“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 (1493-1541) 1

“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

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

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

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

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

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

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

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

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

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

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 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

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

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

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. 16

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

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 18

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 20

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

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