FUNDAMENTALS OF OCCUPATIONAL TOXICOLOGY

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FUNDAMENTALS OF OCCUPATIONAL TOXICOLOGY

• Vesa Riihimäki, MD, PhD, MSc
• Finnish Institute of Occupational Health

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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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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 lt1000
  chemicals, some data for 20 000 chemicals

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Basic concepts in toxicology
Intrinsic toxicity
Exposure
HAZARD, RISK
Individual factors
Risk management
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General principles in chemical safety assessment

• Chemical identity CAS number
• Compound specific, "selective" toxicity

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? Physical chemical properties
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? Physical chemical properties, cont'd
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?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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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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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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Uptake from the respiratory system - particle
size lt 5 µm 5-10 µm gt 10 µm - water solubility
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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
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
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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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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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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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Importants determinants of exposure

• Subtance concentration / dose of substance
• Duration of exposure
• Dose rate
• Exposure route

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Dimethylformamide
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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