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FUNDAMENTALS OF OCCUPATIONAL TOXICOLOGY Vesa Riihimäki, MD, PhD, MSc Finnish Institute of Occupational Health
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TYÖTERVEYSLAITOS 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
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TYÖTERVEYSLAITOSNumbers... 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
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TYÖTERVEYSLAITOS
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Chemical identity: CAS number Compound specific, "selective" toxicity General principles in chemical safety assessment
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TYÖTERVEYSLAITOS Physical chemical properties
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TYÖTERVEYSLAITOS Physical chemical properties, cont'd
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TYÖTERVEYSLAITOS Main toxicological data for a chemical Types of toxicity Toxicokinetics Mode of action/mechanism of action Dose-effect and dose-response relationships
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TYÖTERVEYSLAITOS 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.
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TYÖTERVEYSLAITOS Toxicokinetics Toxicokinetic phases are: absorption, tissue distribution, metabolism, excretion ABSORPTION: Substance specific properties: physical form, particle size, water solubility, lipid solubility influence absorption
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TYÖTERVEYSLAITOS Uptake from the respiratory system - particle size < 5 μm 5-10 μm > 10 μm - water solubility
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TYÖTERVEYSLAITOS 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
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TYÖTERVEYSLAITOS
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Biotransformation, disposition Detoxification to thiocyanate URINARY EXCRETION Butadiene Reactive epoxide metabolites Cyp450 Glutathione conjugation Toxic Effects Cyanide CN - Chemical may exert toxicity: A) As such, for instance B) After metabolism to reactive metabolites, for instance:
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TYÖTERVEYSLAITOS 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
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TYÖTERVEYSLAITOS 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?
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TYÖTERVEYSLAITOS Dose-effect and dose-response relationship: lead decreased erythrocyte delta-ALAD activity increased zinc protoporphyrin anemia CNS effects decreased peripheral nerve conductivity Nervous paralysis, lead colics Adapted from Elinder C-G et al., Biologisk monitoring av metaller hos människa. Arbetsmiljöfonden, Uppsala, 1991
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TYÖTERVEYSLAITOS Importants determinants of exposure Subtance concentration / dose of substance Duration of exposure Dose rate Exposure route
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TYÖTERVEYSLAITOS
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Dimethylformamide
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TYÖTERVEYSLAITOS 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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