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FUNDAMENTALS OF OCCUPATIONAL TOXICOLOGY

FUNDAMENTALS OF OCCUPATIONAL TOXICOLOGY. Vesa Riihimäki, MD, PhD, MSc Finnish Institute of Occupational Health. What do we know of chemical hazards?. We know more than ever, but: Some 3000 chemicals are classified as dangerous New substances and processes are adopted constantly

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FUNDAMENTALS OF OCCUPATIONAL TOXICOLOGY

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  1. FUNDAMENTALS OF OCCUPATIONAL TOXICOLOGY Vesa Riihimäki, MD, PhD, MSc Finnish Institute of Occupational Health

  2. What do we know of chemical hazards? • We know more than ever, but: • Some 3000 chemicals are classified as dangerous • New substances and processes are adopted constantly • Many modern industrial processes depend on reactive chemicals • The worker is regularly exposed to several compounds

  3. Numbers... • In the EU, 16% of the workforce has major contact to dangerous chemicals • Some 5000 chemicals are widely used • European Chemicals Inventory (EINECS) encompassed about 100 000 substances (1971-1981), since then hundreds of new chemicals have been introduced per year • Complete toxicity data are available for <1000 chemicals, some data for 20 000 chemicals

  4. Basic concepts in toxicology Intrinsic toxicity Exposure HAZARD, RISK Individual factors Risk management

  5. General principles in chemical safety assessment • Chemical identity: CAS number • Compound specific, "selective" toxicity

  6. Physical chemical properties

  7. Physical chemical properties, cont'd

  8. Main toxicological data for a chemical Types of toxicity Toxicokinetics Mode of action/mechanism of action Dose-effect and dose-response relationships

  9. Types of toxicity: - Acute toxicity - Irritancy and corrosivity - Sensitisation - Repeated dose toxicity - Mutagenicity - Carcinogenicity - Reproductive toxicity For most chemicals toxicity data are based on animal testing results only.

  10. Toxicokinetics Toxicokinetic phases are: absorption, tissue distribution, metabolism, excretion ABSORPTION: Substance specific properties: physical form, particle size, water solubility, lipid solubility influence absorption

  11. Uptake from the respiratory system - particle size < 5 μm 5-10 μm > 10 μm - water solubility

  12. Uptake through the skin Determinants of skin absorption: - Compound properties: e.g. water and lipid solubility, molecular mass, ionic charge - Vehicle - Occlusion, e.g. "protective" glove - Anatomic area and individual physiological factors

  13. Biotransformation, disposition Chemical may exert toxicity: B) After metabolism to reactive metabolites, for instance: A) As such, for instance Cyanide CN- Toxic Effects Butadiene Cyp450 Detoxification to thiocyanate Reactive epoxide metabolites URINARY EXCRETION Glutathione conjugation

  14. Elimination and accumulation Elimination half-time T½ Long elimination half-time leads to accumulation for instance, lead (T½ 10 years in cortical bone). Steady State: uptake and excretion are in balance - time to steady state about 5 x T½

  15. Mode of action/mechanism of action Local effect / Systemic effect Reversible effect / Irreversible effect Cumulative toxicity Dose threshold (deterministic effect) vs. no threshold (stochastic effect) Mechanism of effect - is it known?

  16. Dose-effect and dose-response relationship: lead decreased erythrocyte delta-ALAD activity increased zinc protoporphyrin anemia CNS effects decreased peripheralnerve conductivity Nervous paralysis, lead colics Adapted from Elinder C-G et al., Biologisk monitoring av metaller hos människa. Arbetsmiljöfonden, Uppsala, 1991

  17. Importants determinants of exposure • Subtance concentration / dose of substance • Duration of exposure • Dose rate • Exposure route

  18. Dimethylformamide

  19. Individual susceptibility • Factors underlying susceptibility • Illnesses and constitutional characteristics, e.g. allergic predisposition • Individual traits of metabolism that increase the amounts of active metabolite in the body • Interactions between occupational chemicals or together with drugs or alcohol

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