Hello everybody. Welcome back to our lecture series on toxicity testing the 21st century. And today I have the important task to tell you that one plus one is more than two, because that's the main message I'm going to give when talking about integrated testing strategies. What is not true in mathematics is true for testing. If you combine two tests in an integrated way, they can give you more, they can give you better results than the two individual tests alone. But very quickly, I'm Thomas Hartung, I'm professor of evidence based toxicology at Johns Hopkins Bloomberg School of Public Health, and I'm directing the set of atoms to animal testing. So, why integrated testing strategies? This topic has actually been covered in a review paper which we put out quite recently, and visions our recommended reading for today, integrated testing strategies for safety assessments. So I invite you to read this and to follow what I'm going to say. Let's start from a 10,000 foot perspective. This 10,000 foot perspective sees that we have a universe of chemicals. This universe of chemicals, it's the real universe, has some areas of problems. I call this the galaxy of human toxicity. And our goal is to identify this galaxy of human toxicity. However, what we typically get is Bret's data. We use animal test in toxicity testing very often on rats, and we get the galaxy of rats toxicity, which is certainly overlapping. There're substance which are toxic for both men and rat but there's also substances which are toxic only for either of these. So what are we doing? We're typically, testing at maximum tolerated doses. So we increase the toxicity in rats to find also things which are only toxic at higher doses in rats. The overlap increases but we are not necessarily picking up all of the human toxicants. So, at the same time, we have problems that we are not covering really in mixtures, individual differences and this is further distorting what we are actually measuring. So, there's limits to how far we can actually approximate these things, and usually they come at the expense of identifying false positives. Non-human toxicants and we're getting more and more of these, the more we are testing, the more we are increasing the sensitivity of all approaches. The more we are using different animal species, we are identifying a little bit more on the expense. We've talked about this in the previous lectures on the limitations of animal testing and the need for change. So, the goal is to identify human toxicity. So, how can we do this in vitro tests? How can we do V cell cultures and other type of tests? They are certainly not perfect. They're not covering the entire universe. They will typically overlap very similar to the animal test, and have a certain area, a part of the galaxy of human toxicity covered. But by adding more and more of these tests, we can produce a test battery and this test battery will give us coverage of some of this. The idea of an integrated testing strategy now is not to use just a battery of tests, several tests, but we tailor them in a way that we can actually combine them to get optimal coverage with all of the different tests we have. So this is the basic idea, not one test, one size use all but the number of tests which are combined in an intelligent integrated way to get the most efficient coverage of what we're interested in. So, the idea is as you can see on this next slide, that a lot of different sources of information inform in the end, what is called, human hazard, and risk assessment. But that there is a way of using especially the information from in-vitro systems, from kinetics, from the computational tools which you also get to know, and that we use integrated testing strategies to optimize the combination of this information. And then other types of information allow us to make the full risk assessment. So we're talking today about this part, we talking about how can we optimize the use of some information streams to inform the construct of human hazard, or of human risk which is a construct, which is not the real life because it will not cover yet human diversity, it will not cover yet complex mixtures, the different exposures we have, and the co-morbidities. There are people with disease histories, all of this is not part of our typical human hazard and risk assessment, but this is something to be covered at another time.
