1. “ALL SUBSTANCES ARE POISONS; THERE IS NONE WHICH IS NOT A POISON
“ALL SUBSTANCES ARE POISONS; THERE IS NONE WHICH IS NOT A POISON. THE RIGHT DOSE DIFFERENTIATES A POISON AND A REMEDY”
PARACELUS ( ) 1

2. “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. 1

3. Criteria for Toxic Effect
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

4. 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 11

5. Absorption, Distribution, Metabolism, and Excretion
Inhalation
Intravenous
Intraperitoneal
Ingestion
Subcutaneous
Gastrointestinal
Intramuscular
Lung
Tract
Dermal
Liver
Blood & Lymph
Extracellular Fluid
Fat
Bile
Organs
Kidney
Lung
Secretory
Structures
Bone
Alveoli
Bladder
Soft
Tissue
Feces
Secretion
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. 6

6. Diagrammatic View of the Dose – Response Relationship C x T = K
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.
Chronic dose - no metabolism or excretion
Chronic dose - accumulation of toxicant
Acute dose
Residual injury 2

7. OSHA Hazard Communication Standard Toxicity Ratings
Route
Highly Toxic
Toxic
Oral
LD50
< 50 mg/kg
> 50 to < 500 mg/kg
Dermal LD50
< 200 mg/kg
> 200 to < 1000 mg/kg
Inhalation
LC50
< 200 ppm
< 2 mg/l
200 to < 2000 ppm
> 2 to < 20 mg/l 12

8. Toxic Considerations Species Dose Duration Frequency Route
Physical and chemical characteristics
Individual sensitivity
Other exposures 11

9. Interaction With Chemicals
Additive (2 + 2 = 4)
Synergistic (2 + 3 = 20)
Potentiation (0 + 2 = 10)
Antagonism (4 + 6 = 8; 4 + (-4) = 0) 8

10. Spectrum of Toxic Effects
Allergic
Idiosyncratic Reactions
Immediate vs. Delayed
Local vs. Systematic
Target Organ Toxicity
Interaction With Chemicals
Reversible vs. Irreversible 7

11. Spectrum of Biologic Responses
Response Grading Description
None NOEL
Adaptive NOAEL
Minimal LOEL
Moderate LOAEL
Frank (LD, LC) FEL 11

12. 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

13. 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

14. Qualitative Evaluation of Chronic Target Organ Toxicity
Organs Affected
Type & Severity of Effect
Exposure (Dose) Levels
Physical Properties
Species Used
No. Species Affected/Tested
Metabolic Comparisons
Acceptance of Test
Availability of Full Data
Biologic Plausibility
Collaborative Data 13

15. OSHA Permissible Exposure Limits Basis For Classification
NOAEL (23)
Physical Irritation & Other Effects (21)
Odor Effects (3)
Analogy to Related Substances (73)
Biochemical/Metabolic Effects (26)
Sensitization (8)
Cancer (10)
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) 15

16. 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. 18

17. 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

18. 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.

19. 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. 16

20. 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. 16

21. 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.

22. 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 18

23. 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.

24. 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 20

25. Criteria For Causal Relationships In Epidemiology
Strength & Significance of Association
Consistency of Association
Specificity
Temporality
Dose-Response Relationship
Biologic Plausibility 20

26. Federal Regulations OSHA (PELs, Standards)
NIOSH (RTECs, Criteria Documents)
OSHA HazCom
ACGIH TLVs
EPA TSCA 20