General Principles of Toxicology

Scope of Medical Toxicology:  Occupational (Chemicals), Environmental (agricultural/air), Clinical (drug toxicity, accidental, intentional)

  • Oral > Eye > Skin > Bites/Stings > Inhalation > Aspiration
  • 90% poisonings occur in the household (children- most common): cosmetics, cleaning products,

plants, pharmaceuticals, etc)

  • Most Deaths: Antidepressants, Analgesics, Stimulants/St. drugs, Alc/glycols, Gases/Fumes, Asthma Rx
  • Most frequently involved in Hu Poison Exp: Cleaning substances, Analgesics, Cosmetics, Cough/Cold

preps, Plants

  • Priority Toxic Agents for Hu: Alcohols (Etoh, Mtoh, ethylene glycol); Gases/Vapors (CO, H2S, CN, NO, ozone); Metals (Fe, Lead, Hg); Drugs (Tylenol, deferoxamine, dimercaprol, penicillamine, pesticides, Cl-hydrocarbons, Nitroso compounds, aromatic amines, aminoazo dyes, alkyl agents)
MECHANISMS OF TOXICITY
1.  Receptor Interactions

2.  Actions due to physical or chemical properties of toxins

3.  Inhibit enzymes, channels, carrier proteins

4.  Antimetabolites (CN blocks O2 binding to cyto. oxidase)

TOXICOKINETICS
Routes of exposure: Oral, inhalation, dermal (fastest-slowest)

  • Absorption: lipid solubility & ionization for oral ingestion, SA of stomach/intestine
  • Distribution: (Initially) Rate of Bld Flow to organs; (later) redistribution e.g. adipose (DDT) or Bone (lead)
  • Biotransformation/Elimination: liver, kidneys; toxic metabolites may be highly toxic and damage these tissues; toxicity (esp. mutagenesis/carcinogenesis) from biotrans and prod of “reactive spp” is almost always due to Phase I biotrans rxns catalyzed by P450 system. Phase II = conjugation by glucuronides.
  • Variability in toxic rxns produced by diff individuals b/c genetic diffs in forms of P450s and other enzs and in the diff levels of such enzs due to genetic or environmental diffs. Biotrans => detoxify or form reactive intermediates (may help or hurt!)
  • Delayed vs. Immediate Toxicity
  • Exp Rate, Elim Rate and Nature of Elim process (1st Order or Zero order) determines the level of toxin in body => toxic effects
  • Special Pop. = neonates/infants (premature/elderly) b/c mech of elim not well devo or maintained.
DOSE EFFECTS & MEASURES OF TOXICITY
Therapeutic Index:

TI = TD50/ED50          or TI = LD50/ED50

TD or LD  =Toxic/Lethal Dose

ED = Effective Dose

Margin of Safety:

MOS = TD1/ED99            or MOS = LD1/ED99

 

MOS  > 1 = Very Safe Drug (Drug A)

NOELs & MOS for Non-Drugs:

MOS = NOEL(animal studies) / Hu “Exp Dose”

NOEL = No Obs Effect Level (used when tox  for hu unk/unattainable, est. of safety  based on animal data) is  highest dose of a chemical which does NOT produce an obs effect. “Exp. Dose” = (mg/L of toxin) (L/day of exp) / (wt=kg)

Acceptable Daily Intake:

ADI = [NOEL](acute/chronic) /(10hv x 10id x 10)

ADI = WHO defines “daily intake of chem which during the entire lifetime appears to be w/o appreciable risk on the basis of all known facts at the time.”  Based on NOEL and uncertainty factors (hu variability, interspecies var, lack of chronic data

Threshold Limit Values:

  • TLV = “safe” concentration in ambient air in the workplace for many common industrial chemicals.
  • TLVs est. by occupational hygienists and published on periodic basis
TOXICATION or ACTIVATION MECHANISMS
  • Approx. 90% of environmental toxicants that cause genotoxicity do so by the generation of reactive metabolites of the parent compound, reactive oxygen spp, free rads, etc.
  • “reactive metabolites” capable of forming covalent bonds w/ proteins, nucleic acids, lipids => loss enz fxn; gen of haptens => Ab production; formation of DNA adducts => mutagenesis, damage membranes integrity/fxn.
  • Production of Reactive Metabolites:

1.  Phase I (P450 or PGH synthase catalyzed biotrans) => “Toxication” processes

2.  Phase II (sulfate or glucuronide conjugation) => “inactivation” and elimination

  • Bioactivation forms electrophiles (e-deficient atom w/ full or partial pos. chg) or free rads (molecule w/ unpaired e(s) in its outer orbital)
  • Reactive Oxygen Species:

1.  O2* (Superoxide anion radical) via toxin + O2 or Mac/Granulocytic O2 resp burst by membrane bound NADPH:

e.g.  paraquat, doxorubicin, nitrofurantoin

2.  H2O2 (Hydrogen peroxide) via SOD or spontaneously

3.  HO* (Hydroxyl radical) via “Fenton Rxn” (FeII, CuI, MnII, CrV, NiII)

DETOXICATION of REACTIVE OXYGEN & FREE RADICALS
  • Glutathione peroxidase (GPO), Superoxide dismutase (SOD), and Catalase (CAT) play a central role in detoxication mechanisms!
  • SOD: O2* + 2H+ >O2 + H2O2
  • GPO or CAT: H2O2 + 2GSH >GSSG + 2H2O

Summary:  SOD + GPO(or CAT) => O2* > 2H2O

MACROMOLECULAR MODIFICATIONS
1.  Covalent Modification of proteins:  loss of enz or protein fxn, hapten formation

2.  Modifications of Nucleic Acids:  DNA damage/mutagenesis.

a.  Adduct formation- alkyl sulfates, N-nitroso cpds, epoxides, mustards

b.  Loss of Purine or Pyrimidine (­ spont. incidence by adducts formation)

c.  Deamination- nitrous acid

d.  ssDNA breaks- peroxides, oxygen radicals and x-rays

e.  dsDNA breaks- x-rays

f.  Cross-linking- alkylating agents (mustards & nitrosureas)

3.  Lipid Peroxidation:  Membrane damage, loss of function, generation of more free radicals. Major mechanism for OXIDATIVE DAMAGE!!!  Resulting from many chemicals which lead directly or indirectly to the formation of O2* or other reactive spp.

REPAIR MECHANISMS
1.  Tissue repair

2.  Molecular repair

a.  Repair of Damaged Proteins- GSH may reduce S-S linkages in damaged proteins

b.  DNA repair enzymes- alkyl transferases remove alkyl adducts from DNA, base/nct excision repair; post

replication repair; mismatch repair

REPAIR MECHANISMS cont…

c.  Membrane repair by antioxidants-  tocopherol (Vit E) & ascorbic acid (Vit C) convert lipid peroxides OH-FA’s

and replace damaged membrane lipids

RISK ASSESSMENT & MGMT
  • Hazard Identification- potential hazards to which hu (humans) may be exposed. What is the structure-activity of chemical (func groups)? Epidemiogical studies (incidence over demographics/geographics)? In vitro toxicity tests, toxicology studies in animals for acute, subacute, subchronic, chronic studies.
  • Risk Characterization- suspected risk. What is potency of agent (LD50), hu exp (exposure) assessment (air, water, diet? Susceptibility based on genetic background, lifestyle, occupation?
  • Control of Risks- d/c production of chemical? Info dissemination to public? Less toxic substitutes available?

NON-METAL TOXICANTS

INTRODUCTION:  Air Pollutants, Gases, Vapors
Five Major Pollutants:  CO (52%), sulfur oxides, volatile hydrocarbons, particulate matter, nitrogen oxides.

  • Occupational ds include: Interstitial fibrosis, bronchogenic CA, mesothelioma (asbestos); coal miner’s pneumoconsiosis; byssinosis (cotton dust), toluene diisocyanate asthma, Western red cedar, silicosis (hwy construction).
  • At risk Pop. for airborne pollutants: infants, elderly, emphysema or COPD, asthma, & smoking hx.
RESPIRATORY TRACT EXPOSURES
  • Gas: solubility determines rate at which gas => resp tract and abs into bldstream
  • Particulates: size of particle determines level to which particle moves
  • Uptake: particle density, particle size, minute ventilation
  • Protection: directional changes within entire resp tree => deposition of particle before it enters alveolar region
  • Elimination
INORGANIC GASES
Sulfur Oxides

Source:  combustion of fossil fuels

Toxic Effects:  bronchospasm, hypertrophy of goblet cells, & mucous glands, & pulmonary edema; may produce sulfuric acid.

Nitrogen Oxides

Source:  auto exhaust, cig smoke, gas stoves

Toxic Effects:  interstitial edema (penetrates alveoli), epithelial cell prolif, fibrosis & emphysema w/ high exp; may produce nitric & nitrous acids.

Ozone

Source:  photochemical rxns involving NO2 + O2 + UV radiation.

Toxic Effects:  (chronic exp) Inflammation, edema, bronchial constriction, & pulmonary vasc changes. Contributes to ­ incidence of asthma.

“AIR TOXICS”
“Air Toxics” are ~ 200 chemicals by EPA => pollutants (3 major classes)

1.  “volatile organic compounds”

2.  “aldehydes”

3.  “reactive chemicals”

  • Include: cig smoke, (indoor) de-gassing of synthetic bldg materials/plastics = “new car smell”
  • “Sick Bldg Syndrome”- collection of sx in atleast 20% of those exposed and relieved by removal from exposure.

Symtoms include:  ENT irritation, HA, ¯ attn span, nasal congestion, dyspnea, nausea, dry skin, nose bleeds

  • “Bldg-related illnesses”- well-documented conditions w/ defined dx criteria, e.g. Legionnaires’ ds (bacterial pneuno)
PARTICULATES
  • ~toxic material on carbon particles from incomplete combustion; may be organic/inorganic.
CARBON MONOXIDE
MOST FREQUENT CAUSE OF DEATH FROM POISONING

CO binds reversibly to Hb w/ affinity 220 times that of O2

CO can also bind to heme Fe in cellular cytochromes

MOT = Mechanism of Toxicity (like MOA)

  • MOT: tissue hypoxia due to:

a.  competes w/ O2 for Hb binding sites => functional anemia

b.  Left shift of Hb curve => less cooperativity, impairs O2 unloading to peripheral tissues

  • SX: (dept on level % bld sat of COHb and length of exposure)

0-10% COHb => no symtoms

10-20%           => tightness across forehead; slight HA, dilatation of cutanesous bv

20-30%           => HA, throbbing in temples

30-40%           => Severe HA, weakness, dizziness, dimness of vision, N/V, collapse

40-50%          => Cherry red appearance, ­RR, ­HR, collapse or syncope

>> 50%           => Cheyne-Stokes respiration, coma w/ convulsions, cardiac/resp failure, death

  • RX: 1) remove from source of CO 2) give O2 (may need hyperbaric tx) until COHb < 10% 3) support ABC -should expect acidosis from anaerobic metabolism, pos pressure vent may be needed for air transport of pt.

REMEMBER!  Simple pO2 no longer predicts O2 carrying capacity.  Co-oximetry is needed!!  Pulse oximetry values will be falsely elevated in setting of CO poisoning.

At Risk populations:  smokers, Ischemic HD, anemia, elderly, unborn infants in utero and fire exposure victims.

NITRITES
  • Inorganic/organic compounds that enter via resp or GI routes.
  • MOT: Oxidation of Fe++ => Fe+++ in Hb => Met-Hb

Met-Hb => ¯ O2 binding to Hb (like CO) and Hb curve shifts to LEFT => umpaired Unloading => tissue hypoxia

  • RX: Methylene blue (1-2 mg/kg) augments Met-Hb reductase in RBCs and spontaneously reverses rxn-

met-Hb®Hb.

**NOTE:  methylene blue => false, transient, decrease in O2 saturation by measured by pulse Ox.

CN (Cyanide)
Source:  electroplating/metal processing industries; byproduct of nitroprusside (vasodilator in OR/ICU) metabolism; combustion of plastics containing nitrogen.

MOT:  Binds strongly to & inhibits cytochrome oxidase => blocks e-transport in oxphos pathway

SX: BRIGHT RED VENOUS BLD & “ALMOND” ODOR

RX:  MUST BE FAST!!  3 Steps:

1.  Transient production of met-Hb w/ nitrites (amyl nitrite via inhalation) + sodium nitrite (IV)

-met-Hb competes w/ cyto. oxidase for CN ion (e-transport is repaired) b/c Met-Hb binds all CN.

2.  Sodium thiosulfate: CN >SCN (thiocyanate)

3.  Methylene blue used to treat met-Hb-emia

H2S (Hydrogen Sulfide)
Source:  natural sources & petrochemical industry.

MOT:  Potent inhibitor of cytochrome oxidase (same effects as CN poisoning)

RX:  nitrite-induced met-Hb formation which reacts w/ H2S to form sulfmet-Hb.  Thiosulfate has little or no role.  O2 recommended for hypoxemic pt.

PESTICIDES, SOLVENTS, INDUSTRIAL CHEMICALS

INSECTICIDES
All toxic to insects, hu, other animals by interfering w/ Neurotransmission.

I.  ORGANOCHLORINE:  DDT, Methoxychlor, Aldrin, Dieldrin, Lindane…

-low cost, low volatility, lipid sol, chem stable.

-accumulate in fat depots (very lipophilic)

-induce P450s

-Three structural types:

a.  DDT & methoxychlor-  breast milk is major source exp in U.S.

b.  Chlorinated Cyclodienes (Aldrin, Dieldrin, Heptachlor, Chlordane)-  very high dermal abs. w/ potential for severe

acute toxicity, incl. Death

c.  Other (Lindane, Kepone, Mirex, Chlordecone, Toxaphene)-  Kwell (Lindane shampoo) used against lice.

MOT:  (axonal cyto.)  interferes w/ nerve conduction by inhibiting repolarization (prolong falling phase of AP) =>

­ sensitivity to very small stimuli that would not normally elicit a response.

SX:  Paresthesias (esp CNV distribution), apprehension, irritability, tremors, ventilatory failure & motor seizures.

RX:  ABC (acute care); BZD or barbs (seizures); Cholestyramine (po) => fecal excreation of compounds

II.  ACETYLCHOLINESTERASE INHIBITORS (AChEI):  Organophosphorus & Carbamate esters

-Two types:

a.  Organophosphate Insecticides (malathion, parathion, diasinon)-

b.  Carbamates (carbaryl, aldicarb)-  usually reversible by hydrolysis

MOT:  (synapse) inactivates AchE enzyme

SX:  Muscarinic storm (meiosis, cramps, ­ secretions, bronchospasm, diarrhea, urinary incontinence, brady =>

Asystole); Nicotinic-R stimulation then blockade (HTN, muscle fasciculations, tremors, then weakness w/ possible

paralysis); and CNS effects (restlessness, ataxia, mental confusion, seizures, coma, and death).

RX:  ABCs if necessary.  Adm of atropine => muscarinic storm & pralidoxime (reactivates the cholinesterases)

NOTE:  Atropine (high doses) => central anticholinergic syndrome => mental confusion, seizures, and death.

Pralidoxime (high doses) => bind Ca => muscle spasms.

III. PYRETHROIDS:  pyrethrin, cypermethrin, deltamethrin

-Acute toxicity relatively low in hu/mammals, but compounds persist in environment longer than organophosphates.

MOT:  (axonal cyto.) interfere w/ neurotransmission by variety of mechanisms (Na channels, GABA-R’s, effects on

Ca levels).

HERBICIDES
I.  CHLOROPHENOXY COMPOUNDS  (2,4-D; 2,4,5-T)

-kills broad leaf weeds/plants by antagonizing plant hormones

-chloroacne, & other dermatitis reported in production workers

-component in “Agent Orange” a defoliant used in Vietnam

MOT:  thought to be due to TCDD, a contaminant from the production process

II.  BIPYRIDYL COMPOUNDS (paraquat)

-most serious toxicity is pulmonary fibrosis (probably from generation of free rads, and O2 adm ­ toxicity)

COMMON SOLVENTS & VAPORS
I.  ALIPHATIC HYDROCARBONS:  Methane, ethane, propane, butane, hexane…

-“asphyxiants”

-“glue sniffing” or hexane => progressive sensorimotor distal axonopathy

MOT:  toxin targets neurofilaments in cytoskeleton of axon => neurofilament aggregates => massive swellings of distal, subterminal axon => demyelination => clinical peripheral neuropathy => “stocking & glove” distribution of sensory loss.

SX:  CNS depression, polyneuropathy

II.  ALIPHATIC ALCOHOLS & GLYCOLS: Methanol, ethylene glycol

a.  Methanol

MOT:  formation of formaldehyde + formic acid by AlcDH

SX:  systemic acidosis (formic acid), blindness- “blind drunk”

RX:  EtOH (IV load 0.6g/kg, MD = 150mg/kg/hr); Hemodialysis

b.  Glycols & glycol ethers

Source:  antifreeze (ethylene glycol), fingernail polish, propylene glycol (foods, cosmetics, meds) are all considered “GRAS” or Generally Recognized As Safe by FDA.

SX (ethylene glycol):  CNS depression, nephrotoxicity (oxalate stones), metabolic acidosis (formic, glycolic, oxalic acids)

III.  HALOGENATED ALIPHATIC HYDROCARBONS:  dichloromethane, chloroform, CCl4

-solvents, cleaning compounds

-cause generalized CNS depression

Toxicities:  hepatic (+P450 rxns => free rads), renal, heart (arrhythmias)

MOT:  sensitizes P450 rxns

IV.  AROMATIC HYDROCARBONS: Benzene, toluene

-solvents in many chemical production syntheses

-Acute Tox => CNS

-Long-term Tox of Benzene (not toluene) => ­ risk of leukemia and aplastic anemia

MOT:  free rads & highly reactive intermediates form DNA-adducts

POLY-CHLORINATED & POLY-HYDROXYLATED AROMATIC HYDROCARBONS
I.  POLYCHLORINATED & POLYBROMINATED BIPHENYLS:  PCB, PBB

-extensively produced in US

-extremely resistant to degradation

II. BY-PRODUCTS of PCB production

-include PCDDs (polychlorinated dibenzo-dioxins) and PCDFs (polychlorinated dibenzo-furans)

III.  TCDD = “Dioxin” or Dioxin-R

-potent inducer of aryl hydrocarbon hydroxylase, P450 dept. Mono-oxygenase

-Ah locus codes for “receptor” for TCDD = nuclear protein which increases transcription of specific P450 genes

(CYP1A1, CYP1A2), UDP-glucuronyltransferase, and one form of glutathione-S-transferase)

-hu Ah-Receptor likely to exist and predicts individual sensitivity to certain classes of drugs and toxicants.

IV.  TOXICITIES

­-Death:   TCDD is one of the most lethal chemicals known in certain species e.g. GUINEA PIG KILLER!

-Hu toxicities:  chloracne, porphyria, psychiatric disturbances, gen CNS effects (acute); leukemias and soft

tissue sarcomas (long term).

-reports of increased thyroid CA

-PCBs and PBBs => neurotoxicity, immunotoxicity, and reproductive toxicity in experimental animals.

HEAVY METALS & CHELATORS

GENERAL CONCEPTS
Exposures:  acute or chronic

Toxicity:  important functional groups (O, S, N, -SH) on proteins serve as ligands for metals; every organ contains proteins w/ these func groups therefore sx are general/non-specific, and multiple organ systems are affected esp.  CNS, resp, GI, Kidney, and immune.

Protection:  Metallothionien (induced by low levels of some metals) in liver and kidney may prevent toxicity to higher levels of metals b/c of its high capacity to bind many molecules of metal per molecule of protein.

TREATMENT of Metal Poisonings:

1.  Removal of exposure source or decontamination, elimination of metal from body.

2.  Supportive treatment for sx (correct lytes, prevent seizures, ABCs)

3.  Chelating agents- remove or prevent the binding of metals to the endogenous “ligand” sites where they produce toxicity, NOT to prevent binding to important molecules (Fe to Hb); chelator-metal complexes are elim in urine, so may accum. in case of renal insuff.

MAJOR CHELATORS:  Dimercaprol (Hg & Ar); EDTA (Pb); Deferoxamine (Fe); Penicillamine (primary for Cu; adjunct for Pb & Hg); Succimer (Pb in children)

LEAD TOXICITY
Lead has no est. physiological function in hu or animals => All actions considered TOXIC!!

  • EXPOSURE: old house paints, leaded gasoline; food, contaminated water, and air, pottery & jewelry making, sandblasters; CDC considers 10 mg/dL => some adverse effects can be observed in hu’s
  • ABSORPTION: GI & Resp Tract => circulation (in RBCs) => Pb binds to Hb; little free Pb in bld => ­ conc in soft tissues w/ good perfusion (esp. liver, kidney), eventually sequestered in bone; elim from body very slow.
  • ACUTE (rare): CNS (paresthesia), muscle weakness/fatigue, gen pain. Hemolysis => anemia & hemoglobinuria => kidney damage.
  • CHRONIC: CNS toxicities MOST SERIOUS! = “Pb encephalopathy”

RX:  1) ABC Support;  2) Diazepam for seizures; 3) Chelate q1wk EDTA and dimercaprol (IV); penicillamine/succimer (po) esp good for children.

MERCURY
Chemistry:  Elemental Hg (liq/vapor); Ionized Hg in hu & mammals (Hg II); methylmercury (organic mercurial)-Hu ingest this form of organoHg made by bacteria via diet.

  • EXPOSURE: Occupational/industrial pollution (mercuric salts in water or mercury vapor); agricultural uses of organoHg; Hg vapor from deposition of earth’s crust (main source of Hg in environment) which is then => Hg salts or organoHg primarily by anaerobic bacteria in oceans => ingested by small crustaceans => food chain => humans.
  • MAJOR SOURCE: eating large amts highly contaminated food!!
  • MOT: thought to bind thiol groups in enz and other protein structures.
  • ABSORPTION:

a.  Elemental Hg:  vapor => lungs =>crosses BBB to brain & membranes within CNS => some Hg converted to Hg II by catalase in RBCs.

Note:  liquid form of elemental Hg rarely ingested & relatively non-toxic if it is b/c not abs well from GI.

b.  Inorganic Hg salts:  oral route => circulation => conc in Kidney; Note:  long t1/2 = 60 days in body;  NO CNS effects b/c charged and can’t cross BBB.

c.  OrganoHg compounds (CH3Hg) :  GI abs => (very lipophilic) enterohepatic recycling => cleared from the body

VERY SLOWLY t1/2 = 50-100 days .  CH3Hg can covalently bind cysteine => ~met => can traverse capillaries =>

CNS/placenta => SEVERE NEUROLOGICAL TOXICITIES in both ADULTS & IN UTERO!!

MERCURY cont…

SX:

a.  Elemental/OrganoHg => NEUROLOGICAL (visual) & BEHAVIORAL = “mad as a Hatter”  (MOST  COMMON); Remember Triad:  1) excitability 2) tremors 3) gingivitis.

b.  Hg Salts (corrosive to mucosa of mouth, pharynx, intestine) => intense pain/vomiting => loss of bld/fluids in stool => hypovolemic shock in severe exposures

c.  Hg vapor => severe interstitial pneumonitis & ¯¯ resp fxn (may have residual interstitial lung fibrosis even after recovery

NOTE:  GI tract & Kidney are major sites of toxicity.

RX:

1.  Removal of/from source of exp (decontamination)

2.  Chelation therapy:

a.  Elemental Hg or Hg salts:  use dimercaprol (IV) or penicillamine (po)- NOT effective in OrganoHg;

Penicillamine-Hg chelate => urine only  (caution w/ ¯ renal fxn); Dimercaprol-Hg chelate => bile & urine.

b.  OrganoHg (methylHg):  use non-abs polythiol resin => excreted in bile => feces- Hemodialysis NOT helful for organoHg b/c Hg compound inside RBCs!

ARSENIC
EXPOSURE:  Natural substance in earth’s crust & groundwater (well water);  Industrial & agricultural chemicals (herbicides & insecticides); industrial accidents release arsine gas (AsH3)

ABSORPTION:  Resp tract & GI tract

MOT (two mechanisms):

1.  Arsenate (AsO4) substitutes for Pi in ox-phos (mitochondria) => unstable AsO4-ADP => ADP + AsO4 + wasted energy

2.  Arsenite (As+++) binds proteins w/ -SH groups; also interacts w/ lipoic acid (cofactor for Pyruvate-DH rxn)

SX:

  • GI, CV, CNS => generalized or nonspecific sx includes mucosal damage => GI bld/diarrhea => hypovolemic shock.
  • Triad of As Gas (rare, but potentially fatal): 1) massive hemolysis 2) abd pain 3) hematuria => kidney damage due to ­ degraded Hg in plasma

RX:  1) decontamination 2) dimercaprol (IM) followed by longer times of 3) penicillamine (po)

Remember to watch for hypovolemic shock.

CADMIUM
Exposure:  Ni-Cd rechargeable batteries; byproduct of Zn mining

a.  Industrial:  mining & smelting operations

b.  Food ingestion (shellfish conc Cd from water)

c.  Cigarette smoke (Cd in leaves of tobacco plants)

Intake:  Resp Tract > GI tract

MOT:

a.  Resp Tract:  (chronic) bronchitis => fibrosis in lower airways => alveolar damage = alveolar macs release lytic enz and  ¯¯ alpha -1-AT activity that normally counteracts lytic enz => emphysema.  Acute effects: chemical pneumonitis and pulmonary edema which can be severe if exposures are high.

b.  Kidney:  protein metallothionien (usually protectant against metal tox) complexes with Cd in liver => enter

circ => taken up by renal tubule cells => metallothionien-Cd complex degraded in lysosomes releasing Cd in cell => renal tubular necrosis

c.  GI tract: (usually due to acute exposures):  N/V, abd pain, usually reversible.

RX:

1)  Decontamination 2) ABC esp respiratory support 3)  EDTA (not clear how effective)

IRON
Sources/Exposures:  Normal diet (tox uncommon in normal individuals).  Special considerations:

a.  Young Children (1-2 yrs):  Household Fe supplements for anemic family members; 0.5 g = serious tox; 2g may be fatal.  OTC preps = 250 mg tabs therefore 10-20 tabs => serious poisoning!!  Children also have >> capacity for Fe abs.

b.  Adults:  chronic poisoning due to: 1) repeated transfusions (thalassemia) or 2) inherited d/o’s

(hemochromatosis); also, miners/steel workers may inhale particulates w/ iron oxide => form deposits in lungs.

MOT:  Destruction of mucosal GI tract => Fe damages endothelial cells (esp. liver & kidney)

SX:  severe gastroenteritis, vomiting, bloody diarrhea, abd. pain, can be followed by => shock, metabolic acidosis, coma, CV collapse, death.

RX:

a.  Early Acute:  1) gastric lavage  2)  carbonate salts to form insol Fe complexes => feces 3) deferoxamine (esp in acute children)

b.  Chronic toxicity: 1) recurrent phlebotomy (esp. hemochromatosis) 2) deferoxamine at time of transfusions in thalassemia pts.

Note:  deferoxamine does not remove Fe from Hg, Mg or cytochromes and only removes it to a ltd extent from transferrin; hypocalcemia not a concern.  Complex excreted in urine & feces.  May cause allergic rxn, pain at injection site. Rare hTN and tachy w/ rapid IV infusion.

TREATMENT:  COMMONLY USED CHELATORS
DIMERCAPROL (IV only)

a.  Primary agent => Hg & Ar poisoning

b.  Adjunct + EDTA => Pb poisoning

CAUTION!  NOT for Fe or Cd poisonings b/c ­ nephrotoxicity with drug-metal complexes; NOT for methylHg poisoning b/c drug actually ­ amt Hg in CNS.

DEFEROXAMINE (IV only)

a.  Fe poisoning (binds ferric Fe+++)

b.  Aluminum poisoning

CAUTION! Use in children for Acute Fe poisoning only, NOT chronic b/c => auditory & ocular probs esp. w/ ¯ renal fxn

EDETATE aka Calcium EDTA (IV only)

a.  Primary agent for Pb poisoning

-If used chronically give “on”/”off” to allow Pb to redist. out of bone stores during “off” times.

-May ¯ duration of action of insulin-Zn preps b/c it chelates Zn well.

PENICILLAMINE (po)

a.  Primary for Cu in Wilson’s ds

b.  Adjunct for Pb, Hg, Ar toxicity

c.  Some cases of RA

SE:  allergic rxns (x-sens w/ penicillin), stomatitis w/ ulcers, sores, and gingivitis (leukopenia & thrombocytopenia)

SUCCIMER (po)

a.  Pb poisoning in Young Children

b.  Adjunct for Hg and Ar

SE:  GI (n/v/d) & rash (sens rxns)

ACUTE POISONINGS & OVERDOSES

EPIDEMIOLOGY OF POISONINGS
  • ~2.5 million hu exp/yr in US
  • 400,000 referred for med tx, 25% admitted
  • 0.03% fatality rate (1998)
  • Over 50% of 2.5 miollion are < 6 yrs old
MOST COMMON EXPOSURES & CAUSES OF DEATHS
CHILD (Age < 6)

Exposure: Cosmetics, cleaning products, analgesics, plants, cough/cold preps

Deaths:  CO (most common across all toxicants and ages!!), Analgesics, Fe, cleaning products, CV drugs,

antidepressants, pesticides

ADOLESCENT (Age 13-17)

Exposure:  Analgesics, cough/cold preps, cleaning products, envenomations

Deaths:  Hydrocarbons, antidepressants, analgesics, CV drugs

ADULT

Exposure:  analgesics, cleaning products, bites/envenomations, sedative-hypnotics, antipsychotics, antidepressants

Deaths:  Analgesics, antidepressants, stimulants/st drugs, CV drugs, sedative-hypnotics, antipsychotics, alcohols,

chemicals

EVALUATION OF POTENTIAL POISONING
HISTORY

  • Interview family, sibs, friends, EMS? What meds is pt taking? Family? What does pt have access to?
  • CAUTION: possible false hx due to hidden motives.
  • Goal of a History:

1) exact ID of toxin-container & poisondex

2) time of exposure

3) conc of liq or # pills

4) Vomit? Other symptoms?

5) Any treatment initiated?

EXAM

  • V/S often have vital clues!!
  • Examine Head-toe
  • Do serial Mental Status checks
  • Many toxins affect ANS!!
  • Goal of an exam are the findings:

Eye:  pupillary changes

Skin/mucosal:  changes? discoloration of skin/nails? Cyanosis? (met-hemoglobinemia => cherry red) caustic burns? Soot? unusual odors? Vesicles?

Lung:  bronchospasm (beta-blockers); ­ secretions, carbamates; pulmonary edema (salicylates, opioids, beta-blockers, Ca-channel blockers)

Abd:  Tender, hepatomegaly (APAP–delayed); Bowel sounds (cholinergic vs. anticholinergic, opioids); Bladder distension (anticholinergics).

RADIOGRAPHS (CHIPES = Radiopaque ingestions)

  • Calcium, chloral hydrate cocaine body packs
  • Heavy metals, halogenated hydrocarbons
  • Fe and Iodine
  • Psychotropics (phenothiazines), potassium, phosphates,
  • Enteric coated preps
  • Slow release prep
ANTICHOLINERGIC/CHOLINERGIC— TOXIDROMES
ANTICHOLINERGIC (…as a…)                                or                                 SLUDS

  • Red as a beet (vasodilation) Salivation,Lacrimation,Urination,Defecation,Sweat
  • Hot as a hare (hyperthermia)
  • Mad as a hatter (delirious)
  • Dry as a bone (no sweat)
  • Blind as a bat (mydriasis)
  • ANS => bowel & bladder lose tone; Brady in the heart

CHOLINERGIC (dumbels)

  • Diarrhea
  • Urination
  • Miosis
  • Bradycard/bronchorr
  • Emesis
  • Lacrimation
  • Salivation
SYMPATHETIC— TOXIDROME
  • “High & M-A-D on drugs” (cocaine, amphetamines, decongestants)
  • “High” = ­ HR (Tachycardia w/ reflex brady), ­ BP (HTN), ­ Tm (Hyperthermia)
  • Mydriasis
  • Agitation & seizures
  • Diaphoresis
TREATMENT OF POISONS
  • ABC-D: Airway, Breathing, Circulation, D: decontamination, D-stick (glucose), Dextrose (1mg/kg IV)
  • COMA protocol: ABC-D plus thiamine (alc), narcan (naloxone if opioid OD); r/o “IT’S COMA!” p.335 First Aid
  • DECONTAMINATION:

a.  IPECAC

USE:  home therapy, recent exposure, charcoal ineffective, prolonged transports, “chunky materials” like berries & large pills

NOT IF:  caustics, hydrocarbons, unprotected airway, bleeding d/o, seizures & altered MS, age < 6 months, pt already vomiting

b.  GASTRIC LAVAGE

USE:  recent (1-2hr ) & potentially life threatening ingestion; delayed gastric emptying; agent not bound by Charcoal (Fe, Li)

NOT IF:  low tox hydrocarbons, alkaline caustics

HOW:  secure airway, use large bore orogastric tube, pt on Left Lat Decub Head Dn position, use water or NS in 50-200 ml aliquots until clear ~2 liters

c.  ACTIVATED CHARCOAL

Most efficacious agent (OTC available)

INITIAL DOSE:  1 gm/kg

USE:  first-line for many toxicants; pt must have normal GI fxn; can be used after lavage

NOT IF:  highly ionized or polar toxins (caustics, Fe, Li, alcohols)

d.  CHARCOAL w/ SORBITOL

Sorbital (non-abs sugar) speeds GI transit & stooling

Can cause dehydration and lytes imbalance

NOT IF: age < 5

e. MULTI-DOSE ACTIVATED CHARCOAL (MDAC)

Works by enterohepatic circulation or gut “dialysis”

USE:  many toxins:  carbamazepine, theophylline, phenobarb, ASA, TCA

DOSE:  1g/kg q 6h or continuous NG infusion (must f/u bowel sounds & function closely)

f.  WHOLE BOWEL IRRIGATION (WBI)

Polyethylene glycol/electrolyte soln (PEG/ELS)

USE:  when charcoal is not effective; Fe, sustained release drugs like Li; body packers

NOT IF:  GI dysfxn

DOSE:  Child: 0.5 L qh oral for kids; Adult: 2.0 L qh x 6h till rectal effluent is clear

**A tip:  when using WBI, place first 250-500 ml then listen for pyloric opening

g.  SKIN & EYES

USE:  acids, alkalis, organophosphates, methylene chloride (CO), trichloroethylene, many other solvents and organometallics, that require immediate removal

HOW:  Copious irrigation of eyes w/ NS, copious soap/water for skin

ELIMINATION

a.  URINE ALKYLINIZATION (Acetazolamide = bicarbonate)

Theory:  drugs are filtered, secreted, then reabs by kidney, if drug gets polarized or ionized once secreted into lumen–drugs get trapped in the urine & can’t be reabs back into circ ; weakly acidic drugs are ionized in alkaline urine => favoring excretion.

USE:  ASA, phenobarb, MTX

HOW:  Nabicarb 1-2meq/kg q3-4h to keep urine pH > 7.5 (avoid hypokalemia cuz it interferes w/ ion xchg)

b.  HEMODIALYSIS

USE:  drug = low mw < 500 daltons, water sol, low Vd (L/kg), not highly bound to protein, low endogenous clearance <4ml/min/kg:  Li, ASA, MeOH, EtOH, ethylene glycol, chloral hydrate, corrects severe acid-base, lytes/fluid disturbances

c.  CHARCOAL HEMOPERFUSION

USE:  (similar drug criteria as hemodialysis except…)

1.  NOT for alc & metals

2.  Can handle drugs more protein bound

3.  Carbamazepine, phenobarb, theophylline, phenytoin

ACETAMINOPHEN (APAP) TOXICITY
General:  Most common ingestion; APAP metab by sulfation/glucuronidation in liver; 5% Therapeutic dose and in OD dose oxidized by CYP-450 (liver) => reactive intermediate NAPQI => usually conjugated by glutathione and excreted in urine

MOT:  APAP overdose, alcoholics, malnutrition, CYP-450 induced states => overworked glutathione detoxifying mechanisms can’t keep up => accumulation of reactive intermediate NAPQI => free electrophilic attack on sulfur containing aa’s in cell membranes proteins & enz => centrilobular necrosis of liver (similar damage in kidney).

ANTIDOTE:  N-Acetylcysteine (NAC) po or IV following Loading Dose (LD); use if 4h APAP > 140mcg/ml

SALICYLATE TOXICITY
General:  Common ingestion too & in many combination meds; approx. 150 mg/kg acute is toxic; ASA tabs- 65-500mg; Pepto- 8.7 mg/ml salicylate; Oil of Wintergreen-1.4 gm/ml methyl salicylate–VERY TOXIC!!

MOT:  Stimulates central resp cntrs => RESPIRATORY ALKALOSIS, then interferes w/ Kreb cycle, uncouples ox-phos => METABOLIC ACIDOSIS (tachypnea, tinnitus, coma, seizures, pulmo edema => RESPIRATORY ACIDOSIS (compensatory).

ANTIDOTE:  Gastric lavage, MDAC, Bicarb alkalinization of urine, hemodialysis for severe cases.

NOTE:  ASA makes BEZOARS (concretions) => delayed gastric lavage may be useful!

ALCOHOL TOXICITY
METHANOL + ANION GAP ACIDOSIS

Source:  solvent, windshield washer fluid, de-icers, canned heat

  • MOT: metab by alc-DH to formaldehyde and formic acid => formic acid can hurt retina “blind drunk”; anion gap acidosis and +OSMOL GAP

2Na + Glc/18 + BUN/2.8 + EtOH/4.6   (Normal = 270-290 mOsm/L)

GAP b/t measured OSMOL and calc OSMOL suggests presence of osmotically active particles but normal results don’t guarantee that ingestion has not occurred.

  • SX: seizures, gastritis, pancreatitis and RETINA damage
  • RX:

1.  EtOH- “keeps ADH busy”

-give initial Loading Dose and Maintenance Dose = 100 mg/dl

-sx pts or those w/ MeOH or ethylene glycol levels > 25-50 mg/dl need definitive tx.

2.  Folate- enhances formic acid metabolism

3.  Hemodialysis

4.  4-MP (4-methylpyrazole)- blocks AlcDH

ETHYLENE GLYCOL + ANION GAP ACIDOSIS

  • MOT: CNS depression => seizures, acidosis, and RENAL FAILURE
  • RX: EtOH, 4-MP, hemodialysis; pyridoxine and thiamine promote non-toxic metabolites

ISOPROPYL ALCOHOL + KETOSIS (better tolerated)

  • MOT: Strong CNS depressant => metab to ACETONE => GI distress (no acidosis) => causes ketosis w/ +OSMOL GAP
  • RX: Supportive
ANTIHYPERTENSIVE TOXICITY
BETA_BLOCKERS (Propranolol is very DANGEROUS!!)

  • MOT: bradycardia, hTN, coma, hypo/hyperglycemia
  • RX: ABC-D + WBI for sustained release; fluids, atropine, glucagon–large doses, epinephrine, pacemaker, amrinone,

ballon pump; some dialyzable

CA-CHANNEL BLOCKERS (Verapamil is most dangerous!)

  • MOT: bradycardia, hTN, coma, etc…~beta’s
  • RX: ABC-D + fluids & atropine, Calcium, glucagon, catecholamines, amrinone
IRON TOXICITY
General:  common and mistaken for candy; most tabs = 65 mg ele.Fe

Toxicity:  based on amt of ELEMENTAL IRON:  ferrous gluconate 12%; ferrous sulfate 20%; ferrous fumarate 33%

10-20 mg/kg => GI sx

20-50mg/kg => systemic sx

> 100 mg/kg => FATAL

MOT:  affects enzyme systems => hypovolemia, vasodilation, myocardial depressant => inhibits aerobic metabolism =>     ANION GAP ACIDOSIS

RX:

1.  Ipecac (home)

2.  Gastric lavage & WBI reasonable

Activated charcoal DOES NOT work!

3.  Deferoxamine chelator (6h Fe level 350-500 mcg/dL) causes urine to be rose colored

INH, PYRIDOXINE, & GABA
ISONIAZID (INH)

  • MOT: INH inhibits production of activated B6 (essential cofactor in GABA production) => ¯ GABA a major inhibitory NT => seizures/polyneuropathy => shock, hyperthermia, acidosis, hyperglycemia

RX w/ PYRIDOXINE DOSING

  • Mass quantities = Gram per gram of INH
  • Empiric: 5g or 70 mg/kg or 0.5 g/min (child)

 

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