Combined Actions and Interactions of Chemicals in Mixtures

cells are deficient in O 6 alkyl guanine-DNA-alkyl-transferase, but the differences in
resistance to ethylating substances may moreover be due to a more efficient
excision repair system in human cells (Galloway 1994).
DNA replication
Changes in the fidelity of the replication of DNA are another source to
combinational effects concerning genotoxic compounds. Errors during DNA
replication may, for example, be caused by imbalances of the intracellular DNA
precursor pool. In this case, the repair system is unable to function because the
right nucleotides are missing. Exposure to hydroxyurea inhibits the
deoxyribonucleotide reductase thereby giving imbalance of the nucleotide pool. A
dramatic enhancement of the mutagenic effect of alkylating agents has, for
example, been observed after co-exposure with hydroxyurea (Walum et al. 1990).
Oxidative damage
In general, metal genotoxicity appears to follow two predominant modes of action,
i.e. interaction with DNA repair processes (described above) and induction of
oxidative damage. Co(II) is known as a transition metal and can therefore, after
reaction with cellular H2O2, generate active oxygen species (AOS) in a Fenton-like
reaction.
Hard metals (WC-Co) are made of a mixture of cobalt metal (5-10%) and wolframcarbide
particles (WC>80%). Excessive inhalation of WC-Co is associated with the
occurrence of different lung diseases including an excess of lung cancers. In human
peripheral lymphocytes Co powder and WC-Co both induced DNA single strand
breaks (ssb) measured by the alkaline COMET and alkaline elution assay (Anard et
al. 1997). On the basis of equivalent cobalt-WC content, WC-Co produced
significantly more ssb than Co. WC alone did not produce ssb. There is strong
experimental evidence (Lison et al. 1995) that the interactive (geno)toxicity of
WC-Co is mediated by AOS produced by the association of Co and WC but not by
Co or WC alone. Anard et al. (1997) showed that 1 M formate, a hydroxyl
scavenger had a protective effect against the production of ssb by WC-Co particles,
which is consistent with the implication of an increased production of hydroxyl
radicals when Co is mixed with WC particles.
Di-(ethylhexyl)phthalate) (DEHP) is a plasticizer used in the production of PVC
plastics products. DEHP is assumed to be a non-genotoxic carcinogen, acting as a
peroxisome proliferator. DEHP is not genotoxic in Drosophila melanogaster, on
the other hand DEHP enhances the genotoxic effect (acts as a co-mutagen) of Nnitrosodimethylamine
(NDMA) in this test organism measured as DNA-dsb. It was
assumed that the co-mutagenic effect of DEHP was caused by oxygen radicals
generated by DEHP (Kawai 1998).
Cell cycle regulation
Some clastogenic agents, e.g. ionising radiation and various cytostatic drugs such
as bleomycin, are able to induce double strand breaks at any time in the cell cycle.
When the cells are exposed prior to DNA synthesis phase (S-phase) the aberrations
are of chromosome-type. When the cells are exposed after the S-phase, the
aberrations are of chromatid-type. Most clastogens, however, are S-phase
dependant. The breaks will manifest as chromatid-type aberrations in the
subsequent metaphase. Many cytotoxic chemicals do prolong the cell cycle time.
This is a potential basis for antagonistic effects, since the longer the period between
exposure and DNA synthesis, the more chance the cell has to repair the damage.
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