FUNDAMENTALS OF OCCUPATIONAL TOXICOLOGY

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

14. 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

15. 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

16. 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?

17. 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

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

20. Dimethylformamide

21. 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