Absorption or kinetic conversion of hazard characterisations
When the hazard characterisation level is internal and points of departure are available for external exposures (e.g., NOAELs from in-vivo animal studies) or when the hazard characterisation level is external and benchmark doses are available at the internal level, then kinetic conversion factors or PBK models are needed to translate the external doses to equivalent internal doses at the target or biological matrix of interest or vice-versa.
In MCRA, this alignment from internal to external or from external to internal is generally termed conversion, associated with a kinetic conversion factor or PBK model. The kinetic conversion factor is a multiplication factor needed to obtain a hazard characterisation on the target level from a hazard characterisation of the point of departure or benchmark dose. Depending on the chosen kinetic modelling tier, this kinetic conversion factor may be 1) assumed to be one, or derived from 2) absorption factors, 3) kinetic conversion factors or 4) using PBK models.
An important detail in the use of kinetic conversion factors for computing hazard characterisations is the order between kinetic conversion and inter-species extrapolation. Notice that when points of departure are determined for animals, a choice should be made regarding the order of inter-species extrapolation and kinetic modelling. That is, one may first choose to convert animal external point of departure to an internal hazard characterisation for that animal, using the available animal kinetic model. Alternatively, one may first extrapolate the animal external point of departure to a human external hazard characterisation, and thereafter apply the human kinetic model to obtain internal hazard characterisations. Currently, in MCRA only the latter approach is implemented.
Extrapolation from external to internal hazard characterisations
The calculation of internal hazard characterisations based on external hazard characterisations is similar to the procedure for computing internal exposures. In the simplest tier, equivalence can be assumed between internal and external hazard characterisations, and in higher tiers absorption factors, respectively PBK models can be used.
Calculation of internal doses using absorption factors
In the simplest form, internal doses are obtained from external exposure concentrations using absorption factors that are specified per combination of substance and route. That is, for a given substance, the internal hazard characterisation \(\mathit{HC}_{\mathtt{int, \dot dose}}\) can be derived from an external hazard characterisation \(\mathit{HC}_{\mathtt{ext}}\) as
Here, \(\mathit{r}\) denotes the route of the external exposure \(\mathit{HC}_{\mathtt{ext}}\), and \(\mathit{f}_{\mathtt{abs}, r}\) denotes the absorption factor of route \(r\). Note that this model assumes that the external hazard characterisations are specified as concentrations (i.e., substance amount divided by the body weight).
Calculation of internal concentration using human PBK models
A more detailed alternative to absorption factors is to use kinetic conversion factors or one of the advanced PBK models available in MCRA. In the last approach, for each substance independently, an external exposure equivalent to the dose of the external hazard characterisation is presented to a representative simulated individual for a number of simulated days to the PBK model of the individual. This representative individual should represent the “average” individual of the population, with nominal physiological properties (e.g., an average bodyweight of 70kg). This yields a time course of the internal substance amount at the specified target or biological matrix from which a long term average substance amount (chronic) or peak substance amount (acute) can be obtained. By dividing this substance amount by the weight of the biological matrix, an internal concentration is obtained, which then represents the internal hazard characterisation.
More details on computing internal concentrations from external doses can be found in the description of the calculation of internal concentrations from external exposures in section kinetic conversion factors or PBK models. For both tasks, the procedure for computing internal exposures/doses is exactly and the same kinetic model settings, such as dosing patterns and non-stationary period period apply for calculation of internal hazard characterisations as well.
Calculation of internal doses using animal PBK models
In the above methods, the assumption is that the external points of departure (often obtained from experiments on animals) are first converted to external hazard characterisations for humans, and a human kinetic model is used for obtaining the internal hazard characterisations. As mentioned, an alternative approach is to use first the animal PBK models to derive an internal hazard characterisation specific for the tested animal species and thereafter extrapolate to humans. When there are more precise kinetic models available for the animal used in the experiments for obtaining the point of departure, this could be a preferred path.
Note
Notice that this procedure is not yet implemented.
Extrapolation from internal to external hazard characterisations
In some cases, hazard characterisations are available at the internal level whereas the specified hazard characerisation level is external. This situation may occur, for instance, in in-vitro in-vivo extrapolation (IVIVE). Then, conversion is needed from the internal level to the external level, where the external level is implicitly defined as coming from the dietary/oral route of exposure.
For absorption factors, the external (dietary) hazard characterisation of a substance is simply computed by dividing the internal hazard characterisation by the dietary absorption factor, i.e.,
For PBK models, reverse dosimetry is needed to find the corresponding external (dietary) dose that yields the internal concentration specified by the internal hazard characterisation. In MCRA, this is done using a bisection algorithm: external doses are systematically fed into the PBK model and convergence is reached when the resulting dose is within a specified precision of the value derived from the hazard characterisation.