine • Hemorrhagic cyss: Cyclophosphamide,Ifosfamide **toxin= acrolein • Renal Failure, Distal tubular necrosis: Cisplan • Hypomagnesium,Hypocalcemia: Cisplan

12

4 Chemotherapeucs

Cardiac Adverse Effects

• Athracycline abx (Danorubicin, Doxorubicin, Idarubicin) —irreversible congesve cardiomyopathy —immediate : dysrhythmia, pericardis,myocardis • Cyclophosphamide —CHF, hemorrhagic pericardis, myocardial necrosis • 5-FU —vasospasm, myocardial ischemia, cardiogenic shock • Vinca Alkaloids Platelet aggregaon, coronary spasm ̶

13

Pulmonary Adverse Effects

• Bleomycin: pulm fibrosis, BOOP, nodular lesions • Methotrexate ( MTX): hypersensavity pneumonis, Hilar adenopathy • Cytosine arabinoside: non-cardiogenic pulmonary edema • Busulfan: alveolar-intersal proteinosis • Nitrosureas :Upper lobe pulmonary fibrosis

14

Mucosis

• MTX • 5FU • Bleomycin • Doxorubicin

15

5 Chemotherapeucs

Andotes

• Dexaroxane : Anthracycline ABX ( Doxurubicin) cardiomyopathy : Iron chelator • NA Thiosulfate: Cisplan • MESNA ( 2-mercaptoethane sulfonate sodium): cyclophosphamaide- inacvates acrolein to thioether • Methylene Blue: Ifosfamide encephalopathy • Amifosne: Cisplan; acvated intracellular by alkaline phosphatase, scavages free radicals • Folinic Acid: MTX • Glutamic Acid: Vincrisine – prevenon neuropathy • DDTC (diethyldithiocarbamate) /Disulfuram: Cisplan, also recall Ni, Ni Carbonyl • KI: 131 Iodine • Prussian Blue: Thallium • DTPA: Plutonium • G-CSF: colchicine, most chemo agents • Pyridoxine: Procarbazine ( hydrazine)

16

Occupaonal Disulfuram Agents

Goldfrank’s Toxicologic Emergencies. 6th edion. 2006. Figure 77.1 p.1177

Clinical Environmental Health and Toxic 17 Exposures .Sullivan and Kreiger.2001 . Table 18-4. P.238

Decontaminaon/Eliminaon

AC: MTX, busulfan, melphalan, chlorambucil MDAC: colchicine Urinary Alkalinizaon: MTX Plasmapharesis: Cisplan,Vincrisine

18

6 Chemotherapeucs

Biologics ( MAB)

An-Inflammatories An-cancer • TNF inhibitors • GF/ Tyrosine Kinases • T cell inhibitors ( VEGF, PDGF, EGF) • IL inhibitors • Serine/threonine kinase • Leukocyte Integrin Blockers ( ATK) • Intracellular protein kinases ( RAS, RAF, APC) • Transcripon factors/genes • G proteins • Phospholipases

19

Extravasaon Andotes

• Dimethyl sulfoxide (DMSO): topical: Antracyclines,Mitomycin: limits free radicals; compress- ICE • Dexrazoxane: IV: Anthracyclines: limits free radicals • Sodium thiosulfate: IV: Mechlorethamine: prevents ssue alkylaon • Hyaluronidase: SubQ : Vinca alkaloids,epipodophyllotoxins: degrades hyaluronic acid; compress- WARM

20

Regulatory Laws EPA Resource Conservaon and Recovery Act 40 CFR

Regulates 9 an-neoplascs: arsenic trioxide, chlorambucil, cyclophosphamide, daunomycin, melphalan, mitomycin c, napthylamine mustasrd, streptozocin, uracil mustard

** Review Regulatory Laws and Programs

21

7 Chemotherapeucs

22

23

24

8 Chemotherapeucs

25

Transplant Immunosuppressive Agents

26

Transplant Biologics

27

9 Chemotherapeucs

Calcineurin Inhibitors: cyclosproin/tacrolimus Side effects • Hypertension, Hyperlipidemia • Nephrotoxicity ( inhibion pepdyl, prolyl-cis transisomerase) • Cardiovascular death increase • CSA: hirsuism, gingival hyperplasia • Tacrolimus:DM

28

Calcineurin inhibitors : cyp3A4 drug interacons

Increased levels Decreased levels • CCB • Rifampin • Emycin • CBZ, Phenobarb, Phenytoin • Fluconazole • Octreode • Allopurinol • St. John’s Wort • Bromocripne • Colchicine • Metoclopramide • Protease inhibitors • Grape fruit juice

29

Sirolimus (Rapamycin)

• Macrolide compound, 3A4 • Inhibits IL-2/5, binds to kinase MTOR also known as FRAP, RAFT • MTOR: signal transducon of GF, PI3 kinase, AKT/ protein kinase B pathway • Side effects:Hyperlipidemia, cytopenia, arthalgias, apthous ulcers, intersal pneumonia, hepac artery thrombosis, wound dehiscence ( liver transplant)

30

10 Chemotherapeucs

Mycophenolate Mofel ( MMF) (Cellcept) • Blocks purine nucleode synthesis inhibits type 2 IMPDH ( inosine monophosphate dehydrogenase) = inhibits conversion of IMP to GMP • No effect on cytokines • Side effects: GI, heme • Do not give with Azathioprine or other an- metabolites

31

MMF drug interacons

Increased levels Decreased levels • Acyclovir,ganciclovir • Antacids: Al/Mg • Probenicid • Iron • Salicyaltes • Metronidazole • Sirolimus • Norfloxacin • rifampin

32

TNF-alpha contraindicaons

• Latent TB or Hep B • Chronic Heart failure • Vaccinaons with live organisms • Other possible side effects: infx, autoimmune disorders, uveis, mulple sclerosis, psoriasis, lymphoma

33

11 Chemotherapeucs

TNF-alpha

34

Pregnancy And Immune Modulators

35

Pregnancy and Biologicals

36

12 Chemotherapeucs

SERMs ( Selecve estrogen receptor modifying drugs) Side effects • Tamoxifen , toremifene ( Fareston), fulvestrant(Faslodex) • Hot flushes, decreased bone mineral density premenopause • Thrombosis ( DVT, PE, Stroke) • Increased endometrial thickness, vaginal bleeding, ovarian cyst

37

Aromatase Inhibitors

• Anstrazole (Arimadex), exemestane (Aromasin),letrozole (Femara) • Side effects: menopause symptoms, muscle cramps • NO increase in endometrial cancer • Less effects than SERMS

38

Signal Transducon Inhibitors: Tyrosine Kinase Inhibitors, side effec ts • EGFR:gefinib(Iressa),erlonib(Tarceva),cetuximab(erbitu x),panitumumab(Vecbix),( RASH-papulopustular, intersal lung disease, diarrhea) • VEGF:Vandetanib(Zacma),Sorafenib(nexavar), suninib(sutent), pazopanib (Votrient) ( coagulopathy, thrombosis) • Her-2:tratuzamab(Hercepn),lapanib(Tykerb), pertuzumab (Omnitarg), fever, chills ( Anthracycline + her-2 = ventricular dysrhythmias, CHF) • BCR-ABL:imanib mesylate ( Gleevac) ( edema) • Fusion protein EML4-ALK: Crizonib(Xalkori)

39

13 Chemotherapeucs

Signal Transducon Inhibitors: mTOR • Temsirolimus (Torisel) • Everolimus (Afinitor) • Hypersensivity reacons, hyperglycemia • Opportunisc infecon • Bowel Perforaon • Coagulopathy • Avoid Live vaccines • CYP 3A4 interacons

40

Signal transducon: serine/threonine kinase BRAF • Vemurafenib (Zalboraf) • Rash, LFTS

41

Gene Expression/Cell Funcon Inhibion • HDAC( Histone Deacytylase):Vorinostat (Zolinza), Romidespsin (Istodax) Thrombocytopenias, rash • Renoids: Bexarotene (Targren),Alitrenoin (Panren), Tresnoin(Vesanoid) Pregnancy X, cataracts, rash/photosensivity, LFTS

42

14 Chemotherapeucs

Angiogenesis Inhibitor Bevacizumab (Avasn) • Endothelial VEGF • HTN, Thromboembolism, Bleeding • Proteinuria, impaired wound healing

43

Apoptosis Inducer

• Proteosome:Bortezomib (Velcade) • Anfolate: Pralatrexate (like MTX):accumulates in cells express RFC-1 protein

44

Immune Cell Modulators

• CD3: orthoclone OKT3 • CD20: Rituximab ( Rituxan), ofatumumab (Arzerra), ibritumomab (Zevalin),tositumomab HSV , dyspnea, intersal pneumonis • CD30:Brentuximab (Adcentris) • CD33:Gemtuzumab • CD52: Alemtuzamab ( Campath) (ITP, autoimmune thyroid) • CTLA-4: Ipilimumav (Yervoy) • IL-2: Denileukin (Ontak), daclizumab (Zenapax) (CD25 , alpha chain IL-2)

45

15 Chemotherapeucs

Rituximab( Rituxan) Side effects

• Monoclonal/chimeric an- CD 20 • HSV , dyspnea, intersal pneumonis

46

Natalizumab (Tysabri) Side effects

• MAB against integrin • progressive mulfocal leukoencephalopathy (PML) caused by reacvaon of the JC virus, • hepatotoxicity

47

16 Plants

Poisonous Plants

ACMT Board Review Course September 9, 2012 Thomas C. Arnold, M.D.

1

Special Acknowledgement

• Thanks to Michelle Ruha and other previous presenters for their efforts on this topic.

2

Plants • Natural Products: 5% of tox boards – Includes food and marine poisonings, herbals, plants, fungi, toxic envenomations • ~ 5% of exposures reported to PCC each year, most in children < 6 years – Often a few deaths per year, but most reported exposures minor

3

1 Plants

Plant Poisoning by Organ System

• GI toxins • CNS toxins • Cardiovascular toxins • Multiorgan-system toxins • Hepatotoxins • Nephrotoxins • Endocrine toxins • Dermal and mucous membrane irritants

4

Lots of calls / Little threat • Euphorbia pulcherrima – Poinsettia • Ilex spp – Holly • Phoradendron spp – Mistletoe • Lantana spp • Spathiphyllum spp – Peace lily 5

• Ingestion of this plant may produce severe vomiting and diarrhea. Purple stains on fingers and a foamy quality to the diarrhea may provide a clue to the species of plant.

Pokeweed AKA Phytolacca americana

Toxin: phytolaccatoxin 6

2 Plants

Phytolacca americana

• Edible if parboiled • Root is the most toxic part, mature berries least toxic • Contains pokeweed mitogen – May see plasmacytosis

• Supportive care

7 Wikivisual.com

Solanum spp

wiki • 1700 species; nightshade, potato • Poisoning usually from ingestion of immature fruit • Solanine glycoalkaloids – Usually produce GI irritant effects – Hallucinations and coma reported

8

Melia azedarach

Toxin: meliatoxins

Chinaberry9

3 Plants

Chinaberry

• Tree grows to 50 feet • Native to Asia, grows in US • Fruit are green berries that turn yellow and remain after leaves shed • Fruit and bark poisonous • Vomiting and diarrhea • Care supportive

10

CNS Toxins

• Anticholinergic plants • Nicotinic alkaloid - containing plants • Hallucinogenic • Sympathomimetic • Epileptogenic

11

Jimsonweed

• 2 adolescent males eat these seeds

• 2 hours later, they are found stumbling, incoherent and their pupils look “blown” • In ED they are combative and hallucinating, have >8mm pupils, and are tachycardic in the 130s.

12

4 Plants

Datura spp

13

Datura spp • Along roadsides, pastures, waste areas • Leaves are long and lobed, with large white funnel-shaped flowers, entire plant toxic • Seed pods = spiny capsules with 50-100 seeds • Toxin = atropine, scopolamine, hyoscyamine • Symptoms begin 30-60 minutes after ingestion and continue 24-48 hours 14

leaves offset at stem

15

5 Plants

What is this plant?

Angel’s Trumpet

Brugmansia spp

16

Other anticholinergic plants to know…

• Atropa belladonna: Deadly Nightshade • Mandragora officinarum: Mandrake • Hyocyamus niger: Henbane • Anticholinergic plants

– Contain tropane (belladonna) alkaloids • atropine, hyoscyamine, scopolamine – Inhibit postsynaptic muscarinic receptors • Produce anticholinergic syndrome • Physostigmine will reverse 17

18

6 Plants

Nicotiana spp

• After ingesting a tea made of the leaves of this plant a patient developed tachycardia, vomiting and diarrhea, salivation, agitation, and convulsions

19

Tobacco Plants • Small plants, shrubs, or trees • Broad green leaves, tubular flowers • Pyridine-piperidine alkaloids • Ingestion, dermal absorption, inhalation – nicotinic syndrome (blockade of nicotinic acetylcholine receptors) • Harvesting wet leaves: green tobacco sickness • 1 cigarette or 3 butts toxic in a child 20

Plant / Toxin • N tabacum (commercial tobacco) – Nicotine • N glauca (wild tree tobacco) – Anabasine • N trigonophylla (desert tobacco) – Nicotine and anabasine • Lobelia inflata (Indian tobacco) – Lobeline Urinary metabolite of nicotine: cotinine 21

7 Plants

Commercial tobacco

Nicotiana tabaccum

Photos: wikipedia.com Tree tobacco Nicotiana glauca22

Plant: Conium maculatum Toxin: coniine

• A woman ate stems and roots from this plant. An hour later she developed vomiting and in the ED seized.

purple spots 23

Poison hemlock • Family Umbelliferae • Along roads and ditches and in wooded areas • Mistaken for wild carrots • Stems and leaves may be purple-spotted • Root most toxic part of plant 24

8 Plants

Betel Nut - Areca catechu

• ‘Quid’ chewed in Far East, Asia, India, South Pacific – Areca nut, betel leaf, lime paste, leaf tobacco • Toxin: arecoline – Nicotinic, muscarinic • Users have red-stained oral mucosa and saliva, dark- stained teeth 25

26

Mescal Bean Bush, AKA Texas Mountain Laurel Shrub with purple flowers, woody pods with bright red seeds

Contains: Cytisine

Latin: Sophora secundiflora 27

9 Plants

Others with nicotinic alkaloids

• Laburnum anagyroides – Golden chain tree • cytisine

wiikipedia • Caulophyllum thalictroides – Blue cohosh (herb) • N-methylcytisine in seeds, roots

28

Hallucinogenic Plants Toxin: ergine

Lysergic acid amide 10% potency of LSD

Ipomoea violacea - Morning Glory29

Argyreia nervosa

Hawaiian Baby Woodrose

Clinically, similar to LSD • euphoria, distortions of perception, hallucinations, panic, nausea and vomiting

30

10 Plants

Myristica fragrans Nutmeg

Seeds = nutmeg • This common household coating = mace spice must be taken in large doses to produce hallucinations • Toxin: myristicin, elemicin – metabolized to amphetamine-like compounds – produce a variety of CNS effects (stimulation to depression) 31

Claviceps purpurea

• Fungus that infects rye, other grains • The toxins are indole derivatives – Ergot alkaloids • ergonovine and ergotamine • Ingestion may produce ergotism (gangrenous or CNS, with hallucinations) 32

Peyote - Lophophora williamsii

• This cactus will make you vomit before you hallucinate

• structurally similar to The toxin: hallucinogen amphetamines mescaline • pharmacologically similar to hallucinogenic indoles

• emetic, hallucinogen, stimulant 33

11 Plants

Sympathomimetic

• The leaves of this plant are chewed in East Africa for stimulant effects • Plant: Khat; Catha edulis • Toxin: cathinone Qat man….wikipedia

– Structurally similar to amphetamines – Indirect sympathomimetic 34

Convulsant Plants

• Believing this to be a wild carrot, a man ingests a few bites from the root and within 30 min develops vomiting followed by seizures

35

OH

HOCH2(CH2)2-(C=C)2-(CH=CH)3-CHCH2CH2CH3 Toxin: cicutoxin A complex aliphatic alcohol

Cicuta maculata

Water Hemlock 36

12 Plants

Water Hemlock

• Umbelliferae family • Grows to 6 feet, compound leaves, small white flowers, chambered tuberous roots • Roots have a parsnip or carrot-like odor, and highest concentration of toxin • Rapid onset GI effects and seizures 37

This plant toxin antagonizes the glycine receptor, resulting in hyperreflexia and muscle spasms Treatment is benzos, barbs, paralysis, intubation Strychnos nux vomica Strychnine 38

Cardiovascular • Plant cardiac glycosides – Inhibit Na-K-ATPase – Clinically identical to digoxin toxicity – Cross react with digoxin assay but levels do not correlate with toxicity – Require higher doses dig Fab • Sodium channel openers • Sodium channel blockers

39

13 Plants

Cardiac Glycosides

• Foxglove – Digitalis lanata, D purpurea – Digitoxin • Purple, pink, white, yellow • Grows to about 3 feet • Whole plant toxic

40

Cardiac Glycosides

• Common oleander – Nerium oleander – Oleandrin wikipedia

• Lily of the valley – Convallaria majalis – convallotoxin, convallarin 41

Cardiac Glycosides • Yellow oleander – Thevetia peruviana – Thevetin

– AKA Lucky Nut

• Common method of suicide in Sri Lanka42

14 Plants

Cardiac Glycosides

• Red squill – Urginea maritima – Scillaren – Rodenticide

• Christmas rose – Helleborus niger – AKA Hellebore wikipedia 43

Sodium Channel Openers

• Grayanotoxins – Rhododendron – Azaleas – Mountain Laurels • Veratrum Alkaloids – Zigadenus spp – Veratrum spp • Aconitine alkaloids – Monkshood, Wolfsbane

– Aconite 44

Rhododendron spp

• Rhododendrons and Azaleas • Leaves toxic • Poisoning has resulted from ingestion of grayanotoxin-contaminated honey – reported in Turkey – ‘mad honey’

– AKA andromedotoxin 45

15 Plants

Veratrum Alkaloids

• False hellebore – Veratridine, germidine • Death camus – Zygacine, zygadenine • Mistaken for wild onions • Toxicity has occurred from sneezing powders made from pulverized roots

of Veratrum spp 46

Aconite

• Found in some herbals • All plant parts contain aconitine • All of the Na channel activators produce: – salivation, emesis, hypotension, bradycardia, arrhythmias, paresthesias, weakness – Effects 30 min to 6 hours following ingestion and persist several days

• Aconite also known for: torsades 47

Taxus spp The Yew Flat, needle-like leaves with black seeds surrounded by a (nontoxic) red aril Effects: N/V/D, arrhythmias, wide QRS What is the primary toxin? Taxine B

How does this toxin act? Na, Ca channel blockade 48

16 Plants

Multi-organ system toxins

• Cyanogenic glycosides • Toxalbumins • Mitotic Inhibitors

49

• A woman ingested a bag of apricot kernals she purchased at a health food store. About 50 min later she was comatose and acidotic.

• To what toxin was she exposed? – Amygdalin – A cyanogenic glycoside

50

Cyanogenic Glycosides

• Prunus spp – cherries, peaches, plums, apricots – Laetrile • Malus spp – apples • Cassava

51

17 Plants

Cyanogenic Glycosides

• Amygdalin - found in kernals and seeds • Hydrolyzed to hydrocyanic acid by beta- glucosidase (amygdalase) • Cyanide toxicity results – Clinically similar to other CN poisoning except delayed onset due to metabolism of amygdalin • Treated with cyanide antidote

52

Cassava

• Roots contain high concentration of the cyanogenic glycoside linamarin • Normally soak the roots to remove toxin • During droughts roots not soaked

Manihot esculenta

53

Chronic ingestion of Cassava may lead to…

Konzo Tropical Spastic Paraparesis Tropical Ataxic Neuropathy

• An upper motor neuron disease • Paresthesias, sensory ataxia, optic atrophy, sensorineural hearing loss 54

18 Plants

Chickling pea • Lathyrus sativa – AKA grass pea, sweet pea • Contains: BOAA

– Beta-N-oxalylamino-L-alanine wiki • Mechanism: AMPA glutamate receptor agonist, leads to degeneration of receptors • Poisoning occurs when this is main diet • Clinical: neurolathyrism, indistinguishable

from cassava-induced spastic paraparesis55

Toxalbumins • These plants contain toxins that bind the 60s ribosomal subunit, inhibit RNA polymerase: Inhibit protein synthesis • Mild symptoms: diarrhea • Severe: vomiting, diarrhea, abdominal pain, hypovolemia, hypokalemia, hepatorenal dysfunction, hyperthermia, seizures

56

Castor Bean - Ricinus communis

57

19 Plants

Castor Bean

• Large leafy plant with brown capsules containing three shiny, hard-coated seeds • Source of castor oil; toxin: ricin • Whole swallowed seeds not toxic • Toxic if chewed • Pure ricin injected IV much more toxic than ingested ricin

58

Jequirity Bean - Abrus precatorius

Toxin: Abrin

AKA rosary pea 59

Other toxalbumin- containing plants • Jatropha spp – Physic Nut – Contains: curcin • Phordendron spp – American mistletoe – Contains: phoratoxin • Robinia spp – Black locust

– Contains: robin wikipedia 60

20 Plants

Anti-mitotic toxins inhibit microtubule assembly (metaphase arrest) • Colchicine – Colchicum spp • Autumn crocus, meadow saffron – Gloriosa superba • Glory lily wikipedia • Clinically: severe GI sx and leukocytosis; then bone marrow suppression,

alopecia, peripheral neuropathy 61

Anti-mitotics • Podophyllum spp – Mayapple • Traditional Chinese herbal remedy wikipedia • Podophyllotoxin • Clinical: similar to colchicine, with GI effects followed by bone marrow suppression and peripheral neuropathy – Early CNS depression, no alopecia 62

Endocrine Grows in West Africa, West Indies, Central America, Florida Akee fruit Blighia sapida Which is toxic? Unripe fruit contains: Hypoglycin A 63

21 Plants

‘Jamaican vomiting sickness’ • Cases have occurred from canned fruit • Hypoglycin A – Inhibits beta-oxidation of fatty acids and gluconeogenesis – Metabolized to methylene-cyclopropyl acetic acid (MCPA), inhibits carnitine- acyl CoA transferase • Microvesicular steatosis, hypoglycemia, vomiting, seizures, death 64

Glycyrrhiza spp Licorice Root • Excessive ingestion may produce a hypermineralocorticoid syndrome – HTN, hypokalemia, edema, metabolic acidosis, weakness, muscle cramps

Glycyrrhizic acid inhibits 11β-hydroxysteroid dehydrogenase; can’t convert cortisol to cortisone 65

Hepatotoxins

• Pyrrolizidine alkaloids – Crotalaria spp – Heliotropium spp – Symphytum spp (Comfrey) – Senecio spp • Can cause hepatitis and hepatic venoocclusive disease

66

22 Plants

Rhubarb • Edible leaf stalk but raw leaf blades are toxic • Contain 1% soluble oxalates – Also anthraquinone glycosides that may cause GI distress • Rare renal dysfunction may occur

67

Dermal and Mucous Membrane Irritants

• Mechanical Stinging nettles • Chemical Urtica dioica • Allergic • Phototoxic

wiki 68

Mechanical and Chemical Dieffenbachia spp

• Common call to PCC when children chew on leaves and develop local pain

• Toxin: – Calcium oxalate

69

23 Plants

• Calcium oxalate crystals are packaged in raphides, arranged in bundles called idioblasts • When bite on leaf, idioblasts fire, depositing proteolytic enzymes with the raphides

• Results in pain and swelling • Potential for life-threatening airway obstruction 70

Other calcium oxalate containing plants • Philodendron spp • Caladium spp • Spathiphyllum spp

wikipedia 71

Agave

72

24 Plants

Capsicum annum Chili pepper • Capsaicin, in spices and pepper spray • Irritating to mucous membranes • May act through depletion of substance P from nerve terminals • Large oral exposure may cause gastroenteritis

73

Toxicodendron spp

poison ivy, poison oak, poison sumac Clusters of three leaflets, green and waxy appearing Oily resin - toxicodendrol, contains urushiol Contact dermatitis in susceptible people Resin under fingernails can continue to produce dermatitis if not removed 74

Allergic Plant Dermatitis

• Type IV hypersensitivity • Treatments: soap and water; steroids, antihistamines • Other plants – Ginkgo, mango, pistachio, cashew

75

25 Plants

Photodermatitis

• Psoralen in celery – Grocery workers • Photodermatitis – Allergen via dermal exposure or ingestion • Activated by light to produce rash

76

Major Summary Points

• Too many – • Suggested reading – Handbook of Poisonous and Injurious Plants by Nelson, Shih and Balick, Second Edition Springer, 2007 77

26 Historical Outbreaks

1

Toxic Outbreaks of Historical Importance

Stephen W. Munday, MD, MPH, MS Sharp Rees-Stealy Medical Group, Inc. San Diego Division, CA Poison Control System

Toxic Outbreaks of Historical 2 Importance

. Ergot Alkaloids – 12th Century France . Thousands affected (St. Anthony’s Fire due to Claviceps purpurea contamination of grain) Claviceps purpurea . Convulsive and/or Gangrenous forms

3 Lead, England 1700s . Devonshire Colic . Likely caused by lead-contaminated cider

1 Historical Outbreaks

4 Cadmium – Japan ~1910-1950s . Itai-itai – “Ouch-ouch” disease . So called due to severe pain from osteomalacia-induced fractures . Prevalence markedly increased in post-menopausal women. . Believed to be caused by cadmium-containing mine tailings that contaminated the irrigation water used to grow rice that was eaten by those affected.

5 Cobalt – Canada 1960s . Beer-drinker’s Cardiomyopathy . Co added to beer to stabilize the foam . Associated with cardiomyopathy in alcoholics but not non- alcoholics . Some have theorized this is due to thiamine deficiency since cobalt affects the thiamine pathway and alcoholics are often thiamine deficient. x =

Medicinal disasters: Thallium 6

. Location: US . Date: 1920s-1930s . Significance: Treatment of ringworm; 31 deaths

2 Historical Outbreaks

7 Medicinal disasters: Diethylene glycol . Location: US . Date: 1937 . Significance: Elixir of sulfanilamide contaminated by DEG caused over 100 deaths due to renal failure . Led to passage of Food, Drug & Cosmetic Act in 1938.

Medicinal disasters: Thorotrast 8

. Location: US . Date: 1930s-1950s . Radiographic contrast agent containing thorium dioxide that was concentrated in the RES including the liver and spleen . Significance: Hepatic angiosarcoma rate increased over 100 fold

9 Medicinal disasters: Phenobarbital

. Location: US . Date: 1940-1941 . Significance: Sulfathiazole antibiotic contaminated with phenobarbital; 82 deaths

Phenobarbital Sulfathiazole

3 Historical Outbreaks

Medicinal disasters: Diethylstilbestol (DES)10

. Location: US, Europe . Date: 1940s-1970s . Used to prevent miscarriages or premature delivery . Significance: Endometrial/Cervical/Vaginal carcinoma in daughters, Testicular cancer in sons & Breast cancer in users.

Medicinal disasters: Stalinon 11

. Location: France . Date: 1954 . Significance: Severe neurotoxicity including cerebral edema from triethyltin – used to treat boils

Medicinal disasters: Clioquinol 12

. Location: Japan . Date: 1955-1970 . Used topically and orally as an antibacterial and antiparasitic agent . Significance: Subacute myelooptic neuropathy (SMON); 10,000 symptomatic with a syndrome that involves sensory and motor disturbances in the lower limbs and visual changes; some had green tongues . Never noted before or after this period so many are not convinced clioquinol was the cause

Bonus: What’s this?

4 Historical Outbreaks

13 Medicinal disasters: Thalidomide

. Location: Europe . Date: 1960s . Used as a sedative and anti-nausea drug in pregnant women . Significance: 5000 cases of phocomelia (fore-limb shortening) in Europe; it never was approved in the US

Medicinal disasters: Pentachlorophenol14

. Location: US . Date: 1967 . Used in hospital laundry . Significance: 9 neonates ill, 2 deaths. . Presented with: fever, sweating, renal failure and acidosis

15 Medicinal disasters: Benzyl alcohol

. Location: US . Date: 1981 (MMWR June 11, 1982) . Used as a preservative in IV solutions . Significance: Gasping syndrome / acidosis seen in neonates receiving large amounts of benzyl alcohol via IV solutions . Disappeared once benzyl alcohol exposure to neonates was limited

5 Historical Outbreaks

Medicinal disasters: Acetaminophen-cyanide16

. Location: Chicago . Date: 1982 . Significance: Tampering incident resulted in 7 homicides due to cyanide poisoning

17 Medicinal disasters: L-Tryptophan

. Location: US . Date: 1989 . OTC supplement . Significance: Eosinophilia-myalgia syndrome . Scleroderma-like skin changes associated with eosinophilia and myopathy . Epidemiologic and chemical evaluation suggested that it MAY have been due to contaminated L-tryptophan from a single manufacturer . Similar to 1981 Spanish toxic oil syndrome

18 Medicinal disasters: Diethylene glycol

. Location: Haiti . Date: 1996 . Significance: Acetaminophen elixir contaminated with DEG; renal failure; >88 pediatric deaths

6 Historical Outbreaks

Toxic Outbreaks of Historical 19 Importance

. Methylenedianiline – Epping, England, 1965 . Contaminated flour caused 84 cases of cholestatic jaundice

Toxic Outbreaks of Historical 20 Importance

. Hexachlorobenzene – Turkey, 1956 . Wheat seed with fungicide was eaten instead of planted . ~4,000 cases of porphyra cutanea tarda

Toxic Outbreaks of Historical 21 Importance cont’d

. PCBs (polychlorinated biphenyls) &PCDFs (polychlorinated dibenzofurans) . Japan, 1968: Yusho or Rice oil contaminated by heat-exchange fluid from a leaking pipe 1,600 affected . chloracne, hyperpigmentation and increased liver cancer and reproductive effects . Taiwan, 1979: Yu-Cheng (Oil Disease) 2,000 affected . Similar to Yusho Effects

7 Historical Outbreaks

Toxic Oil Syndrome 22

. Spain, 1981 . Associated with 2% aniline denatured rapeseed oil . Scleroderma-like plus eosinophilia and pulmonary hypertension . Caused over 600 deaths . 1989 Eosinophilia-myalgia syndrome possibly associated with some tryptophan supplements was clinically similar

23 Arsenic

. France, 1828 . 40,000 with neuropathy due to arsenic in bread and wine . Staffordshire, England 1900 . Arsenic-contaminated sugar in beer with 6,000 cases of neuropathy and 70 deaths

24 Arsenic

. Bangladesh/West Bengal India . Arsenic contaminated ground water from wells . 60 million exposed in Bangladesh alone . Over 220,000 in West Bengal affected (skin changes/skin cancer)

8 Historical Outbreaks

Methyl Mercury 25 . Minamata Bay, Japan 1930s-1950s . Industrial waste contaminated with inorganic Hg was concentrated up the food chain as methyl Hg after being dumped in the bay. . Many cases of methyl Hg poisoning in humans & animals who ate seafood from the bay . Iraq, 1971 . Methyl Hg treated seed grain intended for planting was mistakenly ingested . >400 deaths

Minamata Disease

26 Methyl Isocyanates

. Bhopal, India 1984 . A series of safety factors that were not appropriately engaged, led to an explosion that released methyl isocyanate . Many humans & animals were acutely affected – . skin, mucous membranes and respiratory tract. . Estimates vary but thousands died acutely and likely hundreds of thousands were injured (many with residual effects)

Bhopal, India 27

9 Historical Outbreaks

Triorthocresyl Phosphate (TOCP) 28 . US 1930-1931 (“Prohibition”) . Alcohol containing patented “medication” (“Jake”) from Jamaican ginger was formulated with TOCP and caused upper and lower extremity neuropathy . Similar to OP pesticides . 50,000 people developed Ginger Jake Paralysis

2, 3, 7, 8 TCDD (Dioxin) 29

. Seveso, Italy 1976 . A nearby 2, 4, 5, trichloropheroxyacetic acid (2, 4, 5 T) facility exploded . Chloracne developed in those most exposed . No clear evidence of increased cancer risk in this group . This industrial accident led to the Seveso Directive (European Community Industrial Safety Regulations)

30 Chloracne due to Dioxin Poisoning

Ukrainian President Viktor Yushchenko

10 Envenomations

Envenomations

ACMT Board Review Course September 9, 2012

Thomas C. Arnold, M.D.

1

Special Acknowledgement

• Thanks to Michelle Ruha and other previous presenters for their efforts on this topic.

2

What to Review? • Natural Products: 5% of tox boards – Includes food and marine food poisonings, herbals, plants, fungi, toxic envenomations • Toxic Envenomations – Marine, snakes, lizards, scorpions, spiders, bees, ants, caterpillars, other random things (blister beetles, toads, newts, etc…) – Native AND non-native!!! 3

1 Envenomations

Keep in Mind

• This presentation attempts to include most important points for the boards – A lot of things not included

• All venoms are ‘complex’ – Will leave out lists of components and try to include the ones to remember (for the most part)

4

Marine Envenomations

• Stingrays • Cnidaria • Scorpaenidae – Jellyfish • Sea snakes • True, ‘not’ true – Fire coral – Anemones – Corals • Echinodermata • Mollusks • Sponges 5

Stingray / Dasyatis spp

• Most common stinging fish • Atlantic / Mediterranean / Indian Ocean • Spine on dorsum of tail has sharp tip and barb, with venom glands under spine – Lacerates and envenomates – A sheath surrounds the spine and may become embedded in wound 6

2 Envenomations

Stingrays

• Extremity injuries - deep ulcers and secondary bacterial infections • Chest injuries - death • Venom produces edema and pain out of proportion to visible tissue injury – Peaks at 60 min, may last 48 hours – Systemic: cramping, weakness, N/V/D • Wound initially cyanotic or dusky, becomes 7 erythematous, necrotic

Management

• Cleanse, explore, debride wound • Tetanus prophylaxis • Prophylactic antibiotics (Cipro, Bactrim, Tetracycline okay) • Pain control: hot water, analgesics • Don’t suture

8

Scorpaenidae

• Next most common fish envenomations • Over 350 species; found in coral reefs • Spines with venom glands • More venomous: Gulf of Mexico, Pacific & Indian oceans • Less venomous: Ca and SE US coasts • Victims: scuba divers, snorkelers, fishermen; people with imported fish in

home aquariums 9

3 Envenomations

Least Scorpaenidae severe • Pterois – Lionfish – Rather escape • Scorpaena – Scorpionfish • Synanceja – Stonefish Most severe– Rather attack 10

Scorpaenidae • Venom – Inflammatory mediators (lionfish) – Stonustoxin, verrucotoxin, catecholamines (stonefish) • Clinical: spectrum, ranges from local with Lionfish to severe with Stonefish – Local - Erythema, pain, induration – Systemic - N/V, syncope, arrhythmia, seizure, pulmonary edema, death 11

Management • Hot water (110-115ºF) inactivates toxin • Analgesic or digital nerve block • Remove barbs or spines • Tetanus • Consider prophylactic antibiotics • Antivenom for life-threatening stonefish envenomation - equine Fab • Don’t suture

12

4 Envenomations

Sea Snakes • Hydrophiidae Hydrophis • >50 species – all venomous cyanocinctus • None in Atlantic or Caribbean • Some relevant species: – Enhydrina schistosa (beaked) – Pelamis platurus (pelagic) – Astrotia stokesii – Hydrophis ornatus 13 – H. cyanocinctus (banded)

Sea Snakes • Front fixed fangs, 80% dry bites • Similar to Australian Elapids • Venom extremely toxic – Neurotoxins, myotoxins • Symptoms within minutes to hours • Minimal local reaction • Ascending paralysis, rhabdomyolysis • No coagulopathy

14

Antivenom

• Treat symptomatic envenomations • Equine-derived, available in Australia • Prepared against Enhydrina schistosa (beaked sea snake) and Notechis scutatis (terrestrial tiger snake)

15

5 Envenomations

Cnidaria • Formerly Coelenterata • > 9000 species, grouped: – Hydrozoans (man-of-war) – Scyphozoans (true jellyfish) – Cubozoa (box jellyfish) – Anthozoans (corals, anemones) • Most contain nematocysts

16

Nematocysts

• Dart-like structures enclosed within venom sacs • Stimulated by pressure / chemical signals • Shoot out of containment sacs, injecting venom as they penetrate flesh

17

Cnidaria • Venom: inflammatory mediators, proteases • Spectrum of severity – Mild: dermatitis, pain – Severe: multi-organ toxicity, death – Anaphylactoid reactions may occur • May be inactivated by 5% acetic acid solution (vinegar) • Antihistamines or steroids prn 18

6 Envenomations

Jellyfish • Long tentacles contain hundreds of thousands of nematocysts • Stinging sensation, pruritus, paresthesias, central radiation of pain • Red-brown-purple lesion in a linear whiplike pattern • Blistering, edema, violaceous petechial hemorrhages 19

Box Jellyfish

• Chironex fleckeri • Off Australia and SE Asia • Most venomous of all stinging marine life • Venom produces catecholamine surge

20

Box Jellyfish • Most victims with severe pain only • Wounds may become necrotic • May develop acute and/or delayed hypersensitivity • Severe: Hypotension, cardiac arrhythmias, respiratory failure, anaphylaxis • Death more common in kids, occurs fast

• Sheep derived whole IgG AV in Australia21

7 Envenomations

Portuguese Man-Of-War • Physalia physalis • Waters along the Florida coast • Tentacles up to 10 feet, nearly transparent • Venom may cause excruciating pain • Rare cardiac arrhythmia, respiratory failure, anaphylaxis, death

22

Irukandji Jellyfish

• Carukia barnesi • Peanut-sized, translucent jellyfish – Australia’s north coast, Pacific, Florida (different species?) • Relative of the box jellyfish • Catecholamine surge, with cardiac and pulmonary effects, death may occur • No antivenom

23

Sea Bather’s Eruption

• AKA ‘sea lice’ • Larvae of jellyfish Linuche unguiculata • Between March and June, SE Florida • Pruritic, erythematous, maculopapular rash in areas covered by bathing suit • Symptoms resolve spontaneously hours to days, up to 2 weeks

24

8 Envenomations

Fire Coral • Millepora spp • Not a true coral • Most commonly found in shallow tropical waters • Sharp skeleton, contain nematocysts • Divers at risk: contact may result in burning pain, urticaria, pruritis • Wheals may take weeks to resolve and

may leave a hyperpigmented scar 25

Anemones

• Flowerlike appearance • Modified nematocysts known as spirocysts • Humans stung when handling them • Varies in severity, from stinging sensation to vesiculation, necrosis

26

Cnidaria Treatment • Supportive care / tetanus • Vinegar often first line – Inhibits d/c of nematocysts from C fleckeri – May increase d/c in some species • Irrigation with seawater may be better in US • Pain may resolve spontaneously in 30-90 min • Antihistamines / corticosteroids prn

• No prophylactic antibiotics 27

9 Envenomations

Echinodermata

• Starfish • Sea urchins • Sea cucumbers

28

Mollusks: Cone Snails

• 300 Conus species • Stings with a modified tooth fired from the proboscis • Venom contains conotoxins – neurotoxins which target multiple specific ion channels • Ziconotide, a conotoxin derivative, is being used to treat neuropathic pain

29

Cone Snails • Local pain, burning sensation, numbness, ischemia, paresthesias • Most cases only local manifestations with resolution in 6-8 hours, although deaths have been reported • Progression to generalized paresthesias, paralysis, respiratory failure, coma, cardiac failure

• Treatment – hot water, supportive 30

10 Envenomations

Mollusks: Blue Ringed Octopus • Found in Indo-Pacific shallow waters • Small, up to 20 cm • Usually harmless, bites rare • Two sets of salivary glands that release venom from a powerful parrotlike beak • Venom contains tetrodotoxin (aka maculotoxin )

– Blocks sodium channels 31

Blue-Ringed Octopus (Hapalochlaena spp) • Initially mild local pain, burning, numbness, ischemia; local progressing to perioral and distal paresthesias • May rapidly progress to paralysis, respiratory failure • Treatment supportive

32

Snakebites

• >8000 bites / year in US; <10 deaths • > 99% venomous bites in US Crotalinae • Snake Families: Crotalinae – Viperidae subfamilies Viperinae – Elapidae – Hydrophiidae – Atractaspididae

– Colubridae 33

11 Envenomations

Colubridae • Rear fixed fangs • Found in most parts of the world • Most species harmless – garter, gopher, sonoran vine snake • Some dangerous, even lethal – Clinical effects: swelling and coagulopathy

34 Rat snake

Atractaspididae • Rear/lateral – directed front fangs • Africa, Middle East • Pain, swelling, lymphadenopathy, vomiting, diaphoresis, fever, coagulopathies

35 African Burrowing Asp

Elapidae • Front, fixed fangs • 60% bites dry • Often neurotoxic venom Krait • Some non-native species: (Malaysia, India)

Cobra Mamba Tiger Snake 36

12 Envenomations

US: Eastern Coral Snake • Micrurus spp • Red on yellow complete bands • Neurotoxic venom: paralysis, symptom onset may be delayed many hours • Treat with antivenom early, if available

• Sonoran coral snake (Micruroides)

- not dangerous 37

Red on yellow, kill a fellow

Red on black, venom lack 38

Viperidae

• Viperinae - old world vipers • Crotalinae - new world or ‘pit’ vipers • Front, mobile fangs • 25% bites dry • Venom into dermis/SQ, to lymphatics • Local tissue effects, hematotoxicity, some neurotoxic

39

13 Envenomations

Viperinae • Old World Vipers • Found in many European and Asian countries, Middle East, Africa • No heat sensing pits

Puff Adder Asp Viper

40 Russell’s Viper African Gaboon Viper

Crotalinae • Pit vipers • Triangular shaped head • Heat sensing pits, elliptical pupil • North, Central, and So America, Asia • In US: all states except ME, AK, HI – Crotalus - Most rattlesnakes – Sistrurus - Massasauga, pigmy – Agkistrodon - Copperhead, cottonmouth 41

US Pit Vipers

Rattlesnakes (Crotalus and Sistrurus)

Copperhead (Agkistrodon) Cottonmouth42

14 Envenomations

US Pit Vipers • Venom Toxicity – Rattlesnakes > cottonmouths > copperheads

• Venom: cytotoxic, myotoxic, hemotoxic, occasionally neurotoxic

43

Rattlesnake Venom (a few of many components) • Fibrinolytic, fibrinogenolytic enzymes – Defibrination, coagulopathy • Thrombin-like enzymes – Coagulopathy • Metalloproteinases – Tissue damage • Phospholipases – Thrombocytopenia, neurotoxicity • Bradykinin-potentiating peptides 44 – Anaphylactoid reactions

Venom Neurotoxins

• Postsynaptic neurotoxins – α neurotoxins – Most elapid and sea snake venoms – Competitively bind nicotinic acetylcholine receptors and produce a nondepolarizing neuromuscular blockade • Neostigmine may reverse 45

15 Envenomations

Venom Neurotoxins

• Presynaptic neurotoxins – β neurotoxins – Some elapid and viper venoms – Inhibit release of acetylcholine at the neuromuscular junction

46

Rattlesnake Neurotoxicity

• β neurotoxins – Common in Mojave and Southern Pacific (C. scutulatus and C. helleri) – Crotoxin, in South American rattlesnake (C. durissus terrificus)

• Fasciculations most common • Severe cases progress to weakness and paralysis with respiratory failure 47

Physical Exam • Tenderness, swelling, ecchymosis • Variable # puncture wounds; oozing • Axillary or inguinal tenderness • Possibly: vomiting, diarrhea, bleeding, tachycardia, fasciculations, erythema near bite, hypotension, angioedema • Rare: DIC, compartment syndrome, anaphylaxis • Labs: low platelets, low fibrinogen, high

PT, high FSP; hemoconcentration 48

16 Envenomations

Local: oozing at bite site, ecchymosis

Severe swelling, third spacing

49

Tissue necrosis, hemorrhagic blisters at bite site – usually with bites to digit

50

Management • IV fluids • No pressure bandages, incision, suction, tourniquet, extractors, etc… • No prophylactic antibiotics • Pain meds • Occasional epinephrine drips prn • Consider antivenom • No blood products unless actively bleeding AND giving antivenom

– Not ‘nuisance bleeding’ 51

17 Envenomations

Antivenom Indications

• Progressive swelling • Thrombocytopenia • Coagulopathy • Neurotoxicity • Shock

• No contraindications

52

Antivenom:CroFab Crotalidae Polyvalent Immune Fab (ovine)

• Sheep derived using Mojave, Western and Eastern Diamondbacks, Cottonmouth • Stops progression of swelling • Usually reverses hematologic toxicity • May prevent compartment syndrome • No evidence that prevents tissue loss 53

Antivenom

• Goal: gain ‘control’ of envenomation – Stop progression of swelling and reverse hematologic abnormalities

– May need to give maintenance doses after establishing control to prevent recurrent venom effects in first 24 hours after control 54

18 Envenomations

Management

• Beware – Late onset coagulopathy or thrombocytopenia – Recurrence of hematologic findings

– May be many days after AV, requires close out-pt follow up 55

All Antivenoms May Produce Hypersensitivity Reactions • Acute anaphylactoid – Most common, rate-related • Acute anaphylaxis – IgE mediated, type 1, pre-sensitized • Above treated with antihistamines, epi prn • Delayed (type IV) serum sickness – 3 - 21 days, rash / fever / arthralgias – Treat with steroids / antihistamines 56

Special Populations

• Pregnant - case reports suggest poor fetal outcome if first trimester – Most would aggressively treat with AV although not studies

• Children - no AV dose adjustments

57

19 Envenomations

Exotic Snakebites

• Attempt to identify species and locate appropriate specific AV – Patient, local zoo, poison center, Antivenin Index, etc… – Do not reflexively administer CroFab • Supportive care

58

Venomous Lizards

• Gila Monster - Heloderma suspectum – Desert areas of southwestern US • Beaded Lizard - Heloderma horridum – Mexico • Large, nocturnal, slow, shy • Forceful bite - only if handled – Difficult to disengage, teeth may break off in the wound 59

Gila Monster

• Venom contains helothermine • Poor delivery system (grooved teeth) • Local pain, tenderness, and edema • Occasional anaphylactoid reactions • No antivenom • Treatment: antihistamines, steroids, epinephrine; airway protection

60

20 Envenomations

Angioedema after gila monster bite

61

Arthropod Envenomations

• Native Spiders – Black widow – Brown Widow – Brown recluse • Non-native – Funnel web • Scorpions

• Hymenoptera 62

Widow Spiders

• Many species worldwide • US: ‘Black widow” = Latrodectus mactans, L hesperus, L variolus, L geometricus • L mactans: shiny black with ventral red hourglass on belly • Venom neurotoxic: α-latrotoxin – Causes release of neurotransmitters from presynaptic nerve terminals

63

21 Envenomations

Black Widow Spider Bite • +/- fang marks with surrounding erythema • 15 min - 6 hrs, “latrodectism” • Characteristic feature: pain • Neuromuscular: cramps, rigidity, tremor, weakness, priapism, uterine contractions • Cardiopulmonary: HTN, tachycardia • Systemic: nausea, diaphoresis, salivation, urinary retention • Latrodectus facies: periorbital swelling, grimacing 64

Black Widow Treatment • Recovery usually in 24 to 48 hours • Supportive care – Analgesics – Benzodiazepines

– If this fails: • 1 vial equine whole IgG AV – Antivenin (Latrodectus mactans) (Equine) – Analatro Fab2 antivenom is in

clinical trail phase presently 65

Brown Recluse Spider

• Loxosceles reclusa – AKA Fiddleback Spider • Violin-shaped mark on cephalothorax • Other Loxosceles: unlikely to interact with humans as much but can probably produce wound • Very reclusive spider, bites uncommon and over-diagnosed

66

22 Envenomations

Brown Recluse Spider

• Venom – sphingomyelinase D: necrosis, hemolysis – Hyaluronidase: facilitates spread of venom

– Leads to neutrophil migration to bite site, inflammation, clotting of small vessels, ischemia, necrosis 67

Brown Recluse Spider • May have only mild and transient skin irritation • May develop dermonecrosis – Blisters, bleeds, ulcerates in 2-8 hours (red, white, and blue lesion) – Lesion may enlarge for a week – Healing may take months • Erythema is gravitational 68

Brown Recluse Spider • Systemic involvement uncommon – More frequent in children – Usually 1-3 days after bite • Fever, chills, nausea, rash, arthralgias, DIC, hemolytic anemia, and renal failure • Treatment: supportive care, delayed debridement for large necrotic wounds; steroids recommended for hemolysis • Evidence does not support dapsone, HBO use in humans 69

23 Envenomations

Non-native: Funnel Web Spider • Atrax robustus • Australia; Sydney funnel web spider • Venom neurotoxic – Robustoxin (atraxotoxin) – NT release • Clinical: no necrosis; autonomic storm, with AMS, HTN, pulmonary edema, muscle writhing, salivation….. • Pressure immobilization

• Rabbit-derived IgG antivenom 70

Scorpions

• 1500 species, 30 dangerous • All dangerous in Family Buthidae – In No America, all Centruroides • In US, single species dangerous – Centruroides sculpturatus • All have venom that affects neuronal sodium channels and causes excessive NT release

71

Clinical Effects • Neurotoxic venom produces – Pain, paresthesias – Neuromuscular agitation

• Most dangerous species – Autonomic storm, cardiovascular collapse, pulmonary edema, death

72

24 Envenomations

The Bark Scorpion • 15-20,000 calls/year to AZ PCCs • 95% mild, managed at home – Grade 1, local pain – Grade 2, distal paresthesias • Severe (Grade 3, 4) mostly peds – Roving eye movements (opsoclonus) – Neuromuscular agitation – Hypersalivation, tachy, fever 73

The Bark Scorpion

• Management – Supportive, with benzodiazepines, opioids, airway protection – Monitor for rhabdomyolysis, aspiration pneumonia – In August 2011 Anascorp® (produced from the Mexican Centruroides species) was approved by the FDA

74

Tick Paralysis

• US - Dermacentor andersoni • US - Dermacentor variabilis • Australia - Ixodes holocylus

• Cases in US in northwest • As tick feeds on blood, secretes venom into host which is absorbed systemically • Neurotoxin: inhibits release of ACh at NMJ 75

25 Envenomations

Tick Paralysis: Clinical

• Tick on person for 4-6 days • Initially: weakness, lethargy, ataxia, • Then: ascending paralysis beginning in lower extremities, can progress to bulbar within 48 hours, can lead to respiratory weakness, death • Absent or decreased DTRs • Treatment: remove tick, supportive

76

Hymenoptera

• Apidae: honeybees, bumblebees – Can sting only once • Vespidae: Wasps, hornets, yellow jackets • Formicidae: Fire Ants

Most common reactions are allergic

77

Africanized Honeybees

• Apis mellifera scutellata • Aggressive, can attack in thousands

• Venom: – Melittin - main component, disrupts cell membranes – Phospholipase A2 - major allergen

78

26 Envenomations

Africanized Honeybees

• > 50 stings may cause systemic toxicity – Vomiting, edema, rhabdomyolysis, hemolysis, DIC, death (>500 stings) • Treatment: supportive care with IVF and pain control, antihistamines and steroids prn, epinephrine prn • Remove stingers by any method 79

Fire Ants: Solenopsis spp

• Solenopsis invicta – Southern US, imported from S America • Grabs skin with mandibles and stings in a circle around bite • Burning pain, wheals evolve to wikipedia pustules, can necrose • Can have systemic and anaphylactic reactions

80

Caterpillars / Lepidopterism

• US most important is Megalopyge opercularis – AKA puss caterpillar or wooly slug – an urticarial toxin can produce severe pain, swelling and erythema • In South America, the most medically important in the world: Lonomia obliqua – pain, coagulopathy, renal failure, DIC

– Antilonomic serum (SALon) in Brazil 81

27 Envenomations

Toads • Bufo spp – Bufo marinus - Cane toad – Bufo alvarius - Colorado River toad • Bufotoxins – Indolealkylamines: hallucinogenic – Bufadienolides: inhibit Na-K-ATPase • Toad licking, toad soup, aphrodisiac preps – cardiac toxicity • Can treat arrhythmias with digibind

82

Major Summary Points

• Stinging fish – hot water inactivation • Nematocysts – acetic acid inactivation • Rattlesnakes – cyto and hemotoxicity • Black widow – pain and hypertension • Brown recluse – necrotic wounds • Bark scorpion – hypersalivation, opsoclonus, neuromuscular toxicity • Massive honeybee - toxic reaction to mellitin – rhabdo, DIC 83

28 Carcinogens

Carcinogenesis

Stephen W. Munday, MD, MPH, MS Sharp Rees-Stealy Medical Group, Inc. San Diego Division, CA Poison Control System

1

Objectives

• Provide a brief framework and terminology for understanding toxic carcinogenesis • Provide an organized database to prepare for the board exam

2

Epidemiology of Cancer

Doll & Peto, 19813

1 Carcinogens

Definitions

• Mutagen – A substance that alters DNA • Carcinogen – A substance that increases the frequency or severity of cancer over background rates • Proximate carcinogen – intermediate forms • Procarcinogen – Requires metabolic activation • Ultimate carcinogen – the form actually causing the injury

4

Carcinogen Activation

H2N NH2 Benzidine (Procarcinogen) N-Hydroxylation

O H O

C N N C

H3C OH CH3 N hydroxy dacetyl Benzidine (Proximate Carcinogen) ] O H + C N N H C H 3 ] N Acetyl Benzidine Nitrenium ion (Ultimate Carcinogen)5

Most widely accepted model of environmental carcinogenesis Linear No-Threshold Effect Multistage Model of Carcinogenesis • Developed from radiation exposure – not chemicals • Not validated for low doses or low-dose rates

• From the New England Journal of Medicine (2007)

6

2 Carcinogens

7

8

Model’s Presumed Dose/ Response Relationship

Experimental Data

Response

Extrapolated Data Hormesis Dose • Most closely describes initiating agents • Assumes that the curve is linear to zero and that dose rates are unimportant • Ignores experimental evidence for hormesis (Decreased rates at low doses presumably due to cellular repair mechanisms) 9

3 Carcinogens

Classification of Chemical Carcinogens in Relation to their Action on One or More Stages of Carcinogenesis • Initiating agent: an agent capable of initiating cells by producing a heritable DNA alteration (ex. Alkylating Agent, Radiation) • Promoting agent: an agent capable of causing the expansion of initiated cell clones (ex. Hormones) • Progressor agent: an agent capable of converting an initiated cell or a cell in the stage of promotion to a potentially malignant cell (increasing karyotipic instability)

Complete carcinogen: an agent possessing the capability of inducing cancer from normal cells, usually possessing properties of initiating, promoting and progressor agents 10

Initiation • Initiation often occurs as the result of irreversible DNA alteration that either activates oncogenes or inactivates tumor suppression genes • Oncogenes primarily affect cellular growth, signal transduction and nuclear transcription (ex. ras) • Tumor supressor genes regulate cell growth and division (ex. p53, BRCA1) • When the DNA alteration occurs in germ cells, it is then heritable. (2 Hit Theory) 11

Promotion

• A reversible process that works by altering gene expression often by interfering with signal transduction • The process requires ligand-receptor interactions and therefore often demonstrates a sigmoid shaped dose/ response relationship • Some promoters demonstrate hormesis – a protective effect at low doses

12

4 Carcinogens

Dose/Response Relationship No Range of Maximum response increasing response range response with range increasing dose Threshold Threshold Increasing Response Increasing

Increasing Dose 13

Examples of Mechanism of Promotion

14

Steroid Tyrosine Kinase G protein-linked

Plasma Membrane AC Cytoplasm Ras Tyrosine G Protein Sos GDP GTP Kinase Receptor B-raf PKA HSP90 MEK Phosphorylation

MAPK

Dimerization RSK Nuclear Membrane Nucleus Transcription p19arf E2F CREB REB HRE 15

5 Carcinogens

Progression

• Irreversible progressive karyotype instability associated with further DNA alteration over time

16

Examples of Organizations with Carcinogenesis Classifications • United Nations (WHO/ • ACGIH (American IARC & GHS*) Conference of Governmental Industrial Hygienists) [*Globally Harmonized System] • OSHA/(IARC, NTP, • EPA (USA) 29CFR1910Hazcom • NTP (USA) Publisher of subpart Z) Review of Carcinogens (RoC), 12th edition currently

17

Inter-Agency comparisons

IARC GHS NTP ACGIH EU Group 1 Cat. 1A Known A1 Cat. 1 Group 2A Cat. 1B Reasonably A2 Cat. 2 suspected Group 2B Cat. 2 A3 Cat. 3 Group 3 A4 Group 4 A5

18

6 Carcinogens

• FDA (National Center for Toxicology Research) • NIEHS/(NIH) • NIOSH/CDC

19

IARC International Agency for Research on Cancer (WHO/UN) [05/2012] Carcinogen Classification

Group 1 Known Human Carcinogens (107) Group 2A Probable Human Carcinogens (63) Group 2B Possible Human Carcinogen (271) Group 3 Not Classifiable (509) Group 4 Probably Not Carcinogenic (1)

20

IARC Classification Data Analysis

Based on: • human epidemiology • in vitro • animal experiments • Other relevant data (SAR, ADME, Dose/ Response, Repair Mechanisms) • They do not conduct the experiments, they just review the data. 21

7 Carcinogens

IARC Classification, cont’d

• Human Epidemiology – frequently involves occupationally exposed cohorts but also case/control or ecologic studies • Generally preferred for IARC 1 classification but exceptions exist (ethylene oxide, neutrons)

22

IARC Classification: in vitro tests Test Endpoint Gene mutation assays in vitro Prokaryote mutagenesis in Back or forward mutations vitro (Ames’ test, etc.) in specific bacterial strains Mouse lymphoma thymidine Mutations in TK kinase (TK) Chinese hamster ovary (CHO) Mutations in HGPRT & V79 hypoxanthine guanine phosphoribosyltransferase (HGPRT) 23

IARC Classification, in vitro tests cont’d Test Endpoint Chromosomal alterations in vivo Heritable translocation test Translocations induced in (mice) germ cells Rat bone marrow Chromosomal aberrations clastogenesis in vivo in bone marrow cells in vivo Micronucleus test Appearance of micronuclei in bone marrow cells in vivo 24

8 Carcinogens

IARC Classification, in vitro tests cont’d Test Endpoint Chromosomal alterations in vitro Mitotic recombination, mitotic Conversion of crossing over, or mitotic gene heterozygous alleles to conversion in yeast homozygous state Induced chromosomal Visible alterations in aberrations in cell lines karyotype Sister chromatid exchange Visible exchange of differentially labeled sister chromatids 25

Ames’ Test

• Salmonella can normally synthesize histadine • Ames’ salmonella strain is genetically unable to synthesize histadine • The Ames’ test examines rate of loss of histadine- dependence due to mutation back to normal gene function allowing histadine synthesis • Generally performed with and w/out microsomes (hepatic homogenate) to evaluate metabolic activation

26

IARC Classification, cont’d

Animal experiments • Gold standard is the 2-year rodent bioassay • Preferences are a minimum of 2 species and both sexes.

27

9 Carcinogens

IARC Classification, cont’d Problems • Extrapolation from test tube to animal models • Extrapolation from animals to humans – Dose/Response relationship – Cell type differences – Metabolic differences

28

Group 1 “Known Human Carcinogens” (107) • Sufficient Human Evidence • Less than sufficient in humans but sufficient in animals and strong evidence in humans of a relevant mechanism.

29

Group 2A “Probable” (63)

• Limited Human Evidence and sufficient animal evidence • Inadequate human and sufficient animal evidence and a relevant mechanism in humans • Rarely: limited Human Evidence Alone

30

10 Carcinogens

Group 1: Agents and Groups of Agents (107 as of 05/12)

Benzo(a)pyrene

31

Antineoplastic drugs and other drug evaluated by the IARC Monograph Working Group

Cancer on which Group 1 Agent sufficient evidence in Established mechanistic events humans is based Busulfan Acute myeloid leukemia Genotoxicity (alkylating agent) Chlorambucil Acute myeloid leukemia Genotoxicity (alkylating agent) Cyclophosphamide Acute myeloid leukemia, Genotoxicity (metabolism to alkylating bladder agent) Melphalan Acute myeloid leukemia Genotoxicity (alkylating agent) Semustine Acute myeloid leukemia Genotoxicity (alkylating agent) (methyl-CCNU) Thiotepa Leukemia Genotoxicity (alkylating agent) Treosulfan Acute myeloid leukemia Genotoxicity (alkylating agent)

32

Antineoplastic drugs and other drug evaluated by the IARC Monograph Working Group Cancer on which Group 1 Agent sufficient evidence Established mechanistic events in humans is based MOPP* combined therapy Acute myeloid Genotoxicity (alkylating agent) leukemia, lung Etoposide in combination Acute myeloid Genotoxicity; translocation involving MLL with cisplatin and bleomycin leukemia gene (etoposide) Etoposide (Group 2A in 2000) Genotoxicity; translocation involving MLL gene Chlomaphazine Bladder Genotoxicity (alkylating agent, metabolism to 2-naphthylamine derivatives) Azathioprine non-Hodgkin Genotoxicity, immunosuppression lymphoma, skin Cyclosporin non-Hodgkin Immunosuppression lymphoma, skin, multiple other sites

*MOPP= chlormethine (mechlorethamine), vincristine (oncovin), procarbazine, and prednisone33

11 Carcinogens

Antineoplastic drugs and other drug evaluated by the IARC Monograph Working Group

Cancer on which Group 1 Agent sufficient evidence Established mechanistic events in humans is based Methoxsalen+ultraviolet Skin Genotoxicity following photo-activation light Plants containing Renal pelvis, ureter Genotoxicity; DNA adducts in humans, aristolochic acid A:T  T:A transversion in TP53 in human tumors Aristolochic acid (Group 2A Genotoxicity; DNA adducts in animals are in 2000) the same as those found in humans exposed to plants, A:T  T:A transversions in TP53, RAS activation Analgesic mixtures Renal pelvis, ureter (See phenacetin) containing phenacetin Phenacetin (Group 2A in Renal pelvis, ureter Genotoxicity, cell proliferation 2000) 34

Hormonal treatments assessed by the IARC Monograph Working Group

Group 1 agent Cancer on which sufficient Established mechanistic Other likely evidence in humans is based events mechanistic events Diethylstilbestrol Breast (exposure during Estrogen receptor- Epigenetic pregnancy), vagina and cervix mediated events (vagina, programming (exposure in utero) cervix), genotoxicity Estrogen-only Endometrium, ovary Estrogen receptor- Genotoxicity menopausal therapy mediated events Combined estrogen- Endometrium (risk diseases Receptor-mediated events Estrogen genotoxicity, progestogen with number of days/month of menopausal therapy progestogen use), breast Combined estrogen- Breast, cervix, liver Receptor-mediated events Estrogen genotoxicity, progestagen oral (endometrium & ovary hormone-stimulated contraceptives DECREASED) expression of human papillomavirus genes Tamoxifen Endometrium Estrogen receptor-mediated (breast DECREASED) events, genotoxicity

35

Evidence for carcinogenicity in humans and for geotoxicity as the main mechanism

Tumor sites with sufficient Evidence of genotoxicity Agent evidence in humans as the main mechanism

Aromatic amines 4-Aminobiphenyl Urinary bladder Strong Benzidine Urinary bladder Strong Dyes metabolized to benzidine Strong* 4.4’-Methylenebis(2-chloroaniline) Strong* 2-Naphthylamine Urinary bladder Strong Ortho-toluidine Urinary bladder Moderate Auramine production Urinary bladder Weak / lack of data Magenta production Urinary bladder Weak / lack of data

*Agents classified in Group 1 on the basis of mechanistic information 36

12 Carcinogens

Evidence for carcinogenicity in humans and for geotoxicity as the main mechanism

Tumor sites with sufficient Evidence of genotoxicity Agent evidence in humans as the main mechanism

PAH-related exposures Benzo(α)pyrene Strong* Soot (chimney sweeping) Skin, lung Moderate Coal gasification Lung Strong Coal-tar distillation Skin Strong Coke production Lung Strong Coal-tar pitches (paving, roofing) Lung Strong Aluminum production Lung, urinary bladder Weak / moderate†‡

*Agents classified in Group 1 on the basis of mechanistic information †Weak evidence in workers, but strong evidence for some chemicals in this industry ‡Due to the diversity and complexity of these exposure, other mechanisms may also be 37relevant

Evidence for carcinogenicity in humans and for geotoxicity as the main mechanism Tumor sites with sufficient Evidence of genotoxicity Agent evidence in humans as the main mechanism Other chemicals Aflatoxins Hepatocellular carcinoma Strong Benzene ANLL Strong Bis(chloromethyl)ether/chloromethyl Lung Moderate/Strong methylether 1,3-Butadiene Haematolymphatic organs Strong Dioxin(2,3,7,8-TCDD) All cancers combined** § 2,3,7,8-Pentachlorodibenzofuran *§ 3,3’,4,4’,5-Pentachlorobiphenyl § (PCB-126) ANLL = acute non-lymphocytic leukemia *Agents classified in Group 1 on the basis of mechanistic information §Strong evidence for an aryl hydrocarbon receptor (AhR)-mediated mechanism 38 **New epidemiological findings.

Evidence for carcinogenicity in humans and for geotoxicity as the main mechanism

Tumor sites with sufficient Evidence of genotoxicity Agent evidence in humans as the main mechanism Other chemicals Ethylene oxide Strong* Formaldehyde Nasopharynx Strong Leukemia¶** Moderate Sulfur mustard Lung Strong Vinyl chloride Hepatic angiosarcoma Strong Hepatocellular carcinoma

*Agents classified in Group 1 on the basis of mechanistic information ¶Particularly myeloid leukemia **New epidemiological findings.

39

13 Carcinogens

Evidence for carcinogenicity in humans and for genotoxicity as the main mechanism Tumor sites with sufficient Evidence of genotoxicity Agent evidence in humans as the main mechanism Other complex exposures Iron and steel founding Lung Strong* Isopropyl alcohol manufacture Nasal cavity Moderate using strong acids Mineral oils Skin Strong Occupational exposure as a Lung, urinary bladder, pleural Strong‡ painter mesothelioma Rubber manufacturing Leukemia, lymphoma**, urinary Strong‡ industry bladder, lung**, stomach** Shale oils Skin Weak / lack of data Strong inorganic acid mists Larynx Weak / lack of data *Agents classified in Group 1 on the basis of mechanistic information **New epidemiological findings. 40 ‡Due to the diversity and complexity of these exposure, other mechanisms may also be relevant

Metals, arsenic dusts and fibers assessed by the IARC Monograph Working Group

Tumor sites (or types) for Group 1 Agent which there is sufficient Established mechanistic events evidence in humans Arsenic and inorganic Lung, skin, urinary Oxidative DNA damage, genomic arsenic compounds bladder instability, aneuploidy, gene amplification, epigenetic effects, DNA-repair inhibition leading to mutagenesis Beryllium and Lung Chromosome aberrations, aneuploidy DNA beryllium compounds damage Cadmium and Lung DNA-repair inhibition, disturbance of cadmium compounds tumor-suppressor proteins leading to genomic instability Chromium (VI) Lung Direct DNA damage after intracellular compounds reduction to Cr (III), mutation, genomic instability, aneuploidy, cell transformation

41

Metals, arsenic dusts and fibers assessed by the IARC Monograph Working Group

Tumor sites (or types) for Group 1 Agent which there is sufficient Established mechanistic events evidence in humans Nickel compounds Lung, nasal cavity, and DNA damage, chromosome aberrations, paranasal sinuses genomic instability, micronuclei, DNA- repair inhibition, alteration of DNA methylation, histone modification Asbestos (chrysotile, Lung, mesothelioma, Impaired fiber clearance leading to crocidolite, amosite, larynx, ovary macrophage activation, inflammation, tremolite, actinolite generation of reactive oxygen and nitrogen and anthrophyllite) species, tissue injury, genotoxicity, aneuploidy and polyploidy, epigenetic alteration, activation of signaling pathways, resistance to apoptosis

42

14 Carcinogens

Metals, arsenic dusts and fibers assessed by the IARC Monograph Working Group

Tumor sites (or types) for Group 1 Agent which there is sufficient Established mechanistic events evidence in humans Erionite Mesothelioma Genotoxicity Silica dust, crystalline Lung Impaired particle clearance leading to in the form of quartz macrophage activation and persistent or crystobalite inflammation Leather dust Nasal cavity and paranasal sinuses Wood dust Nasal cavity and paranasal sinuses, nasopharynx

43

Evidence for carcinogenicity in humans of Groups 1 agents assessed – Personal Health

Tumor sites for which there is sufficient evidence Tobacco Smoking Oral cavity, oropharynx, nasopharynx, and hypopharynx, esophagus (adenocarcinoma and squamous-cell carcinoma), stomach, colorectum*, liver, pancreas, nasal cavity and paranasal sinuses, larynx, lung, uterine, cervix, ovary (mucinous)*, urinary bladder, kidney (body and pelvis), ureter, bone marrow (myeloid leukemia) Parental smoking Hepatoblastoma* (cancer in the offspring)

*New sites 44

Evidence for carcinogenicity in humans of Groups 1 agents assessed – Personal Health

Tumor sites for which there is sufficient evidence Second hand smoke Lung Smokeless tobacco Oral cavity, esophagus*, pancreas Areca nut Betel quid w/added Oral cavity, pharynx, tobacco esophagus Betel quid w/o added Oral cavity, tobacco esophagus* Alcohol consumption Oral cavity, pharynx, larynx, esophagus, liver, colorectum, female breast

*New sites 45

15 Carcinogens

Evidence for carcinogenicity in humans of Groups 1 agents assessed – Personal Health

Tumor sites for which there is sufficient evidence Acetaldehyde Esophagus*, head and associated with neck* alcohol consumption Chinese style salted Nasopharynx fish Indoor emissions Lung from household combustion of coal

*New sites

46

Radiation exposures with sufficient evidence in humans Tumor sites (and types) on Radiation type Major study populations which sufficient evidence is based Alpha-particle and beta-particle emitters Radon-222 and decay products General population Lung (residential exposure), underground miners Radium-224 and decay Medical patients Bone products Radium-226, radium-228, and Radium-dial painters Bone, paranasal sinus and mastoid decay products process (radium -226 only Thorium-232 and decay Medical patients Liver, extrahepatic bile ducts, gall products bladder, leukemia (excluding CLL) Plutonium Plutonium-production Lung, liver, bone workers CLL: chronic lymphocytic leukemia 47

Radiation exposures with sufficient evidence in humans

Tumor sites (and types) on Radiation type Major study populations which sufficient evidence is based Alpha-particle and beta-particle emitters Phosphorus-32 Medical patients Acute leukemia Fission products, including General population Solid cancers, leukemia strontium-90 following nuclear reactor accident Radioiodines, including Children and adolescents Thyroid iodine-131 following nuclear reactor accident

48

16 Carcinogens

Radiation exposures with sufficient evidence in humans

Tumor sites (and types) on which Radiation type Major study populations sufficient evidence is based X-radiation or Atomic bomb survivors, medical Salivary gland, esophagus, stomach, gamma-radiation patients, in-utero exposure colon, lung, bone, skin (BCC), female (offspring of pregnant medical breast, urinary bladder, brain and CNS, patients and of atomic bomb leukemia (excluding CLL), thyroid, survivors) kidney (atomic bomb survivors, medical patients), multiple sites (in-utero exposure Solar radiation General population Skin (BCC, SCC, melanoma) UV-emitting General population Skin (melanoma), eye (melanoma, tanning device particularly choroid and ciliary body) CLL: chronic lymphocytic leukemia BBC: basal-cell-carcinoma SCC: squamous-cell-carcinoma 49

Biological agents assessed by the IARC Monograph Working Group

Cancers for which there is Established mechanistic Group 1 Agent sufficient evidence in events humans Epstein-Barr Virus (EBV) Nasopharyngeal carcinoma, Cell proliferation, inhibition Burkitt’s lymphoma, of apoptosis, genomic extranodal NK/T-cell instability, cell migration lymphoma (nasal type), Hodgkin’s lymphoma Hepatitis B virus (HBV) Hepatocellular carcinoma Inflammation, liver cirrhosis, chronic hepatitis Hepatitis C virus (HCV) Hepatocellular carcinoma, Inflammation, liver cirrhosis, non-Hodgkin’s lymphoma* liver fibrosis

* Newly identified link between virus and cancer 50

Biological agents assessed by the IARC Monograph Working Group

Cancers for which there is Established mechanistic Group 1 Agent sufficient evidence in humans events

Kaposi’s sarcoma herpes Kaposi’s sarcoma*, primary Cell proliferation, inhibition virus (KSHV) effusion lymphoma* of apoptosis, genomic instability, cell migration Human immunodeficiency Kaposi’s sarcoma, non-Hodgkin’s Immunosuppression (indirect virus type 1 (HIV-1) lymphoma, Hodgkin’s action) lymphoma*, cancer of the cervix*, anus*, conjunctiva* Human papillomavirus type Carcinoma of the cervix, vulva, Immortalisation, genomic 16 (HPV-16)` vagina, penis, anus, oral cavity, instability, inhibition of and oropharynx & tonsil DNA damage response, anti- apoptotic activity *Newly identified link between virus and cancer `For other types, see next slide 51

17 Carcinogens

Group HPV types

Group HPV Types Comments Alpha HPV types 1 16 Most potent HPV type, known to cause cancer at several sites 1 18, 31, 33, Sufficient evidence for cervical cancer 35, 39, 45, 51, 52, 56, 58, 59 2A 68 Limited evidence in humans and strong mechanistic evidence for cervical cancer

52

Biological agents assessed by the IARC Monograph Working Group

Cancers for which there is Established mechanistic Group 1 Agent sufficient evidence in humans events

Human T-cell lymphotropic Adult T-cell leukemia and Immortalisation and virus, type-1 (HTLV-1) lymphoma transformation of T cells Heliobacter pylori Non-cardia gastric carcinoma, low- Inflammation, oxidative grade B-cell mucosa-associated stress, altered cellular turn- lymphoid tissue (MALT) gastric over and gene expression, lymphoma* methylation mutation Clonorchis sinemsis Cholangiocarcinoma* Opsithochis viverrini Cholangiocarcinoma Inflammation, oxidative stress, cell proliferation Schictosoma haemetobium Urinary bladder cancer Inflammation, oxidative stress,

*Newly identified link between virus and cancer 53

Oral Cavity

• Alcoholic beverages • Betel quid with tobacco • Betel quid without tobacco • Human papillomavirus type 16 • Tobacco, smokeless • Tobacco smoking

54

18 Carcinogens

Tonsil

• Human papillomavirus type 16

55

Pharynx

• Alcoholic beverages • Betel quid with tobacco • Human papillomavirus type 16 • Tobacco smoking

56

Nasopharynx

• Epstein-Barr virus • Formaldehyde • Salted fish, Chinese-style • Wood dust

57

19 Carcinogens

Digestive tract, upper

• Acetaldehyde associated with consumption of alcoholic beverages

58

Esophagus • Acetaldehyde associated with consumption of alcoholic beverages • Alcoholic beverages • Betel quid with tobacco • Betel quid without tobacco • Tobacco, Smokeless • Tobacco smoking • X-radiation, Gamma-radiation

59

Stomach

• Heliobacter pylori • Rubber production industry • Tobacco, Smokeless • Tobacco smoking • X-radiation, Gamma-radiation

60

20 Carcinogens

Colon and rectum

• Alcoholic beverages • Tobacco smoking • X-radiation, Gamma-radiation

61

Anus

• Human immunodeficiency virus type 1 • Human papillomavirus type 16

62

Liver and bile duct • Aflatoxins • Alcoholic beverages • Clonorchis sinensis • Estrogen-progestogen contraceptives • Hepatitis B virus • Hepatitis C virus • Opisthorchis viverrini • Plutonium • Thorium-232 and its decay products • Tobacco smoking (in smokers and in smokers’ children) • Vinyl chloride 63

21 Carcinogens

Gall bladder

• Thorium-232 and its decay products

64

Pancreas

• Tobacco, Smokeless • Tobacco smoking

65

Nasal cavity and paranasal sinus

• Isopropyl alcohol production • Leather dust • Nickel compounds • Radium-226 and its decay products • Radium-228 and its decay products • Tobacco smoking • Wood dust

66

22 Carcinogens

Larynx

• Acid mists, strong inorganic • Alcoholic beverages • Asbestos (all forms) • Tobacco smoking

67

Lung

• Aluminum production • Arsenic and inorganic arsenic compounds • Asbestos (all forms) • Beryllium and beryllium compounds • Bis(chloromethyl)ether; chloromethyl methyl ether (technical grade)

• Cadmium and cadmium compounds (cont’d)

68

Lung

• Chromium(VI) compounds • Coal, indoor emissions from household combustion • Coal gasification • Coal-tar pitch • Coke production • Hematite mining (underground) (cont’d)

69

23 Carcinogens

Lung

• Iron and steel founding • MOPP (vincristine-prednisone-nitrogen mustard-procarbazine mixture) • Nickel compounds • Painting • Plutonium • Radon-222 and its decay products (cont’d)

70

Lung

• Rubber production industry • Silica dust, crystalline • Soot • Sulfur mustard • Tobacco smoke, secondhand • Tobacco smoking • X-radiation, gamma-radiation

71

Bone

• Plutonium • Radium-224 and its decay products • Radium-226 and its decay products • Radium-228 and its decay products • X-radiation, gamma-radiation

72

24 Carcinogens

Skin Melanoma

• Solar radiation • Ultraviolet-emitting tanning devices

73

Skin (non-melanoma malignant neoplasms) • Arsenic and inorganic arsenic compounds • Azathioprine • Coal-tar distillation • Coal-tar pitch • Cyclosporine • Methoxsalen plus Ultraviolet A • Mineral oils, untreated or mildly treated • Shale oils • Solar radiation • Soot • X-radiation, gamma-radiation 74

Mesothelium (pleura and peritoneum)

• Asbestos (all forms) • Erionite • Painting

75

25 Carcinogens

Endothelium (Kaposi sarcoma)

• Human immunodeficiency virus type 1 • Kaposi sarcoma herpes virus

76

Breast

• Alcoholic beverages • Diethylstilbestrol • Estrogen-progestogen contraceptives • Estrogen-progestogen menopausal therapy • X-radiation, gamma-radiation

77

Vulva

• Human papillomavirus type 16

78

26 Carcinogens

Vagina

• Diethylstilbestrol (exposure in utero) • Human papillomavirus type 16

79

Uterine cervix

• Diethylstilbestrol (exposure in utero) • Estrogen-progestogen contraceptives • Human immunodeficiency virus type 1 • Human papillomavirus types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 • Tobacco smoking

80

Endometrium

• Estrogen menopausal therapy • Estrogen-progestogen menopausal therapy • Tamoxifen

81

27 Carcinogens

Ovary

• Asbestos (all forms) • Estrogen menopausal therapy • Tobacco smoking

82

Penis

• Human papillomavirus 16

83

Kidney

• Tobacco smoking • X-radiation, gamma-radiation

84

28 Carcinogens

Renal pelvis and ureter

• Aristolochic acid, plants containing • Phenacetin • Phenacetin, analgesic mixtures containing • Tobacco smoking

85

Urinary bladder

• Aluminum production • 4-Aminobiphenyl • Arsenic and inorganic arsenic compounds • Auramine production • Benzidine • Chlornaphazine • Cyclophosphamide (cont’d)

86

Urinary bladder • Magenta production • 2-Naphthylamine • Painting • Rubber production industry • Schistosoma haematobium • Tobacco smoking • ortho-Toluidine • X-radiation, gamma-radiation 87

29 Carcinogens

Eye

• Human immunodeficiency virus type 1 • Ultraviolet-emitting tanning devices • Welding

88

Brain and central nervous system

• X-radiation, gamma-radiation

89

Thyroid

• Radioiodines, including Iodine-131 • X-radiation, gamma-radiation

90

30 Carcinogens

Lymphoid, hematopoietic and related tissue: Leukemia &/or lymphoma

• Azathioprine • Benzene • Busulfan • 1,3-Butadiene • Chlorambucil • Cyclophosphamide • Cyclosporine (cont’d)

91

Lymphoid, hematopoietic and related tissue: Leukemia &/or lymphoma

• Epstein-Barr virus • Etoposide with cisplatin and bleomycin • Fission products, including Strontium-90 • Formaldehyde • Heliobacter pylori • Hepatitis C virus • Human immunodeficiency virus type 1(cont’d)

92

Lymphoid, hematopoietic and related tissue: Leukemia &/or lymphoma

• Human T-cell lymphotropic virus type 1 • Kaposi sarcoma herpes virus • Melphalan • MOPP (vincristine-prednisone-nitrogen mustard-procarbazine mixture) • Phosphorus-32 • Rubber production industry (cont’d)

93

31 Carcinogens

Lymphoid, hematopoietic and related tissue: Leukemia &/or lymphoma

• Semustine (methyl-CCNU) • Thiotepa • Thorium-232 and it’s decay products • Tobacco smoking • Treosulfan • X-radiation, gamma-radiation

94

Multiple sites (unspecified)

• Cyclosporine • Fission products, including Strontium-90 • X-radiation, gamma-radiation (exposure in utero)

95

All cancer sites (combined)

• 2,3,7,8-Tetrachlorodibenzo-para-dioxin

96

32 Miscellaneous Toxins

ACMT Board Review

Miscellaneous Toxicants

Brandon Wills, DO, FACEP, FACMT Fellowship Director, Medical Toxicology Department of Emergency Medicine VCU Medical Center Virginia Poison Center VCU TOX 1

2.2.10 Miscellaneous Toxicants 2.2.10.1 Acrolein 2.2.10.2 Acrylamides 2.2.10.3 Acrylates 2.2.10.4 Amines 2.2.10.5 Aniline Compounds 2.2.10.6 Azides 2.2.10.7 Bromide Compounds 2.2.10.8 Butadienes 2.2.10.9 Carbon Disulfide 2.2.10.10 Chlorates 2.2.10.11 Coal Tar Products 2.2.10.12 Diamines 2.2.10.13 Dibromochloropropane (DBCP) 2.2.10.14 Dimethylacetamide (DMAC) 2.2.10.15 Dimethylformamide (DMF) 2.2.10.16 Dinitrobenzene 2.2.10.17 Dinitrotoluene (DNT) 2.2.10.18 Epichlorohydrin 2.2.10.19 Ethylene Dibromide (EDB) 2.2.10.20 Ethylenediamine (EDA) 2.2.10.21 Fluoride Compounds 2.2.10.22 Fuels 2.2.10.23 Hexachloro-1,3-Butadiene (HCBD) 2.2.10.24 Isocyanates (eg, toluene diisocyante) 2.2.10.25 Maleic Anhydride 2.2.10.26 Mercaptans 2.2.10.27 Methylene Diamine (MDA) 2.2.10.28 Nitriles 2.2.10.29 O-Phenylenediamine (OPD) 2.2.10.30 Phosphorus/phosphides 2.2.10.31 Phthalates 2.2.10.32 Polymers 2.2.10.33 Resins 2.2.10.34 Styrene 2.2.10.35 Trimellitic Anhydride 2.2.10.36 Triorthocresylphosphate (TOCP) 2 2.2.10.37 Xylidine

Our Gameplan

 Organize your memory

 Using study aids (quick look at flashcards)  60 min: brief review- focus on test rather than content

 20 min: Miscellaneous Toxicants Jeopardy overview

3

1 Miscellaneous Toxins

Sources

 Dr. Sean Bryant

 Dr. Mike Greenburg

 Sullivan, 2nd Ed  Greenburg, 2nd Ed

 My board review notes

 http://pubchem.ncbi.nlm.nih.gov/ (structures)

4

Legend for this talk

U= Uses

I= Industry

T= Toxicity

M= Miscellaneous factoids

5

Acrylaldehyde, propenal, allyl aldehyde Acrolein Ethylene aldehyde, aqualin, (CH2=CHCHO)

Acrolein = Acrid = IRRITATING

I: Contact herbicide I: WWI Lacrimator

T- Water soluble irritant

T- Cellular toxin via oxygen free radicals

M- Metabolite of cyclophosphamide

6

2 Miscellaneous Toxins

Propenamide, acrylic amide, Acrylamides akrylamid Heating Starches U- Polymer production (SDS-PAGE), flocculator

T- Axonopathy T- Dermatitis (peeling, red/blue, hyperhidrosis)

T- IARC 2A (poss gyn CA) M- Polymer = non-toxic, Monomer= toxic

7

Acrylates, methylacryates, Cyanoacrylates Acrylates Ethyl, methyl, 2-ethyl hexyl, butyl…

U- Cross-linking properties (plexiglass)

T- Irritant (skin, MM, and pulmonary) T- Contact dermatitis

M- Penetrates latex/ rubber easily

8

Dimethylamine Trichlorotriethylamine Benzidine Benzidine Amines β-naphthylamine

Dimethylamine

AZO Dyes

-Vulcanization

9

3 Miscellaneous Toxins

Aniline 4-chloroaniline Aniline Compounds 4-aminophenol Nitrobenzene 4,4’-Methylene dianiline Aniline

U- Precursor for polyurethane, indigo= blue jean die I- Smells like rotten fish

T- Acute: MetHb, irritant

T- Chronic: Bladder CA Methylenedianiline: Hepatitis (Epping jaundice)

Due to contaminated bread T- Aniline (Spain) Toxic oil syndrome Due to contaminated rapeseed oil (interstitial pulm dz) 10

Azides

U- Airbag accelerant; pesticde, explosives I- Labs and manufacturing plants

T- Cellular asphyxiant, resp failure/ pulm edema T- Eye irritant

11

Bromide Compounds

U- Photographic, hot tub chemicals, fumigants...

T- Crosses membrane faster than Cl, replacing Cl

causing sedation/ neuropsych (KBr- 19th century)

T (chronic)- neuropsych, acne (30% facial), axonopathy

M- Low anion gap (false high Cl)

12

4 Miscellaneous Toxins

1,3-butadiene Hexachloro-1,3- butadiene Butadienes Many others Butadiene

U- Monomer for plastics (ABS plastic*), tobacco smoke

T- Irritant (skin and mucous membranes)

T- IARC 2A (lymphohematopoetic, testicular, thyroid, mammary)

*ABS: Acrylonitrile-butadiene-styrene

13

Carbon Disulfide U- Volatile organic solvent I- Rayon, fumigation

T- Acute: Irritant (defatting), disulfiram rxn T- Chronic: 1. Distal axonopathy 2. Optic nerve (resembles optic neuritis) 3. CV (HTN, CAD) 4. Repro (SAB, prematurity, decreased libido)

14

Potassium chlorate Calcium chlorate Chlorates Sodium perchlorate, etc

U- Oxidizer, pesticide, explosives, bleaching paper

U- Prior uses: pryotechnics, mouthwash

T- Oxidizer= MetHb, hemolysis, renal failure

M- FYI- Perchlorates= Also oxidizers but more stable

15

5 Miscellaneous Toxins

Coal Tar Products

Sources: wood creosote= beach wood

(phenol, cresols, guaiacols, xylenols)

coal tar creosote= by-product of coal tar

(85% polycyclic aromatic hydrocarbons (PAH))

U- Wood: wood protectant

Coal tar: wood preservative (railroad ties), Rx psoriasis

T- Dermal irritant, pulmonary= restrictive/ obstructive

Cancer d/t PAH (lung, oral, stomach, bladder, scrotal, skin)

16

Diamine (Hydrazine) Hexamethylene diamine Toluene-2,4-diamine (TDI) 2-methyl-1,4- benzenediamene Diamines TDI Hydrazine

U- Hydrazine= Rocket fuel (reducer), insecticides, plastics

U- P-phenylenediamine= henna & all hair dyes...

T- Irritant/ sensitizer (dermal & pulmonary), lupus-like

T- Hydrazine=INH (seizures, hepatitis, MetHb, skin sensitizer)

17

Dibromochloropropane (DBCP)

U- Nematicide (D/C’d in 1979)-> replaced by dibromoethane

T- Dermal / ocular irritant

T- Testicular (aspermia, oligospermia)

De Balls Can’t Produce (DBCP)

18

6 Miscellaneous Toxins

Dimethylacetamide (DMAC)

U- Paint remover, solvent for plastics (dissolves PVC)

Smells like fish/ ammonia

T- Potent hepatotoxin: ↑ LFT, jaundice, hepatomegaly, liver necrosis

T- Irritant: esophagitis, conjunctivitis, dermal burn

19

Dimethylformamide (DMF) “Universal Solvent”

U- Penetrates most plastics (makes them swell) I- Acrylic fiber production, paint strippers Vehicle for transdermal drug delivery

T- Potent hepatotoxin (CLN, steatosis) T- Disulfiram rxn T- Pulm irritant

20

Dinitrobenzene

U- EXPLOSIVES, spandex, dyes

T- Retrobulbar neuritis & optic neuropathy

T- MetHb (potent)

T- Subacute hepatic necrosis, aplastic anemia

T- May have bitter almond odor, hair/skin/ eye yellowing

21

7 Miscellaneous Toxins

Dinitrotoluene (DNT)

U- EXPLOSIVES, diisocyanate production, dyes

T- Uncouples oxidative phosphorylation

T- MetHb

T- Hemolytic anemia

T- Retrobulbar & optic neuropathy

M- Turns skin yellow

22

Epichlorhydrin

U- Highly reactive plastics production I- Production of dye, lubricants, adhesives, drugs

T- Strong Irritant (sensitizer): respiratory, dermal, ocular T- Nephrotoxicity, CNS depression, hypotension

M- Penetrates rubber M- Sweet, chloroform odor has poor warning property

23

Ethylene Dibromide (EDB) (AKA Dibromoethane)

U- Replaced dibromochloropropane as nematicide

U- Fumigant (grain- banned 1948), fire extinguishers, lead scavenger in gasoline

T- Hepatotoxicity (GSSH depletion)

T- Strong irritant (dermal, pulmonary)

24

8 Miscellaneous Toxins

Ethylenediamine (EDA)

U- Dyes, solvent, emulsifier (skin creams/ latex)

U- Drug production:

(EDTA, imidazolines, aminophylline, antihistamines)

T- Sensitizer (contact dermatitis, occ asthma)

T- MetHb

25

Fluoride Compounds

U- NaF: electroplating, toothpaste/ water additive HF: cleaning brick/ rust, glass etching

T- Chelates divalent cations (Ca++, Mg++), results in ↓ Mg/ Ca, ↑ K = ventricular fibrillation

T- Chronic= fluorosis: bone density, calcification of ligaments, hyperostosis, white-brown dental spots (axial osteosclerosis/ nerve compression) 26

Fuels

U- Energy-producing hydrocarbons

T- PULMONARY (pneumonitis)

M- Jet fuels (kerosene, benzene, xylene, toluene)

JP-7 & JP-8 ∼ pure kerosene

27

9 Miscellaneous Toxins

Hexachloro-1,3-Butadiene (HCBD)

U- Heat transfer liquid (transformers/ hydraulic fluid)

U- Fumigant in vineyards (don’t confuse with Bordeaux= copper sulfate)

T- Irritant (Pulmonary hemorrhage)

T- Hepatic fatty degeneration

T- Renal tubular necrosis, tubular adenomas

28

Methylisocyanate (MIC) Toluene diisocyanate (TDI) Isocyanates MIC

U- Producing polyurethane polymers

(don’t confuse with aniline also a polyurethane precursor) U- Methylisocyanate (MIC)- production of carbamates

T- MIC: Major irritant (pulm, derm, ocular) T- TDI: #1 Occupational asthma (HP)

29

Maleic Anhydride

U- Enamels, bonding, synthesis of malathion

T- Allergic sensitizer (occupational asthma)

Hypersensitivity pneumonitis (HP)= extrinsic allergic alveolitis= Immunologic

T- Irritant (dermal, ocular)

30

10 Miscellaneous Toxins

Mercaptans Mercaptomethane

Chemicals with a –SH group (noxious≈ cabbage)

U- Odorant (natural gas= t-butylmercaptan) U- Intermediate in synthesis of fuels, pesticides…

T- Irritant (derm, MM, respiratory)

T- MetHb & hemolysis (worse in G6PD)

31

acetonitrile propane nitrile Nitriles butanenitrile Acetonitrile Chemicals with a –CN

U- Solvents (eg. artificial nail remover), reagents

T- Liberation of –CN  Cellular asphyxiant T- Irritants (derm, MM, ocular) M- Prolonged observation for delayed CN toxicity

32

O-Phenylenediamine (OPD) P-Phenylenediamine (PPD)

*This compound is also listed under “Diamines”* PPD

U- OPD: dyes, fungicides, vet antihelminthic U- PPD: hair dyes and henna tattoos

T- OPD=severe urticaria/dermatitis (eye blindness)

T- PPD= bladder cancer

33

11 Miscellaneous Toxins

Phosphorus Red Phosphides Zn Phosphide Phosphorus

U- Making phosphates, detergents, fertilizer, match tips (red)

U- Zn & Al phosphide: Insecticides, rodenticides

T- Yellow: strong oxidizer, causes burns (Red is benign)

Ingestion: 1. “smoking”, glowing stool, smells of garlic

2. Asymptomatic (hrs-weeks) 3. Hepatic/ renal failure Chronic: “Phossy Jaw”- mandibular necrosis

T- Phospine gas: cellular asphyxiant + pulm edema + #3 above 34

Phthalates diethylhexyl phthalate

U- Plasticizing for vinyl, softens PVC

T- Controversial whether phthalates have health effects. Some claim association with asthma, “sick- building syndrome”, or endocrine problems but little supporting data

T- Diethylhexyl Phthalate (DEHP)= occ asthma

35

Polymers tetrafluoroethylene

*Diverse group of plastics*

One class= Fluoropolymer plastics:

Polytetrafluoroethylene (PTFE = Teflon)

T- Polymer Fume Fever (heating polymers)

-Pulm irritant, flu-like syndrome (similar to MFF)

-Resolves in 24-48 hrs

36

12 Miscellaneous Toxins

Resins methylenedianiline

Resins = Plastics

Combustion can liberate: CO, CN, phosgene

Methylenedianiline – Toxic hepatitis (Epping Jaundice)

Anhydrides – Occupational pneumonitis

37

Styrene

U- Styrene = Styrofoam

Also ABS, SBR plastics

T- “Styrene Sickness”: HA/fatigue/weakness, intoxicated after exp to vapor

T- Peripheral neuropathy

T- CNS (balance, memory, color vision) T- Chronic= Hearing loss

38

Trimellitic Anhydride

U- Plasticizer for polymers (PVC)

T- Sensitizer/ irritant; 4 syndromes:

1. Asthma/ rhinitis (IgE) 2. Irritant syndrome (dust/ fumes)

3. Late respiratory systemic syndrome (LRSS)

“Trimellitic Flu”- Like MFF, 4-12 hours after shift

4. Hypersensitivity pneumonitis + hemolytic anemia

“Pulmonary disease- anemia” (PDA)

Dyspnea, cough, hemoptysis, anemia May lead to restrictive lung dz; pulm hemosiderosis 39

13 Miscellaneous Toxins

Triorthocresylphosphate (TOCP) U- Plasticizer in lacquer, hydraulic fluid

T- Weak AchE inhibitor (like organophosphate)

Inhibits neuro-target-esterase (NTE)

T- Delayed sensory-motor neuropathy

“O-P ester induced delayed neurotoxicity (OPIDN)”

M- Jamaican Ginger (Jake) adulterated by TOCP

“Jake Walk”= Jake leg paralysis M- Morocco: OPIDN after TOCP adulterated cooking oil 40

Xylidine O-xylidine Xylidine 2-6-methylaniline

U- Making dyes/ pharmaceuticals, gas additive…

T- Acute: MetHb, cyanosis, intoxication

T- Chronic: Liver/ renal damage (animals)

41

Now…

Group by some reoccurring themes

42

14 Miscellaneous Toxins

Irritants

- Acrolein

- Acrylates

- Epichlorohydrin

- Ethylene Dibromide (EDB)

- Ethylenediamine

- Methylisocyanate (MIC)

- Mercaptans

-Many more

-So many, decide if this category works for you...

43

Cancer Causing

-Acrylamides (2A)

-Aromatic Amines (Benzidine, β-naphthylamine) (1): bladder

-Aniline (1): bladder

-P-Phenylenediamine (PPD): bladder, leukemia

-Butadienes (2A): lymphohematopoetic

-Coal tar: lung, oral, stomach, bladder, scrotal, skin

-Vinyl Chloride: Angiosarcoma of liver

-CCl4: Liver

44

Peripheral Neuropathy

-Acrylamide (A)

-Bromide (Methyl) (A) -Carbon disulfide (A)

-Styrene (?)

-TOCP

-Trichloroethylene (M)

45

15 Miscellaneous Toxins

Hepatotoxins

-Dimethylacetamide (DMAC): Necrosis, jaundice

-Dimethylformamide (DMF): CLN, steatosis

-Hexachloro-1,3-Butadiene (HCBD): fatty degen -Phosphorus (yellow or white)

-Xylidine (in animals; also renal damage)

-Methylenedianiline: Hepatitis (epping jaundice)

46

MetHb Inducers

-Chlorates

-Dinitrobenzene (potent)

-Dinitrotoluene (DNT)

-Ethylenediamine

-Mercaptans

-Xylidine

47

Sensitizers Pulmonary= Occupational Asthma

- Anhydrides: occupational pneumonitis (HP)

- Maleic Anhydride: Allergic & hypersensitivity pulm dz

- Trimellitic Anhydride: Asthma, “Trimellitic Flu” (HP)

- Ethylenediamine (EDA): occup asthma, contact dermatitis

- Toluene diisocyante (TDI)/ isocyanates: (#1 occ asthma)

- Diethylhexyl Phthalate (DEHP): occ asthma

48

16 Miscellaneous Toxins

Hypersensitivity Pneumonitis (HP) Some overlap with previous slide

- Anhydrides/ Maleic Anhydride

- Pyrethrum

- Trimellitic Anhydride - Isocyanates (TDI, MDI)

49

50

VCU TOX 51

17 Accreditation Statement The University of Alabama School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The University of Alabama School of Medicine designates this educational activity for a maximum of 22.5 AMA PRA Category 1 credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The University of Alabama School of Medicine is an equal opportunity/affirmative action institution.

Program Objectives: • Present study content specifically designed for the medical toxicology subspecialty exam offered jointly by ABEM,ABP, and ABPM • Present a comprehensive review of medical toxicology • Allow attendees to gain new insight into current clinical issues

Target Audience: Physicians preparing for the biennial certification and recertification examination in Medical Toxicology, and others with an interest in medical toxicology.

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