Combined Actions and Interactions of Chemicals in Mixtures

mixture. These interactions may deviate from additivity (no interactions) and be
expressed as synergistic or antagonistic effects due to interactions in either the
toxicokinetic and/or toxicodynamic phase.
Although the ultimate target molecule for genotoxic agents is the DNA there are a
number of different mechanisms by which chemicals can damage DNA. This
makes the prediction of the net outcome of the genotoxicity of complex mixtures
very difficult.
7.2.2 Types of damages to the hereditary material (DNA)
7.2.2.1 Primary DNA alterations
Primary DNA alterations can be caused by radiation (UV or ionising radiation) or
by reactive electrophilic agents. Chemicals may be either reactive per se or be
metabolically activated to reactive molecules. These reactive agents can react with
nucleophilic centres in DNA and cause different primary DNA alterations (figure
7.2.2.1).
Chemicals may react with numerous sites in all four bases in DNA. However, not
all nucleophilic sites have the same reactivity. Ring oxygen and -nitrogen are
nucleophilic centres, and in general ring nitrogen atoms are more nucleophilic than
ring oxygen atoms, with N 7 in guanine and N 3 in adenine being the most reactive.
Primary DNA lesions include:
DNA Adducts
A large number of chemicals and/or their metabolites are able to bind covalently to
DNA forming DNA adducts. Well known examples are polycyclic aromatic
hydrocarbons (PAH) like benzo[a]pyrene, heterocyclic compounds, aromatic
amines, and aflatoxins, just to mention a few groups of compounds that produce
bulky adducts. A number of small molecular-size compounds, such as nitrogen
mustards and N-nitroso compounds, are able to alkylate DNA. The formation of
DNA adducts may subsequently result in mutations in daughter cells or in a
number of the following other primary DNA damages.
DNA strand breaks
Single and double stranded DNA breaks may be caused by radiation, reactive
chemicals or failure in repair of other DNA damages such as DNA adducts.
DNA base modifications
Alkylating agents can cause DNA base modifications like deamination.
Loss of DNA bases
Alkylating agents and agents forming bulky adducts can cause loss of DNA bases
(depurimidation/depyrimidation). Such agents can be either mono-functional or bifunctional
(with one or two reactive groups).
DNA cross-links
Inter- or intrastrand cross-links are formed as a result of reaction with bi-functional
alkylating agents (with two reactive groups like e.g. mitomycin or nitrogen
mustard) with nucleophilic centres in the DNA strands. If the sites of reaction are
on opposite polynucleotide strands, interstrand DNA cross-links result. If these
sites are situated on the same polynucleotide chain, the reaction product is referred
to as an intrastrand cross-link.
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