Now, the committee considered four options for future toxicity testing strategies.
Option I is the standard in vivo toxicity tests,
based on animal biology and high doses, the low throughput, and
it's expensive, time consuming, it uses large numbers of animals.
And it's based on the apical endpoints that I mentioned previously in another
section of this lecture.
So the first report pretty much reviewed the tests and
the issues associated with Option I.
In Option II, the committee thought about tiered in vivo tests.
In vivo is tests still using animals.
It would be based on animal biology and it would still have to use high doses.
But there could be improved throughput because down at the bottom as I've circled
a sum screening would be done, using computational and in vitro approaches.
And this would provide more flexibility than the current methods.
In other words, chemicals could be screened using computational methods,
determining their structure, activity, properties, and
then some in vitro approaches.
And you'll see, when you hear the talk on environmental estrogens,
that some of this occurs in the endocrine disruptor screening program.
It can reduce costs and also time.
It can result in fewer numbers of animals but it's still based on apical endpoints.
Option III that the committee considered was a combination of in vitro and in vivo,
primarily based on human biology because the in vitro would be mainly
human cells and it would also incorporate some human epidemiology.
One could use a broad range of doses.
When using cells in culture, you can use many, many doses,
expose the cells to many doses.
There would be opportunity for high and medium throughput.
In other words, when using cells in culture,
there are ways in which one can do assays that can be done using robotics.
It would be less expensive and less time consuming, and use substantially fewer
animals because animal tests would only be done in certain circumstances.
And it would be based on perturbations of critical cellular processes.
And this comes back to our concept of pathways of toxicity.
And it would also use screening via computational approaches.
Possible limited animal studies that focus on mechanism and metabolism.
One of the critical aspects of in vitro approaches, or
cell culture approaches, is that many times the cells in culture don't have
the ability to metabolize the chemical in a way that occurs in vivo.
And so one either has to know all the metabolites and
test them in a culture, or go to animal studies.
So that when the animal's exposed metabolism of the chemical does occur, and
if there's toxicity, the metabolites may be contributing to that.
And finally, Option IV was almost totally in vitro, primarily human biology.
A broad range of doses, as I indicated, can be used.
Can be very high throughput.
It's less expensive, less time consuming, and would use virtually no animals.
It's based on perturbations of critical cellular responses.
Again, these pathways of toxicity.
And screening can be done Using computational approaches.
So you'll see that where the committee ended up was mainly with Option IV.
But a little bit of Option III involved.
The big thing here is that this is kind of revolutionary.
It's really a shifting away from the normal approach to toxicity testing.
To one that involves virtually no animal use.
There are a number of issues that are related to this and
it's certainly not going to happen overnight.
The committee thought, well maybe 10 to 20 years before
the vision of the committee will be able to be fully implemented.
And there will be things in the in vitro systems that are just
at this point hard to think about how they would be tested.
For instance, novel agents like nanoparticles or
physical agents like biomedical implants that are used also have to be tested.
And how to test them with in vitro systems is
at this particular point not immediately apparent.
But there is a shift away from apical endpoints, and whole animal studies.