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

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

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 substances ( ), since then hundreds of new chemicals have been introduced per year Complete toxicity data are available for <1000 chemicals, some data for chemicals

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

TYÖTERVEYSLAITOS Physical chemical properties

TYÖTERVEYSLAITOS Physical chemical properties, cont'd

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

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.

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

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

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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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:

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

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?

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

TYÖTERVEYSLAITOS Importants determinants of exposure Subtance concentration / dose of substance Duration of exposure Dose rate Exposure route

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Dimethylformamide

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