Environmental Health Criteria 214

HUMAN EXPOSURE ASSESSMENT
The ADD is used to make route and route-to-route comparisons and
allows one to consider the relative significance of several exposure
routes. With the ADD, we compare inhalation, ingestion or dermal
exposures to the same medium such as tap water and compare exposures
through indirect pathways (e.g., food-chain transfers) to those from
direct pathways (e.g., inhalation or ingestion). As an example, the
ADD for the ingestion route for chloroform for a 70-kg individual
ingesting 2 litres/day of tap water containing 1 µg/litre chloroform,
365 days/year for a lifetime is 2 µg/day divided by 70 kg or 0.029
µg/kg -1 day -1 . This ADD can be used as the basis for determining the
relative significance of dermal, inhalation, and other ingestion
exposures attributable to tap water.
6.8 Physiologically based pharmacokinetic models
Human exposure to contaminants results in dose to the critical
organs. A mass balance on the contaminants that enter the body
accounts for the distribution in the various organs, transformation
into by-products, and excretion via specific mechanisms. The three
major exposure routes by which contaminants enter the human body are
inhalation, dermal absorption and ingestion. The vehicle that moves
contaminants between organs is blood. Transformations include the
metabolism of specific contaminants in specific organs. Mechanisms of
excretion include exhaled air, sweat, urine and faeces.
The above processes that occur in the human body can be modelled
by using physiologically based pharmacokinetic (PBPK) principles
(Masters, 1991). These principles can be applied at differing levels
of complexity. Simple models assume steady states and total absorption
and estimate dose to critical organs in a gross manner. They can be
solved by using linear algebraic relationships. Complex models include
time dependency, assume the human body to consist of multiple
homogeneous boxes, each representing an organ or a portion thereof,
and determine the distribution of contaminants in the different boxes
as a function of time. The relationships usually end up as non-linear
ordinary differential equations that are solved by using numerical
integration techniques. Examples of PBPK models may be found in Cox
(1996) for inhalation of benzene, Bookout et al. (1997) for dermal
absorption of chemicals and Rao & Ginsberg (1997) for multiple-route
exposure to methyl tert-butyl ether. A wide array of PBPK models
have been developed for other chemicals and chemical classes and may
be found in the relevant literature.
Whatever the complexity of the model representing the human body,
the difficulty is interpreting the dose results to characterize risk.
Usually, these human models are extrapolated to parallel animal models
for which toxicological data are available.
6.9 Validation and generalization
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