BOX 5-1Simplified Illustration of Integration and
Decision-making
Models and End Points: At Tier
1, a single quantitative structure–activity
relationship (QSAR) model is being used to predict rat
LD50 values from chemical structure and
physicochemical properties. No other models or end points
are being considered. To illustrate a simplified approach,
chemicals outside a specified applicability domain are
placed in the “inadequate data” category for
this example. For chemicals inside the applicability domain,
the output of the model is an LD50 estimate with
a confidence interval that reflects uncertainty.
Integration: Because only a
single model and a single end point are being considered,
there is no integration of different predictions.
Category Benchmarks: A set of
reference chemicals based on DOD interests that have known
(possibly more than one) LD50 values are selected
to represent the “high toxicity” and
“low toxicity” categories from which category
benchmarks are derived. For example, the “high
toxicity” benchmark could be defined as the highest
LD50 of the least toxic “high
toxicity” reference chemical. For some end points,
generic toxicity benchmarks are available, such as the
European Union and Global Harmonized System categories for
acute toxicity.
Decision-making: Decisions as
to how to place chemicals into categories are based on the
confidence bounds for each prediction:
A chemical is categorized as “high confidence
of high toxicity” if the upper confidence
bound on the predicted LD50 is less than
or equal to the “high toxicity”
benchmark.
A chemical is categorized as “high confidence
of low toxicity” if the lower confidence
bound on the predicted LD50 is greater
than or equal to the “low toxicity”
benchmark.
The remaining chemicals are categorized as having
“inadequate data.”
