Hazard characterisations calculation

Hazard characterisations are defined as deterministic threshold values (e.g. ADI, ARfD) or as distributions (using probabilistic models). They are linked to an effect of interest. Hazard characterisations depend on the risk type (acute or chronic) and the target level of the human body (external via some route of exposure or internal for a specific defined organ or compartment). Hazard characterisations are derived from points of departure provided as data and/or from dose-response models. The procedure for computing hazard characterisations has two main phases: 1) collection of all available hazard characterisation candidates and alignment with the target system, and 2) aggregation over multiple available hazard characterisations and imputation of missing hazard characterisations.

Collection of available hazard characterisation candidates involves collecting the appropriate points of departure data and/or dose-response models that are used for deriving the hazard characterisations. In MCRA, a distinction is made between three methods for computing hazard characterisations:

1. Calculation of hazard characterisations from externally specified in-vivo PoDs (BMDs, NOAELs, other).

2. Calculation of hazard characterisations from PoDs (in this case BMDs) calculated from dose response data.

3. Calculation of hazard characterisations based on an in-vivo PoD for the index substance and in-vitro RPFs from dose-response models for the other substances (IVIVE model) (cumulative assessments only) .

For all three methods, the collected points of departure and benchmark doses should be aligned with the target system. This alignment may involve various conversion steps for each point of departure and specific substance, and can be formally specified as:

\[\mathit{HC} = \mathit{f}_{\mathtt{expression-type}} \cdot \mathit{f}_{\mathtt{kinetic}} \cdot \frac{1}{\mathit{f}_{\mathtt{inter-species}}} \cdot \frac{1}{\mathit{f}_{\mathtt{intra-species}}} \cdot \frac{1}{\mathit{f}_{\mathtt{additional}}}\cdot \mathit{PoD}\]

where:

• \(\mathit{HC}\) denotes the hazard characterisation.

• \(\mathit{f}_{\mathtt{expression-type}}\) denotes the expression type correction factor, e.g., for extrapolation from LOAEL or NOAEL, or from NOAEL to BMD.

• \(\mathit{f}_{\mathtt{kinetic}}\) denotes the kinetic conversion factor for conversion from internal to external or external to internal hazard characterisations.

• \(\mathit{f}_{\mathtt{inter-species}}\) denotes the inter-species factor for extrapolation from animal to human (inter-species).

• \(\mathit{f}_{\mathtt{intra-species}}\) denotes the intra-species factor for extrapolation from the average to the sensitive human or probabilistic calculation of the distribution of human individuals (intra-species).

• \(\mathit{f}_{\mathtt{additional}}\) denotes the additional assessment factor for extrapolation from the POD to the hazard characterisation in humans for sources where appropriate data or information is scarce or missing (additional).

• \(\mathit{PoD}\) denotes the point of departure.

Note that inter- and intra-species extrapolation and the use of an additional assessment factor are optional. However, expression type correction and the kinetic conversion are always applied (when relevant) whatever option is chosen.

Occasionally, for some substances multiple hazard characterisations are available (e.g., obtained from multiple experiments) and for others substance hazard characterisations are still missing. Hence, two final steps remain to come to the final set of hazard characterisation:

• Aggregation over multiple available hazard characterisations.

• Imputation of missing hazard characterisations.