Oral Bioavailability - Dealing with Contaminated Sites: From Theory Towards Practical Application - page 296

The three-step approach described above, with accessibility, absorption and
metabolisation is suitable for a pharmaceutical approach, i.e. relating to a drug
which reaches its target. However, it may fail to properly represent the toxic poten-
tial of some contaminants, such as such as PAHs, which express their toxic (car-
cinogenic) effects through their hydroxy-metabolites. In this case the metabolism
activates toxicity. This is an important consideration that needs to be addressed when
considering the choice of method used to assess oral bioavailability. Because of ana-
lytical limitations, PAH metabolites such as hydroxy-PAH conjugated to sulphates,
glucuronic acid or glutathione cannot be detected in plasma. Metabolites are thus
excluded from the AUC determination, although they are the very origin of PAHs
toxicity. Consequently, due to the biotransformation processes, the bioavailable frac-
tion is underestimated when analysing only the native PAHs in blood (scenario 1).
In addition, under circumstances when the analysis of PAH metabolites in plasma is
technically feasible, the fraction that has been excreted via the bile is not taken into
account in the bioavailability calculation (scenario 2). This results in biotransfor-
mation processes reducing the calculated bioavailable fraction, which is used in the
resulting Risk Assessment, but not for the same reason and not to the same extent: in
the first case 100% of the metabolites are 'forgotten' due to the analytical procedure
chosen, in the second a proportion of the metabolites is lost through bile excretion.
This example shows that term definition (the definition of what is considered to be
bioavailable) and method of assessment are not truly independent, and that it is very
difficult to obtain a consensual absolute bioavailability.
The methylation process is the primary process by which inorganic arsenic is
metabolised in the body (Fowles et al. 2005 ). This process is generally consid-
ered to be a detoxification process, whereby the majority of the ingested arsenic is
metabolised to form methyl arsenic species (mainly dimethylarsenic acid), which
are then excreted in the urine. Analysis of urine has identified arsenate, arsen-
ite, monomethylarsonic acid and dimethylarsinic acid (Cullen 2008 ) amongst other
species, which have a lower affinity for tissue sulfhydryl groups than other inorganic
arsenic species (Fowles et al. 2005 ).

7.1.2 Relative Bioavailability Factor

Since the bioavailability of inorganic contaminants when measured in a water sol-
uble form is different when compared to the contaminants bound to soil, it is
necessary to use a correction factor which takes the effect of the sample matrix
e.g. a soil or an aqueous solution into account. This correction factor is considered
to be the relative oral bioavailability factor . This factor is generally less than one,
because the accessibility of contaminants in the soil is less than in a water soluble
form through physico-chemical interactions with the solid phase of the soil.
The relative oral bioavailability factor of the contaminant in a specific matrix,
e.g. a specific soil sample, is expressed as a percentage of the contaminant in the
reference matrix, e.g. reference sample according to Eq. ( 7.3 ):

( AUC PO ) TM / ( AUC PO ) RM × 100 (7.3)