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 or alternatively are defined for the critical effect. Hazard characterisations depend on the exposure 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 biological matrix). 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 in-vivo points of departure (PoD, e.g. BMD, BMDL, NOAEL, LOAEL).

  2. Calculation of hazard characterisations from PoDs (in this case BMD) 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:

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:

Specify with setting Use lower limit of BMD whether a BMD or BMDL is used in the risk assessment. The BMDL is a parametric estimate based on the profile likelihood method or is the p5 estimate of the bootstrapped BMD values in an uncertainty run. See module dose response models for more information on the estimation of the BMDL.

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Figure 99 Risk characterisation ratio (exposure/hazard) based on BMD, POCE = 0.18%.

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Figure 100 Risk characterisation ratio (exposure/hazard) based on BMDL, POCE = 32%.

In above figures the risk characterisation ratio (exposure/hazard) based on a BMDL is conservative compared to the ratio based on the BMD.