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Types of toxicity
Types of Toxicity
Acute toxicity Irritation and corrosivity Sensitization Repeated dose toxicity Genotoxicity Carcinogenicity Reproductive toxicity
Types of toxicity
continues
Mechanisms of toxicity:
Direct local toxicity to tissues first in contact with the substance Systemic effects due to the absorption of the substance Mechanism may be relevant to all species or it may be species-specific Quite often with industrial chemicals the mechanism is unknown Does the mechanism of toxicity possess a threshold? (What is the shape of the doseresponse curve like?)
Examples
Sulphuric acid:
strong acid, miscible in water corrosive, exposure to fumes may cause damage to the respiratory tract, and in repeated exposure in the respiratory tract cancers (laryngeal cancer) type and mechanism of toxicity:
locally toxic at the first site of contact mechanism of cancer related to its destructive effect on respiratory tract epithelium threshold
Examples, cont
Cyanides
toxic when absorbed into the body, mechanism well-known and apply to all species
Dose-response
D O S E
non-linear, threshold
linear, no threshold
EFFECT
Adapted from Elinder C-G et al., Biologisk monitoring av metaller hos mnniska. Arbetsmiljfonden, Uppsala, 1991
Information of the potential health hazards of chemicals is derived from... 1) Toxicological studies (in vivo, in vitro) 2) Case reports 3) Epidemiological studies
Toxicity testing
Systematic toxicity testing started in 1960s testing guidelines: OECD guidelines, EU guidelines for industrial chemicals GLP guidelines
acute oral, dermal or inhalation toxicity provides information on acute health hazards likely to arise from acute exposure to the substance by the given route, and on the magnitude of acute toxicity of the substance usually these tests are made with rodents, dermal test quite often with rabbits LD50/LC50 values (dose level which is caused
death to 50% of animals)
oral LD50 test is not used anymore, new substitutive tests are fixed dose test and acute oral class method which give an idea of the magnitude of the toxicity, but do not define the LD50 value
Acute skin irritation/corrosion test (Draize test) usually albino rabbits are used, the test substance is applied to the skin of the rabbits and held under the semi-occlusive dressing usually for four hours. The degree of irritation is scored at specified intervals. NOT if the substance is a strong acid or a strong base (pH<2 or >11.5), or it has not caused skin irritation at maximal dosage in acute dermal toxicity test. Note: albino rabbits are usually more sensitive to the skin irritation/corrosion than humans
Alternative methods:
Two in vitro skin corrosion test included in EU test guidelines (rat skin
TER assay and human skin model assay)
Several promising in vitro skin irritation tests have been developed but have not yet been ready for systematic use in skin irritation testing
Skin sensitization
28- or 90day toxicity tests (usually oral or inhalation studies) provide information on health hazards likely to arise from repeated exposure by the given route of exposure throughout evaluation of every organ system interpretation of the results demands careful consideration
Special tests...
Genotoxicity
the ability of the substance to induce genetic damage in cells In vitro tests:
bacterial tests (e.g. Ames test); gene mutations mammalian cell gene mutation assays in vitro chromosomal aberration test
Genotoxicity cont
In vivo tests:
e.g. bone marrow micronucleus test or chromosomal aberration test germ cell mutagenicity tests
Carcinogenicity
2-year cancer bioassay usually rat or mouse are used, can be performed by any relevant route of exposure (usually oral or inhalation) should be performed if some indication that the substance could be carcinogenic laborous and costly, high number of animals needed
Reproductive toxicity
T R E A T M E N T
(Developmental neurotoxicity)
EU classification and labelling is very much based on the data obtained from toxicity tests
T+
T Xn
Very toxic
Toxic Harmful
C
Xi F+ F O
Corrosive
Irritating Extremely flammable Flammable Oxidizing
E
N
Explosive
Environmentally dangerous
labelling: R 26 (very toxic by inhalation) R 27 (very toxic in contact with skin) R 28 (very toxic if swallowed)
Toxic (T)
labelling R23/24/25 (toxic by inhalation, in contact with skin or if swallowed) Cat 1 and 2 carcinogens (R45 or R49), mutagens (R46) and reproductive toxicants (R60, R61)
Harmful (Xn)
LC50 between 1-5 mg/l for aerosols and 2-20 mg/l for gases or fumes
labelling R20/21/22 (harmful by inhalation, in contact with skin or if swallowed) if there is data showing that prolonged exposure can cause serious damage to health at the dose levels significantly lower than the dose levels used for acute toxicity classification (R48)
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Possible risk of impaired fertility or R 63, Possible risk of harm to the unborn child)
Irritants:
R-phrases: R36/R37/R38 and R41(risk of
irreversible eye damage)
Corrosive:
R-phrases R34 or R 35 (causes burns or causes severe burns)