FUNDAMENTALS OF FUNDAMENTALS OF OCCUPATIONAL OCCUPATIONAL

TOXICOLOGYTOXICOLOGY

Vesa Riihimäki, MD, PhD, MSc

Finnish Institute of Occupational Health

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What do we know of chemical What do we know of chemical hazards?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...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

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Chemical identity: CAS numberCompound specific, "selective"

toxicity

2. COMPOSITION/INFORMATION ON INGREDIENTS2.1 Dangerous ingredients2.1.1 CAS-number orcode

2.1.2 Name of ingredient 2.1.3Content

2.1.4 Label, risk phrases, safetyphrases

SAFETY DATA SHEET REGISTRATION DATA

Date: Previous date:

General principles in chemical General principles in chemical safety assessmentsafety assessment

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Physical chemical properties

9. PHYSICAL AND CHEMICAL PROPERTIES9.1 Common data (physical form, colour, odour)

9.2 Important data for health, safety and the environment9.2.1 pH

9.2.2 Boiling point

9.2.3 Flash point

9.2.4 Flammability (solids, gases)

9.2.5 Explosivity9.2.5.1 Lower explosion limit

9.2.5.2 Upper explosion limit

9.2.6 Oxidizing properties

9.2.7 Vapour pressure

9.2.8 Relative density

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Physical chemical properties, cont'd

9.2.9 Solubility

9.2.9.1 Solubility in water

9.2.9.2 Solubility in fats (solvent-oil, specify)

9.2.10 Distribution coefficient: n-octanol/water

9.2.11 Viscosity

9.2.12 Vapour density

9.2.13 Evaporation rate

9.3 Other data

10. STABILITY AND REACTIVITY10.1 Conditions to avoid

10.2 Incompatible materials

10.3 Hazardous decomposition products

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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< 5 μm5-10 μm> 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

Detoxification to thiocyanate

URINARY EXCRETION

Butadiene

Reactive epoxidemetabolites

Cyp450

Glutathione conjugation

ToxicEffects

CyanideCN-

Chemical may exert toxicity:

A) As such, for instanceB) After metabolism to reactive metabolites, for instance:

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Elimination and accumulationElimination 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 Mode of action/mechanism of actionaction

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 activityincreased zinc protoporphyrin

anemia

CNS effectsdecreased peripheral nerve conductivityNervous paralysis, lead colics

Adapted from Elinder C-G et al., Biologisk monitoring av metallerhos människa. Arbetsmiljöfonden, Uppsala, 1991

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Importants determinants of Importants determinants of exposureexposure

Subtance concentration / dose of substance

Duration of exposureDose rateExposure route

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Dimethylformamide

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Individual susceptibilityIndividual susceptibilityFactors 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