Finals 06. Toxicology

toxicology

study of adverse effects of xenobiotics in humans

xenobiotics

chemicals & drugs that are not normally found or produced in the body

mechanistic toxicology

elucidates the cellular, molecular, and biochemical (adverse) effects of xenobiotics

mechanistic toxicology

to create therapeutic design & develop lab tests for assessing degree of exposure

descriptive toxicology

uses the results from animal experiments to predict the level of exposure that will cause harm in human (risk assessment)

regulatory toxicology

establish standards that define the level of exposure that will not pose a risk to public health or safety

regulatory toxicology

uses interpretation of data from mechanistic and descriptive studies

• Food and Drug Administration

• U.S. Environmental Agency

• Occupational Safety and Health Administration

regulatory agencies

forensic toxicology

concerned w/ medicolegal consequences of exposure to chemicals or drugs

forensic toxicology

validates the methods used to generate evidence in legal situations

clinical toxicology

study of interrelationships between xenobiotics & disease states

clinical toxicology

emphasizes in diagnostic testing & therapeutic intervention of patients with acute poisoning or chronic exposures

environmental toxicology

evaluation of environmental chemical pollutants and their impact on human health

xenobiotics

exogenous agents that may have an adverse effect on a living organism

xenobiotics

drug such as antibiotics, anti-depressants

xenobiotics

environmental chemicals (fluorinated or brominated compound)

poisons

toxic or toxicant that gets into the body via swallowing, inhaling, or absorption

poisons

agents that have an adverse effect on a biological system

toxins

substance that are biologically synthesized

toxins

examples are living cells or microorganisms, hemotoxins of venomous snakes, botulinum toxin of C. botulinum, mycotoxins of fungus

toxicant

substance not produced within a living cell or microorganism

toxicants

examples is environmental chemicals

suicide attempts

50% of poisoning cases (highest mortality rate)

accidental exposure

30%, most frequent in children, drug overdose in adolescents and adults

homicidal or occupational

remaining poisoning cases

• ingestion

• inhalation

• transdermal

routes of exposure

poison

any substance that can cause a harmful effect on exposure

TD50

does that would predict toxic response in 50% of the population

LD50

dose than would predict death in 50% of the population

ED50

dose that would predict effective & therapeutic benefit in 50% of the population

therapeutic index

ratio of TD50 (or LD50) to ED50

individual dose-response relationship

change in health effects based in xenobiotic exposure levels

quantal dose-response relationships

changes in health effects of a population based on xenobiotics exposure levels

acute toxicity

single short-term exposure to a substance sufficient to cause immediate toxicity

chronic toxicity

repeated frequent exposure for extended periods (>3 months), related to an accumulation of toxicant

analysis of toxic agents

to support the investigation of a known exposure

analysis of toxic agents

to comply with occupational regulations or guidelines

analysis of toxic agents

to confirm clinical suspicions of poisoning

• urine

• blood

specimen of choice

random urine

used for screening & qualitative detection

royal blue

tube color for most elements

tan

tube color for lead

screening

good analytic sensitivity but lack specificity

screening

a negative result can rule out a drug/toxicant

presumptive

a positive result in screening in ??? until confirmed by a more specific method

• immunoassays

• thin-layer chromatography

• gas chromatography

examples of screening method for tetrahydrocannabinol

• gas chromatography-mass spectrometry

• inductively coupled plasma-mass spectrometry

• atomic absorption method

reference methods

ingestion

alcohol routes of exposure

ethanol

source of exposure: liquors

methanol

source of exposure: commercial products, homemade liquors

isopropanol

source of exposure: rubbing alcohol

ethylene gylcol

source of exposure: hydraulic flui, antifreeze

• acetaldehyde adducts

• acetic acid

ethanol metabolic intermediate end products

• formaldehyde

• formic acid

methanol metabolic intermediate end products

acetone

isopropanol metabolic intermediate end products

• oxalic acid (Ca Oxalate)

• glycolic acid

ethylene glycol metabolic intermediate end products

ethanol

might lead to alcoholic hepatitis, cirrhosis

methanol

might lead to metabolic acidosis, optic neuropathy

isopropanol

might lead to disorientation, unconsciousness

ethylene glycol

might lead to tubular damage, metabolic acidosis

GGT

increases can be seen before the onset of pathologic consequences

GGT, AST

increases in serum activity can occur in many non-ethanol-related conditions

AST/ALT ratio

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

HDL

high serum ??? specific for ethanol consumption

MCV

increase is commonly seen with excessive ethanol consumption

MCV

increases are not related to folate or vitamin B12 deficiency

• serum

• plasma

• WB

specimen

capped

specimen consideration

4 deg C, RT (not more than 14 days), Na fluoride

storage

enzymatic

method: ethanol + NAD+ - ADH ←> acetaldehyde + NADH

freezing point osmometry

measures osmolar gap

gas chromatography

reference method

0.01-0.05%

no obvious impairment, some changes observable on performing testing

0.03-0.12%

mild euphoria, decreased inhibitions, some impairment of motor skills

0.09-0.25%

decreased inhibitions, loss of critical judgement, memory impairment, diminished reaction time

0.18-0.30%

mental confusion, dizziness, strongly impaired motor skills (staggering, slurred speech)

0.27-0.40%

unable to stand or walk, vomiting, impaired consciousness

0.35-0.50%

coma and possible death

≥0.10

presumptive evidence of driving under alcohol influence

inhlation

ROE of carbon monoxide

carbon monoxide

SOE: gasoline engines, woof and plastic fires

carbon monoxide

manifested by hypoxia (brain and heart)

cyanine

suicide agent

cyanide

SOE: industrial processes, insects-rodenticides, burning plastics

• inhalation

• ingestion

• trasndermal

ROE: cyanide

cyanide

manifested by respiratory depression (binds heme iron seizure, coma)

• ISE

• photometric

• 2-well microdiffusion

laboratory diagnosis for acute poisoning

urinary thiocyanate

laboratory diagnosis for chronic poisoning

arsenic

“homicide & cyanide agent”

arsenic

natural manmade; occupational (agriculture, smelting)

• inhalation

• ingestion (water)

arsenic ROE

arsenic

non specific (CNS, renal, vascular)

blood & urine

specimen for arsenic in short term exposure

hair & fingernail

arsenic specimen long term exposure

cadmium

mining industrial (electroplating galvanizing)

• inhalation

• ingestion (food)

cadmium ROE

cadmium

itai-itai disease (contaminated rice)

• WB

• urine

specimen for cadmium

lead

household paints, gasoline, pipes

• inhalation

• ingestion (food)

lead ROE