CCHM - TOXICOLOGY AND TDM

Toxicology

Study of the adverse effects of xenobiotics in humans.

Mechanistic toxicology

Cellular and biochemical effects of toxins. Provides a basis for rational therapy design and the development of tests to assess the degree of exposure of poisoned individuals.

Descriptive toxicology

Uses the results from animal experiments to predict what level of exposure will cause harm in humans (risk assessment)

Regulatory toxicology

Involves the interpretation of the combined data from mechanistic and descriptive studies. Used to establish standards that define the level of exposure that will not pose a risk to public health or safety.

Forensic toxicology

Medicolegal consequences of toxin exposure. Establishing and validating the analytic performance of the methods used to generate evidence in legal situations, including the cause of death.

Clinical toxicology

The study of interrelationships between toxin exposure and disease states. Emphasizes not only diagnostic testing but also therapeutic intervention.

Environmental toxicology

Includes the evaluation of environmental chemical pollutants and their impact on human health.

Xenobiotics

Exogenous agents that have adverse effect on a living organism

Poison

Exogenous agents having adverse effect on a living organism coming from animals, plants, minerals, gases.

Toxins

Endogenously synthesized agents with adverse effect on living organism

Toxicant

Substances that are not produced within a living cell or microorganism that have an adverse effect on other living organisms

50%

Percentage of exposure to toxins due to intentional suicide attempts

30%

Exposure to toxins percentage due to accidental exposure

20%

Exposure to toxins percentage due to homicide or occupational exposure

Acute toxicity

Single, short term exposure

Chronic toxicity

Repeated exposure for extended period of time

TD₅₀

The dose that would be predicted to produce a toxic response in 50% of the population

LD₅₀

The dose that would predict death in 50% of the population

ED₅₀

The dose that would be predicted to be effective or have therapeutic benefit in 50% of the population

Tan Top tube

Type of test tube specific for lead. Contains EDTA.

GC-MS

ICP-MS

AAS

Confirmatory method for toxic agents analysis

Alcohol

CNS depressant. Symptoms of intoxication begin when the concentration is >0.05% w/v.

GGT

Increases can be seen before the onset of pathologic consequences. Increases in serum activity can occur in many conditions unrelated to ethanol use.

AST

Increases in serum activity can occur in many conditions unrelated to ethanol use.

AST/ALT

A ratio of >2.0 is highly specific for ethanol-related liver disease.

HDL

High serum ____ is specific for ethanol consumption.

MCV

Increased erythrocyte ___ is commonly seen with excessive ethanol consumption. Increases are not related to folate or vitamin B12 deficiency

0.01-0.05% w/v BA

Subclinical. Influence/effects not apparent or obvious, behavior nearly normal, by ordinary observation, impairment detectable by special test.

0.03-0.12% BA

Euphoria. Mild euphoria, sociability, talkativeness, increased self confidence, decreased inhibitions, diminution of attention, judgement, control, some sensorimotor impairment, slowed information processing, loss of efficiency in finer performance tests, impairment of perception, memory

0.09-0.25% BA

Excitement. Emotional instability, loss of critical judgment, comprehension, decreased sensory response, increased reaction time, reduced visual acuity, peripheral vision, and glare recovery, sensorimotor, incoordination, impaired balance, drowsiness.

0.18-0.30% BA

Confusion. Disorientation, mental confusion, dizziness, exaggerated emotional states. disturbances of vision, and of perception color, form, motion, dimensions, increased pain threshold, increased muscular incoordination, staggering gait, slurred speech, apathy, lethargy.

0.27-0.40% BA

Stupor. General inertia, approaching loss of motor functions, markedly decreased response to stimuli, marked muscular incoordination, inability to stand or walk, vomiting, incontinence of urine and feces, impaired consciousness, sleep or stupor.

0.35-0.50% BA

Coma. Complete unconsciousness, coma, anesthesia, depressed or abolish reflexes, subnormal temperature, impairement of circulation, and respiration, possible death.

0.45+% BA

Death. Death from respiratory arrest.

Ethanol

Most common abused drug. Causes acidosis-accumulation of ketones and lactate. Causes diuresis. Hangover symptoms are due to the effect of acetaldehyde. 80 mg/dL has been established as the statutory limit for operation of a motor vehicle.

Methanol

Commonly used solvent and a contaminant of homemade liquors. It is converted first to formaldehyde, then finally to formic acid in the liver. Fatal dose: 60-250 ml. Preferred sample: whole blood. Methods: GC and headspace analysis

Isopropanol

Metabolized by hepatic ADH to acetone, which is its primary metabolic end product. Intoxication may result in severe acute-phase ethanol-like symptoms that may persist for an extended period. Fatal dose: 250ml

Ethylene glycol

Common component of hydraulic fluid and antifreeze. Sweet taste. Final product leads to deposition of caox (converted to oxalic acid and glycolic acid) in renal tubules. Fatal dose: 100 gram

Sodium fluoride

Nonsterile specimen for ethanol determination is preserved with?

GLC

Legal method for ethanol determination

Osmometry

Serum osmolality increases by about 10 mOsm/kg for each 60mg/Dl increase in serum ethanol

Enzymatic

Non human alcohol dehydrogenase, this enzyme oxidizes ethanol to acetaldehyde with reduction of NAD+ to NADH (340nm)

12 hours

Ethanol determination detection limit

300-400 ml of pure alcohol

Ethanol fatal dose

250-400mg/dl

Ethanol toxic blood level

Carbon monoxide

Produced from incomplete combustion of carbon containing substances like gasoline engines, organic materials in fire, cigarette smoking and improperly ventilated furnaces. Toxic effects are manifested by binding with heme proteins. Major organ affected: CNS and Heart. Net effect: tissue hypoxia. Toxic levels: 20%. Indicator of toxicity: cherry red color of the face. Sample for testing: EDTA whole blood. Method for testing: spot testing, differential spectro, gas chromatography (ref method), co-oximetry)

Carboxyhemoglobin

Inhibits cellular respiration and electron transport

Cyanide

Caustic agent. Component of some insecticides and rodenticides. Common suicide agent. Supertoxic product of burning plastic. Expresses toxicity by binding to heme iron. Inhibits cellular respiration, electron transport and ATP formation. Characteristic odor bitter almonds. Antidote: sodium thiosulfate. Toxic symptoms: tachypnea, convulsion, and coma. Toxic level: >2 ug/ml.

Lab analysis: Ionspecific electrode methods and photometric analysis

Urinary thiocyanate concentration

Arsenic

Component of ant poisons, rodenticides, paints and metal alloys. Common homicide and suicide agent (heavy metal poisoning) It inhibits sulfhydryl enzymes throughout the body. Expresses its toxicity by high affinity binding to thiol groups in protein. Odor of garlic with metal taste. Arsine, inorganic form, organic form. Known as “Romantic poison” Was used to treat syphilis (salvarsan 606). Fever, anorexia, and gastrointestinal distress are seen with chronic or acute ingestion. Rapidly cleared from the blood.

Arsenobetaine and arsenocholine

“Fish arsenic” that is cleared in the urine within 48 hours.

Meese lines

Hair and nails specimen used to evaluate long term exposure with arsenic

AAS/Blood and urine

Arsenic evaluation for short term exposure

120 mg

Acute fatal dosage for arsenic

Reinsch test

Other test for arsenic

Activated charcoal, chelating agents (British Anti-Lewisite, penicillamine and succimer)

Treatment for arsenic

Cadmium

Used in electroplating and galvanizing. Pigment found in paints and plastics and is the cathodal material of nickelcadmium batteries. Expresses its toxicity primarily by binding to proteins. Toxicity may also result to destruction of type 1 epithelial cells in the lungs and decreased resistance to bacterial infection. AAS. Tobacco-containing product is a common route of exposure. Encountered in mining. Cause of Itai itai disease

Kidney

Organ involved in cadmium toxicity

(+) GGT

Toxic renal indicator for cadmium

Lead

Common environmental contaminant. A potent enzyme inhibitor. Low level exposure may cause behavioral changes - hyperactivity and attention deficit disorder and affects IQ. Vitamin D and heme synthesis are affected. It blocks D-ALA synthetase. Wrist drop or foot drop manifestation. Acute exposure- abdominal or neurological symptoms. Neruologic symptoms - encephalopathy characterized by a cerebral edema and ischemia. Severe poisoning can result in stupor, convulsions, and coma.

<10 ug/dl

CDC cut off for normal level of lead in children

EDTA and Dimercaptosuccinic acid

Treatment for lead poisoning

Indicators of Lead toxicity

Urinary D-ALA

Free RBC porphyrin

Presence of basophilic stippling in RBC.

Tests for lead toxicity

Graphite furnace AAS

Inductively coupled plasma emission spectrophotometry

Anodic stripping voltmmetry

Zinc protoporphyrin or free RBC protoporphyrin

Mercury

Binds with protein and an enzyme inhibitor. Exists in three forms: Elemental, inorganic salt, component of organic compounds.

Inorganic mercury

Tachycardia, tremors, thyroiditis, and most significant, a disruption of renal function

Organic mercury

Neurologic symptoms. Low levels of exposure causes tremors, behavioral changes, mumbling speech, and loss of balance. Higher levels of exposure result in hyporeflexia, hypotension, bradycardia, renal dysfunction and death.

AAS

Mercury testing for whole blood (organic mercury).

Anodal stripping voltametry

Mercury testing for urine (inorganic mercury)

Reinsch test

Method of testing for mercury

>50ug/dL

Significant exposure to mercury level (whole blood).

Pesticides

Organophosphates and carbamates function by inhibition of acetylcholinesterase. Low levels of exposure are associated with salivation, lacrimation, and involuntary urination and defecation. Higher levels of exposure results in bradycardia, muscular twitching, cramps, apathy, slurred speech, and behavioral changes. Deaths due to respiratory failure may occur. Method: evaluation of erythrocytic acetylcholinesterase activity. Measurement of serum pseudocholinesterase.

Bioavailable fractions

Fraction of drug that reaches the circulation

First order elimination

Represents the linear relationship between the drug eliminated per hour and the blood level of the drug.

Pharmacodynamics

Concentration of drug vs response.

Pharmacokinetics

Activity of the drugs in the body.

Therapeutic index

Ratio between the minimum toxic dose and the maximum therapeutic serum concentration.

Therapeutic range

Difference between the highest and the lowest effective dosages.

Liberation

The release of drug

Absorption

The transport of drug from the site of administration to the blood

Distribution

Refers to the delivery of drugs to different tissues.

Metabolism

Refers to the chemical modification of drugs by the cells

Excretion

The process by which the drug and its metabolites are excreted from the body.

Hydrophobic drugs

Can easily traverse cellular membranes and partition into lipid compartments, such as adipose and nerve cells

Non ionized polar drugs

Also cross cell membranes but do not sequester into lipid compartments

Increases in serum alpha-1-acid glycoprotein

Increase in ___ during acute phase reactions will lead to increased bindings of drugs such as propanolol, quinidine, chlorpromazine, cocaine, and benzodiazepines.

Hepatic portal system

All substances absorbed from the intestine enter the ____

Biotransformation

The enzymatic processes involved in metabolizing drugs through metabolic process generating a therepeutically active metabolite

Mixed function oxidase

The biochemical pathway responsible for the greatest portion of drug metabolism

Phase I reaction

Produces reactive intermediates.

Phase II reaction

Conjugates functional groups (glutathione, glycine, phosphate, and sulfate) to these reactive sites, the products of which are water soluble.

First order elimination

Independent of the clearance mechanism, decreased in the serum concentration of drug most often occur as a ____

Hepatic metabolism or renal filtration

Eliminates most drugs

Pharmacokinetics

The mathematical modelling of drug concentration in circulation. Assists in establishing or modifying a dosage regiment. Serum concentration rises when the rate of absorption exceeds distribution and elimination. Concentration declines as the rate of elimination and distribution exceeds absorption. Most drugs are not administered as a single bolus but are delivered on a scheduled basis.

Pharmacogenomics

Science concerned with the ways to compensate for the genetic difference in patients which cause varied response.

Responders

Patients benefiting from the therapeutic and desired effects of the drug.

Nonresponders

Do not demonstrate a beneficial and desired therapeutic effect.

Quinidine, Procainamide, Lidocaine

Class I cardioactive drugs

Propranol

Class II cardioactive drugs

Amiodarone

Class III cardioactive drugs

Verapamil

Class IV cardioactive drug.