Combined Actions and Interactions of Chemicals in Mixtures

Four inhibitors of DNA topoisomerases: nalidixic acid, campothecin, mamsachrine
and etoposide, have been evaluated for genotoxic effects in the wing
spot test of Drosophila melanogaster. Tested alone only campthothecin and
etoposide was significantly genotoxic in this assay. A significant proportion of the
total spot induction was due to mitotic recombination. On the other hand, the cotreatment
of each topoisomerase inhibitor with the alkylating agent ethyl
methansulfonate (EMS) indicate that, while nalidixin acid, m-amsachrine and
etoposide show a tendency of antagonistic effect, campothecin shows an additive
effect, suggesting mechanistic differences between the activity of the four
inhibitors of DNA topoisomerases (Torres et al. 1998).
In some complex mixtures especially single class mixtures like PAH containing
mixtures, additive interactions may be assumed. Although both synergistic and
antagonistic effects have been demonstrated in binary mixtures of different PAH
(Hermann 1981, Hughes & Phillips 1990) (se also section on carcinogenesis) linear
correlation between mutagenicity in Salmonella and PAH content in city air have
been demonstrated at lower PAH concentrations, but at high PAH concentrations
the mutagenicity increased much more than the PAH content (Nielsen et al. 1999).
Booth et al. (1998) demonstrated linear correlation of DNA adducts in mouse skin
in vivo with PAH content and mutagenicity in Salmonella in a range of petroleum
products.
7.2.7.1 Toxicokinetic interactions
Bioavailability
If a substance is not absorbed or cannot pass biological barriers it will not react
with DNA. Most chemical compounds are absorbed via a passive diffusion-driven
process and interaction with such compounds will normally not be expected.
However, some solvents like DMSO are known to facilitate the cellular uptake of
some chemical compounds. Interaction can be expected when active transport
processes or a specific transporter is involved. An example of the latter is the
absorption of cobalt. Iron is known to interfere with the absorption of cobalt in the
gastrointestinal tract. Iron deficiency increases the absorption of cobalt, thus,
simultaneous administration of ion reduces cobalt absorption (Elinder & Friberg
1986). Also, amino acids and proteins in the diet reduce the absorption of cobalt,
since both amino acids and sulfhydryl groups complex with cobalt ions. It has also
been shown that the genotoxic effect of cobalt is reduced with addition of the
amino acid adenine (Binderup 1993, Binderup 1999), these antagonistic effect
might be due to a decrease in the absorption of the cobalt-adenine complex
compared to the cobalt ion.
Biotransformation
Many genotoxic compounds must undergo biotransformation before they can react
with DNA, and some observed species differences in susceptibility to
mutagens/carcinogens have a metabolic basis. Also individual susceptibility among
humans can be due to differences in metabolism.
Cytochrome P-450 enzymes carry out many of the reactions that convert stable
promutagens to electrophilic, reactive agents. Multiple cyt. P-450 isozymes exist
with different substrate specificities or differences in their distribution among
organs, species, and individuals. However most chemicals are enzymatically
deactivated in the organism, while rather non-polar, lipid-soluble compounds are
converted by phase I enzymes (eg oxidised by cyt. P450) to more polar and water
soluble compounds which are more readily excreted. The oxidation product may be
further metabolised by phase II enzymes (e.g., by hydroxylation, sulphuronidation
or glucuronidation). Competition between metabolic activation and detoxification
processes can strongly influence the genotoxic effect of complex mixtures, as some
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