Transcript Overview of toxicology

“ALL SUBSTANCES ARE
POISONS; THERE IS NONE
WHICH IS NOT A POISON. THE
RIGHT DOSE DIFFERENTIATES
A POISON AND A REMEDY”
PARACELUS (1493-1541)
“Toxic Effect” : any reversible
or irreversible harmful effect
on the body as a result of
contact with a substance via
the respiratory tract, skin, eye,
mouth or other route.
Criteria for Toxic Effect
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Measurable physiological effect in an organ
Reproducible from animal to animal
Normal protective mechanism(s) impaired
Effect is reversible when stimulus removed
Effect reduces efficiency/functionality of organ
Reproducible by others
Toxicity vs. Hazard
Toxicity: ability to produce an
effect at a specific concentration
at a body site
Hazard: probability that the specific
concentration will occur at that
body site
Absorption, Distribution, Metabolism, and Excretion
Inhalation
Intravenous
Intraperitoneal
Ingestion
Subcutaneous
Gastrointestinal
Intramuscular
Lung
Tract
Dermal
Liver
Blood & Lymph
Extracellular Fluid
Bile
Organs
Kidney
Lung
Secretory
Structures
Bladder
Alveoli
Feces
Bone
Secretion
Soft
Tissue
Urine
Expired Air
Ref: Klaasen, CD, Doull, J. Absorption, distribution, and excretion of toxicants. In: Toxicology, the basic science of
poisons, 2nd ed (Doull, J., Klassen, CD, Amdur,MO, eds.) New York: Macmillan Pub. Co., 1980; 29.
Fat
Diagrammatic View of the
Dose – Response Relationship
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The acute dose can be
related to a chronic dose
with minimal metabolism or
excretion and with a chronic
dose and partial
accumulation.
All of these are related to the
circumstance of a “residual
injury” with the elimination
of the toxicant.
Ref: Klaasen, CD, Doull, J. Evaluation of safety:
toxicologic evaluation. In: Toxicology, the
basic science of poisons, 2nd ed (Doull, J.,
Klassen, CD, Amdur, MO, eds.) New York:
Macmillan Pub. Co., 1980; 15.
Acute dose
CxT=K
Chronic dose accumulation
of toxicant
Residual injury
OSHA Hazard Communication
Standard Toxicity Ratings
Route
Highly Toxic
Toxic
Oral
LD50
Dermal
LD50
< 50 mg/kg
> 50 to < 500 mg/kg
< 200 mg/kg
> 200 to < 1000 mg/kg
Inhalation
LC50
< 200 ppm
< 2 mg/l
200 to < 2000 ppm
> 2 to < 20 mg/l
Toxic Considerations
Species
Dose
Duration
Frequency
Route
Physical and chemical characteristics
Individual sensitivity
Other exposures
Interaction With Chemicals
• Additive (2 + 2 = 4)
• Synergistic (2 + 3 = 20)
• Potentiation (0 + 2 = 10)
• Antagonism (4 + 6 = 8; 4 + (-4) = 0)
Spectrum of Toxic Effects
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Allergic
Idiosyncratic Reactions
Immediate vs. Delayed
Local vs. Systematic
Target Organ Toxicity
Interaction With Chemicals
Reversible vs. Irreversible
Spectrum of Biologic Responses
Response Grading
Description
None
Adaptive
Minimal
Moderate
Frank (LD, LC)
NOEL
NOAEL
LOEL
LOAEL
FEL
Common Toxicity Defaults
• Test animals are appropriate models for
humans
• High dose exposures in animals accurately
predicts adverse effects at lower doses
• The most sensitive sex, strain, species, and site
of action are proper bases for risk assessment
• The most sensitive response is used as the basis
for risk assessments
Common Toxicity Defaults
• Doses from animals toxicity tests can be scaled to
equivalent human doses based on body weight
• Risks for long-term exposures can be determined
from short-term studies by assuming that toxic
effects are a constant product of dose and
duration
• Factors of up to 10 account for individual sources
of uncertainty
• At low doses. Dose-response curves are linear for
carcinogenicity
Qualitative Evaluation of
Chronic Target Organ Toxicity
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Organs Affected
Type & Severity of Effect
Exposure (Dose) Levels
Physical Properties
Species Used
No. Species
Affected/Tested
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Metabolic Comparisons
Acceptance of Test
Availability of Full Data
Biologic Plausibility
Collaborative Data
OSHA Permissible Exposure Limits
Basis For Classification
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Neuropathic Effects (20)
Narcotic Effects (19)
Sensory Irritants (79)
Liver & Kidney Toxins (17)
Ocular Effects (5)
Respiratory Effects (35)
Cardiovascular Effects (7)
Systemic Toxicity (34)
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NOAEL (23)
Physical Irritation & Other Effects (21)
Odor Effects (3)
Analogy to Related Substances (73)
Biochemical/Metabolic Effects (26)
Sensitization (8)
Cancer (10)
OSHA Permissible Exposure Limits
Category Examples
PHYSICAL IRRITATION & OTHER EFFECTS
malathion: OP insecticide
PNOC
zinc oxide: physical irritation, possible pulmonary (metal
fume fever)
RESPIRATORY
iron oxide (dust & fume): siderosis (benign
pneumoconiousis), accumulation.
sulphur dioxide: bronchoconstriction, decreased pulmonary
function.
OSHA Permissible Exposure Limits
Category Examples
NARCOTIC
toluene
gasoline
methyl chloride
NEUROPATHIC
n-butyl alcohol: auditory nerve damage, vestibular nerve
damage.
n-hexane: peripheral neuropathy.
mercury (elemental) vapor: CNS (tremors), neuropsychiatric
disturbances, insomnia, hyperactivity
OSHA Permissible Exposure Limits
Category Examples
SENSITIZATION
cobalt metal fume & dust: pulmonary sensitization.
toluene diisocyanate (TDI): pulmonary sensitization.
SENSORY IRRITANTS
methyl ethyl ketone: eye, nose, throat.
ethylene glycol: throat and respiratory tract.
VM & P naphtha: upper respiratory and eye.
OSHA Permissible Exposure Limits
Category Examples
ANALOGY TO RELATED SUBSTANCES
diazinon (parathion): cholinesterase inhibition.
isobutyl alcohol (n-butanol): irritant narcosis.
nonane (octane): narcosis.
BIOCHEMICAL / METABOLIC EFECTS
carbon dioxide: hyperventilation (effects metabolic & electrolyte
balance).
carbon monoxide: carboxyhemoglobin (cardiovascular disease).
ACGIH TLV of 25 ppm based on neurobehavioral effects
(psychomotor functions) .
chloropyrifos (Dursban): cholinesterase inhibition.
OSHA Permissible Exposure Limits
Category Examples
CANCER
perchloroethylene: kidney and bladder (humans); liver (by gavage),
leukemia (inhalation), kidney (inhalation) in rodents.
chromic acid (CR 6): lung.
asphalt fumes: based on rodent studies.
CARDIOVASCULAR
carbon disulfide: cardiovascular disease.
fluroethanes: cardiac sensitization.
OSHA Permissible Exposure Limits
Category Examples
LIVER & KIDNEY TOXICITY
dioxane: neoplasms, liver pathology.
ethylene dichloride: neoplasms, liver.
hexone (methyl isobutyl ketone): kidney/body weight ratios,
tubule nephrosis, hyaline droplet degeneration.
NOAEL
oil mist: lung irritation, pneumonitis, skin cancer.
petroleum distillates: neuropathic effects, eyes and throat
irritation.
diethanolamine: visual effects, irritation.
OSHA Permissible Exposure Limits
Category Examples
OCULAR
naphthalene: optical neuritis, corneal damage, lens
opacity.
hydrogen sulfide: eye irritation, conjunctivitis.
methanol: blurred vision.
ODOR
isopropyl ether
OSHA Permissible Exposure Limits
Category Examples
SYSTEMIC TOXICITY
2-butoxyethanol: severe hemoglobinuria, hemolytic anemia,
RBC fragility, lung, kidney and liver changes.
welding fumes: pulmonary irritation, metal fume fever.
glycidal: pneumonitis, emphysema, skin, eye.
Epidemiology
• Descriptive: identifies a difference in
prevalence in a population
• Retrospective: reveals a relationship
between exposure after the effect
• Prospective: reveals a relationship
between exposure during the effect
Criteria For Causal Relationships
In Epidemiology
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Strength & Significance of Association
Consistency of Association
Specificity
Temporality
Dose-Response Relationship
Biologic Plausibility
Federal Regulations
• OSHA (PELs, Standards)
• NIOSH (RTECs, Criteria Documents)
• OSHA HazCom
• ACGIH TLVs
• EPA TSCA