Biology Reference
In-Depth Information
UPTAKE, DISTRIBUTION, AND TOXICOKINETICS
One of the central aims of toxicology in general, and pesticide disposition/biotransfor-
mation in particular, is the determination of the absorption, distribution, metabolism,
and elimination of the pesticide. Increasingly this is assisted by the use of physiologically
based pharmacokinetic (PBPK) models. These models divide the organism into discrete
compartments with mathematical expressions to describe the affinity of the pesticide for
the compartment as well as the partitioning between compartments. This is discussed
in further detail in Chapters 3 and 6 of this topic. However, to build a physiologically
based model, one has to have physiological parameters based on experiments in vivo.
Dosing studies carried out in rodents can use a variety of dosing techniques, including
oral dosing, inhalation, percutaneous absorption, intravenous (iv) injection, or iv infusion.
When using an oral dosing design there are a number of considerations to take into
account. First, because of the various biological barriers to absorption in place, a larger
dose can generally be administered compared with an iv administration. In general,
most laboratory animals may be successfully dosed by gavage, with rabbits being the
exception. Other important considerations include the composition, pH, and volume
of the solution containing the pesticide. Ideally, the vehicle should be at neutral pH,
and different dosing levels should still use the same total volume of vehicle to avoid
artifacts in the data. In general, a vehicle volume of less than 10 ml/kg will not cause
interference with uptake kinetics.
Determining uptake via inhalation is more problematic than oral exposure, the
primary challenge being the differentiation of the true inhalation exposure from that
which is swallowed (e.g., through grooming) or absorbed dermally. This can be remedied
through the use of nose-only exposures (
Langenberg et al., 1998; Pauluhn and Mohr,
2006
). For example,
Yoshida et al. (1991)
observed a difference in the calculated LC
50
of Chloropicrin in rats exposed via nose-only exposure versus whole-body inhalation
exposure.
The dermal route of exposure can be an important consideration for pesticides,
given the nature of work performed by agricultural and commercial pesticide applica-
tors. There are many considerations in the choice of animal model. On one hand, most
disposition and metabolism studies are carried out in mice and rats, so for comparability
between routes of administration one would favor these models. However, the structure
and functions of the skin in humans are very different from those of rodents, and thus
the animal models with the closest physiology to human skin would be some primates as
well as the pig. One technique to determine uptake of pesticides in intact skin is through
the use of the isolated perfused porcine skin flap (
Riviere et al., 1986; Chang et al., 1994
).
This device uses a surgically prepared vascularized flap of porcine skin, which can be
removed and placed into a chamber. The intact vasculature can be attached to a pump
and the perfusate monitored for the presence of the compound being tested.
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