Combined Actions and Interactions of Chemicals in Mixtures

of uncertainty i.e. differences in toxicokinetics (aspects such as absorption,
distribution, biotransformation, and elimination which determine delivery of the
chemical to its site of action/toxicity) and toxicodynamics (aspects such as target
organ sensitivity, cytoprotective mechanisms and homeostatic control which
determines the extent of any effect or response due to the presence of the
chemical). The default values of the four individual factors were modified by the
International Programme on Chemical Safety (IPCS) in 1994 (IPCS 1994) (Table
3.1.1). These default values may be further modified when appropriate data exist
on the toxicokinetic and/or toxicodynamic properties of the compound in
experimental animals and humans. Although there are still only few examples
where the data on a compound are of such quality as to allow for replacement of
the default values it is anticipated that this approach will gain widespread use in the
future.
In connection with the elaboration of health based quality criteria for chemical
pollutants in air, soil and drinking water the Danish EPA establish TDI –values
using three safety factors. The safety factors account for:
SF1: Interspecies extrapolation (from animal to human). This factor is
historically set at 10 as a default value.
SF2: Variation in susceptibility among humans, i.e. to account for possible
increased susceptibility in the pregnant, children, elderly or sick people.
This factor is often set at 10.
SF3: The adequacy, quality and relevance of the data set. To account for lack
of a NOAEL value, lack of long-term testing, lack of data on specific end
point, etc. This factor is set at a value from 1 to 100 depending on a
concrete evaluation.
When using this approach in connection with chemical pollutants the overall safety
factor (SF1 x SF2 x SF x SF3) most often has been set in the range of 100-1000.
Table 3.1.1. Subdivision of the uncertainty factor. Default values (IPCS 1994).
Uncertainty
Default UF Default UF
Interspecies variation 10
Toxicokinetics 4.0
Toxicodynamics 2.5
Interindividual (human) variation 10
Toxicokinetic 3.2
Toxicodynamic 3.2
Total 100 100
37