Toxicology UWK 2012

Toxicology

PWM OLLY INDRAJANI2012

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What is toxicology?

• The study of the negative effects of chemicals

on living things

• A chemical is considered toxic depending on – How much of it is necessary to cause harm

– How easily it can enter the body

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Chemicals in the body

• Distribution - spread throughout the body• Metabolism - broken into smaller chemical

compounds• Storage - kept in the body for a long time• Excretion - passed out through urine, feces,

exhaled air, or sweat

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Toxic effects

• Toxic chemicals disrupt the normal functions of the body. Effects can be– Local - at the site of exposure– Systemic - affecting the entire body• target organs - organs or systems where

symptoms of exposure appear

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Dose and response

• The reaction is dependent on the amount of the chemical received, but...– Some doses are so small they produce no

response–Once the maximum reaction has occurred,

increasing the dose doesn’t change the reaction

Dose-response curve - alcohol

No effect

Relaxed

Slurred speech

Sleep

Coma

Labored breathing

Death

Important Relationship

For water at STP (standard temperature [23oC] and pressure [15 psi])

1 cc = 1ml = 1g

Which means that

1 liter of water = 1 kg

1 mg / kg = 1 ppm

1mm3 / liter = 1 ppm

1 mg / liter = 1 ppm

Measures of Toxicity

• Toxicity of chemicals is determined in the laboratory• The normal procedure is to expose test animals– By ingestion, application to the skin, by inhalation, or some

other method which introduces the material into the body, or

– By placing the test material in the water or air of the test animals’ environment

Measures of Toxicity

• Toxicity is measured as clinical “endpoints” which include– Mortality (death)– Teratogenicity (ability to cause birth defects)– Carcinogenicity (ability to cause cancer), and,– Mutagenicity (ability to cause heritible change in the DNA)

• At this time we will discuss 2 measures of mortality – the LD50 and the LC50

Measures of Toxicity:The Median Lethal Dose

LD50

The amount (dose) of a chemical which produces death in 50% of a population of test animals to which it is

administered by any of a variety of methods

mg/kgNormally expressed as milligrams of substance per

kilogram of animal body weight

Measures of Toxicity:The Median Lethal Concentration

LC50

The concentration of a chemical in an environment (generally air or water) which produces death in 50%

of an exposed population of test animals in a specified time frame

mg/LNormally expressed as milligrams of substance per liter

of air or water (or as ppm)

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Routes of exposure

• In order for a chemical to cause injury, it must enter the body– Inhalation– Ingestion–Absorption through the skin– Injection

Primary Routes of Exposure: Oral Exposure

Any exposure to pesticide/ poison which occurs when the chemical is taken in through the mouth and passes through the gastrointestinal tract

During oral exposure, although carried within the body, the pesticide is still outside of the body cavity

Primary Routes of Exposure: Dermal Exposure

Exposure of the skin to a pesticide

Most common route of human exposure

With proper hygiene this type of exposure is generally not serious unless there is a specific, rapid toxicological effect (often eye effects) which is of concern

Pesticide Application

Primary Routes of Exposure:Inhalation Exposure

Occurs when a pesticide is breathed into the lungs through the nose or mouth

Significant route of exposure for aquatic organisms

Not of toxicological concern until it crosses from the lung into the body (unless the chemical is corrosive)

Duration of Exposure

Three terms are commonly used to describe the duration of dose(s)

AcuteChronic

Subchronic

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Acute and chronic effects

• Acute - lasting hours

• Chronic - lasting a long time - possibly years

Duration of Exposure:Acute Exposure

Application of a single or short-term (generally less than a day) dosing by a chemical

If toxic symptoms are expressed, they are referred to as symptoms of “acute toxicity”

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Acute and chronic exposures

• Acute - sudden, brief– A bee sting

• Chronic - repeated small doses over time– Smoking cigarettes for years

Duration of Exposure:Chronic Exposure

Expression of toxic symptoms only after repeated exposure to a chemical in doses regularly applied to the organism for a time greater than half of its life-expectancy

If toxic symptoms are expressed, they are referred to as symptoms of “chronic toxicity”

Duration of Exposure:Subchronic Exposure

Toxic symptoms are expressed after repeated applications for a timeframe less than half the life expectancy of the organism – but more often than a single dose or multiple doses applied for only a short time

If toxic symptoms are expressed, they are referred to as symptoms of “subchronic toxicity”

• Largest number of deaths were:– analgesics– Antidepressants– sedative/hypnotics/antipsychotics– Stimulants– “street” drugs– cardiovascular drugs– alcohols

• Of all deaths: – 5% increase compared to 1999– 88% occurred in 20- to 99-year old individual– The mortality rate was higher in intentional rather

than unintentional exposures (79% vs 10.5%, respectively).

DIAGNOSIS

• History and physical examination• Vital signs• Ocular findings• Mental status, behaviour and muscle tone• Poison control center consultation

• Laboratory evaluation:– Anion gap– Osmolal gap– Oxygen saturation gap– Toxicology screening

History and Physical Examination

• Although the history is important, it may be unreliable or incomplete

• Consider that family members, friends, and pharmacists may have additional information

• In the absence of a classic presentation or toxidrome, separating patients with suspected poisoning into broad categories based on:– vital signs– ocular findings– mental status– muscle tone

can help determine drug or toxin class

Vital Signs

• Anticholinergic and sympathomimetic substances increase heart rate, BP, and temperature

• In contrast organophosphates, opiates, barbiturates, β-blockers, benzodiazepines, alcohol, and clonidine cause hypothermia, bradycardia, and respiratory depression.

Ocular Findings

• Anticholinergics and sympathomimetics cause mydriasis• In contrast to anticholinergics overdose, the pupils remain

somewhat light responsive in cocaine intoxication• Horizontal nystagmus is common in alcohol intoxication• Other drugs causing nystagmus are lithium, carbamazepine,

solvents, meprobamate, quinine, and primidone• Phencyclidine and phenytoin cause horizontal, vertical, and

rotary nystagmus

Mental Status, Behavior, and Muscle Tone

Laboratory Evaluation

• Anion gap• Osmolal gap• Oxygen saturation gap• Toxicology screening

Anion gap

• The normal range of anion gap may vary from 3 to 12 mEq/L in some laboratories

• An increase in anion gap ( 20 mEq/L) suggests: – lactic acidemia– Uremia– Ketoacidemia– selected intoxications

• A normal anion gap does not preclude intoxication because most toxins do not elevate the anion gap or there may be a coexisting condition that lowers the gap (Table 10)

• Common among these conditions is hypoalbuminemia for every 1 g/L decrease in the plasma albumin, the anion gap falls by 2.5 mEq/L

• Also, in methanol or polyethylene glycol poisoning, concurrent ethanol use delays the development of an elevated anion gap metabolic acidosis In this case, an elevated osmolal gap may be the only early clue to the diagnosis

Osmolal Gap

• Low-molecular-weight drugs and toxins increase the discrepancy between measured and calculated plasma osmolality (Table 12)

• Normal plasma osmolality is 285 to 295 mOsm

• The calculated value is determined as follows:1.86[Na] + BUN/2.8 + glucose/18 + ethanol/4.6

Oxygen Saturation Gap

• An oxygen saturation gap is present when there is more than a 5% difference between the saturation calculated from an arterial blood gas and the saturation measured by co-oximetry

• Co-oximetry determines oxygen saturation by detecting the absorption of four different wavelengths, enabling it to directly measure levels of four types of hemoglobin species:– Oxyhemoglobin– Reduced hemoglobin– Carboxyhemoglobin– Methemoglobin

• However, arterial blood gas analysis calculates oxygen saturation from the measured oxygen tension using an assumed standard oxygen-hemoglobin dissociation curve

• Toxins that are associated with an elevated oxygen saturation gap include carbon monoxide, methemoglobinemia, cyanide, and hydrogen sulfide (sulfhemoglobin is not routinely measured by co-oximetry)

• Pulse oximetry estimates oxygen saturation by emitting a red light (wavelength of 660 nm) absorbed mainly by reduced hemoglobin and a near-infrared light (wavelength of 940 nm) absorbed by oxyhemoglobin

Resuscitation• first priority in treating poisoned patients– assessment and stabilization of cardiopulmonary

function (e.g., the ABCs)• use of antidotes – very rare take precedence over stabilization of

ABCs

• empiric administration of antidotes ("coma cocktail")– supplemental oxygen– naloxone– glucose– thiamineshould be considered after medical history, vital

signs, and immediately available laboratory data these treatments are simple, inexpensive, and

generally without undue risk of an adverse reaction when used appropriately

• naloxone– is a competitive opioid antagonist – no any intrinsic toxicity – can be administered IV/IM – use in a hypoventilating opioid-intoxicated patient who is

not intubated– opioid intoxication often presents with classic triad

• CNS depression• miosis

– unreliable as the sole indication for naloxone administration because» many other toxins can produce small pupils along with mental

status depression» some opioids classically leave pupil size unaltered (e.g.,

meperidine, propoxyphene)

• respiratory depression– only a respiratory rate of <12 breaths/min is useful as a predictor of

response to naloxone

– duration of action 20-60 min• if become re-sedated may require additional

naloxone doses either in – intermittent boluses – continuous infusion

» administration of 2/3 dose of naloxone that fully aroused the patient in the initial bolus, infused over an hour, with dose adjustments made as directed by the patient's ventilatory status

– risks of naloxone treatment • precipitation of acute opioid withdrawal syndrome

– vomiting from withdrawal can result in aspiration thus administration of large doses of naloxone should be discouraged

PRINCIPLES OF GASTROINTESTINAL DECONTAMINATION

• Gastrointestinal (GI) decontamination refers to therapies that may decrease the amount of poison absorbed from the GI tract lumen.

• The following methods of GI decontamination are available:

A. Induced emesisB. Gastric lavageC. Activated charcoalD.Whole-bowel irrigation

A. Induced Emesis

• Induced emesis utilizes syrup of ipecac to induce vomiting, theoretically emptying the stomach and reducing absorption of an ingested agent.

• Syrup of ipecac induces vomiting by activation of both local and central emetic sensory receptors.

• Induced emesis has largely been abandoned in clinical practice. The most recent policy statements released by both the American Academy of Pediatrics(2003) and the American Association of Poison Control Centers (2005)discourage the use of syrup of ipecac in the out-of-hospital setting.

B. Gastric LavageINDICATIONS

• Ingestion of a substance with high toxic potential and: ■ Within 1 hour of ingestion ■ Ingested substance is not bound by activated charcoal or has no effective antidote. ■ Potential benefits outweigh risks.

CONTRAINDICATIONS ■ Substance not meeting above indications

■ Spontaneous emesis ■ Diminished level of consciousness/unprotected airway reflexes (intubate first)

■ Ingestion of hydrocarbons or caustic agents

■ Foreign body ingestion ■ Patient is at high risk for esophageal or gastric injury (GI hemorrhage, recent surgery, etc.).

TECHNIQUE ■ Recommended tube size is 36–40 French for adults, 22–28 French for children. ■ Secure airway via intubation, if necessary. ■ Position patient in left-lateral decubitus position, with head lowered below level of feet. ■ Confirm tube placement following insertion. ■ Aspirate any available stomach contents. ■ Lavage with 250 mL (10–15 mL/kg in children) aliquots of warm water or saline. ■ Continue until fluid is clear and a minimum of 2L has been used. ■ Instill activated charcoal through same tube, if indicated.

COMPLICATIONS ■ The primary risks are vomiting, aspiration, and esophageal injury or perforation.

C. Activated CharcoalINDICATIONS

• Activated charcoal (AC) is ingested by the patient in order to adsorb poisons within the GI tract lumen.

■ Patient presents within 1 to 2 hours after ingestion. ■ Patient has ingested a potentially dangerous amount of a poison adsorbed by charcoal

CONTRAINDICATIONS

■ Ingested substance is poorly adsorbed by AC (eg, iron, lithium, heavy metals,toxic alcohols).

■ Diminished level of consciousness/unprotected airway reflexes (AC can be given by naso- or orogastric tube following intubation)

■ Patient presents over 2 hours after ingestion.

■ Ingestion of caustic agents ■ Cases where endoscopy will be required

DOSE

■ The recommended dose of AC is a 10:1 ratio relative to the ingested poison(ie, ingestion of 1 g of poison requires 10 g of AC). Hence, the commonED practice of administering 50 to 100 g (1 g/kg) of AC to an overdose patient may be inadequate for larger ingestions.

RISKS

■ The primary risk of single-dose AC is vomiting. ■ Constipation and diarrhea ■ Bowel obstruction does not occur from single-dose AC. ■ Repeated doses of cathartics given with charcoal may cause dehydration or electrolyte abnormalities.

D. Whole -Bowel IrrigationWhole-bowel irrigation (WBI) flushes the GI tract to decrease the transit timeof luminal contents, thereby limiting absorption.

INDICATIONS

■ Removal of ingested drug packets (eg, body stuffers) ■ Large ingestion of a sustained-release drug ■ Potentially toxic ingestion that cannot be treated with activated charcoal (eg, lithium, lead, iron)

CONTRAINDICATIONS

■ Diminished level of consciousness/unprotected airway reflexes (intubate first) ■ Decreased GI motility or bowel obstruction ■ Significant GI hemorrhage ■ Persistent emesis

DOSE

Polyethylene glycol (PEG) solution is administered at a rate of 1–2 L/hour.

This rate of administration usually requires a naso- or orogastric tube.

Endpoints for therapy are the appearance of clear rectal effluent or a total irrigation volume of 10 L.

COMPLICATIONS

The primary risk associated with WBI is vomiting.

Patient discomfort: Bloating, cramping, and flatulence

WBI with balanced PEG solutions does not generally cause electrolyte abnormalities.

PRINCIPLES OF ENHANCED ELIMINATION

The goal of enhanced elimination is to increase the clearance of a poison from the body after it has been systemically absorbed.

The following methods of enhanced elimination are available:A. Multiple-dose activated charcoalB. Urinary alkalinizationC. Hemodialysis

Enhanced Elimination: Drug Characteristics and Examples

A. Multiple-Dose Activated Charcoal

Uses repeated doses of activated charcoal (every 2–4 hours) to increase poison clearance.

MDAC exerts its effects through disruption of enterohepatic circulation or direct adsorption across the GI mucosal surface.

RISKSThe risks associated with MDAC are similar to those with

AC; however,there is a greater risk of bowel obstruction with MDAC.

INDICATIONS

Drugs that have enterohepatic circulation and can possibly be treated with MDAC include:

■ Phenobarbital ■ Carbamazepine (Tegretol) ■ Theophylline ■ Aspirin ■ Dapsone

CONTRAINDICATIONS

MDAC is contraindicated in the same settings as AC.

B. Urinary Alkalinization

Urinary alkalinization attempts to increase renal elimination of a drug by increasing urine pH.

Urinary acidification to increase the clearance of weak bases is not recommended due to the risk of renal injury.

RISKSCan precipitate hypokalemia and decrease ionized

calcium levels

INDICATIONS CONTRAINDICATIONS

■ Poisoning with agents that are not weak organic acids and are not primarily cleared by the kidneys ■ Patients who cannot tolerate excess sodium/water loading (eg, CHF, renal failure)

Urinary alkalinization only affects the clearance of drugs that are weak organic acids.

■ Aspirin (most common use for alkalinization) ■ Phenobarbital ■ Formic acid

C. Hemodialysis

Hemodialysis (HD) directly removes toxins from a patient’s plasma, using the same technology applied to renal failure.

RISKS ■ HD requires central venous access, with all the usual accompanying risks

(bleeding, pneumothorax, etc.). ■ HD must be used cautiously in patients that are hemodynamically unstable.

INDICATIONS CONTRAINDICATIONS

■ Toxins that do not satisfy the conditions listed above.

For HD to be useful in a poisoned patient, the ingested poison should have the following characteristics:

■ Low molecular weight ■ Low plasma protein-binding ■ Small volume of distribution ■ Poor endogenous clearance ■ HD can also treat severe acidosis caused by a toxin, even if the toxin it self is not readily dialyzable.

Thank you