This course familiarizes students with the novel concepts being used to revamp regulatory toxicology in response to a breakthrough National Research Council Report “Toxicity Testing in the 21st Century: A Vision and a Strategy.” We present the latest developments in the field of toxicology—the shift from animal testing toward human relevant, high content, high-throughput integrative testing strategies. Active programs from EPA, NIH, and the global scientific community illustrate the dynamics of safety sciences.
Toxicology for the Twenty-First Century
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Do curso por Johns Hopkins University
Toxicology 21: Scientific Applications
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Module 1
This model will give you a broad introduction to the Toxicology 21st century (Tox21c) field and familiarize you with the main document, which summarize the main ideas and principles of Tox21c.
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Lena SmirnovaResearch Associate
Center for Alternatives to Animal Testing
Thomas HartungProfessor
Environmental Health and Engineering
Let's come to part four of our lecture.
This is what the lecture series will be about,
the Toxicology for the 21st Century.
I've taken here a picture,
a logo from a conference and on future talks.
This is a series of conferences which was started here
and I've had the privilege to be the opening keynote lecturer for this one,
the very first one which is held by the American Society for Toxicology.
The Society of Toxicology is addressing
here the new movements which are about to change the face of toxicology,
and this is what our lecture series wants to address.
The tipping point in this discussion has actually been a report
which coined the term of "Toxicology for the 21st Century."
It was done by the National Academy of Science,
the National Research Council.
The important thing here is that
scientists unanimously advocated a change in how toxicology has to be done.
The report is entitled,
"Toxicity Testing for the 21st Century, A Vision and a Strategy"
And you will hear in this lecture series several of the members
of this panel introducing the work and its implementation
which has taken place since 2007.
I can tell you,
this has really changed toxicology.
Since this report, nothing is the same.
An atmosphere of departure has been introduced and there's essentially
no conference in toxicology in U.S. We were
not discussing no longer whether we have to change,
but how we have to change.
Its key messages are,
we should move forward and use
the technologies from the biotech and the bioinformatics revolution.
So we should use our computer tools,
we should use our modern biotech tools in order to substitute,
and on the long term replace animal testing.
It is about growing for mechanism.
So it is about mapping the pathways of toxicity, the mechanism,
the adverse outcome pathways,
and you will hear about these different concepts in the lecture series.
Just to illustrate these things,
this is a quote from Francis Collins who first authored
the paper in Science in 2008 responding to this report,
and he and his co-authors wrote at the time,
Francis Collins is now heading the NIH as many of you know,
"We propose a shift from primarily in vivo animal studies to in vitro assays,
in vivo assays with lower organisms,
and computational modeling for toxicity assessments."
And he is actually actively pursuing this in his new role as head of NIH.
This is Peggy Hamburg who used to head the FDA until recently,
and in this editorial also published in Science in 2011.
She is arguing that,
with an advanced field of regulatory sciences, new tests,
and she mentions all of the technology we'll get to know in this lecture series,
we can replace current toxicological assays with tests
that incorporate the mechanistic underpinnings of
disease and of underlying toxic side effects.
This could have been written by an animal welfare activist a few years before,
and shows you that even one of
the most important regulatory agencies in the world
is moving towards replacing animal testing.
And Lisa Jackson at the time,
administrator of the Environmental Protection Agency,
went even a step further,
it made the top 21 paradigm.
They are the basis for the risk assessment of chemicals.
So you can see FDA, EPA,
NIH a lot of support for a new deal in toxicology.
This is an article I wrote in 2009 on invitation by Nature,
and this is one of the materials we're handing you
for an introduction into the topic of Toxicology for the 21st Century.
But I also maintaining a certain 10,000 foot perspective on what is happening here,
wrote the second article which I advise you to read,
which was a challenge.
I asked in 2009,
what needs to be done if we want honestly
to implement this vision of a toxicology for the 21st century?
What do we know about the road ahead?
And the tension and just put forward here
are challenges which we are going to address in this lecture series.
You will hear about them,
you will hear how we have been tackling this since 2009.
So these are some of the elements which are making a difference.
Moving toxicology from the 20th century to the 21st century.
It is new technologies which have actually become
available only around the turn of this century,
it's the omics technologies, genomics,
transcriptomics, proteomics, metabolomics, even be introduced in these.
It is about high-content methods other than omics like image analysis.
It is about HTS,
the high throughput screening processes,
the opportunities of robots,
running assays on many substance at the same time,
but a lot is about the bioinformatics,
the use of data mining technologies and of bioengineering to produce
better cell cultures which are actually enabling
technologies to move us into a new way of doing things.
Three elements which we are pursuing in our center are the organotypic cultures.
We are trying to move away from simple cell cultures to
actual organs on a chip or even combined organs to humans-on-chip.
And we also advocating for the combined use of this methodologies,
it is not about one-cell culture to replace an animal,
but it's about a combination of various tools with the computer,
with cell cultures, with lower organisms
together to satisfy the information needs we are having.
And you will hear about our Human Toxome Project,
a project sponsored by the NIH which is trying
to map the pathways of toxicity starting with pathway number one,
number two, building up a catalog which we can refer to as a point of reference.
A lot of this needs to be done on the basis of the best evidence available.
EBT, stands for evidence-based toxicology,
and this is so important for us that we actually devote
another lecture series in the next term to evidence-based toxicology,
and you will hear in detail how these concepts of evidence-based medicine
are starting to impact on how toxicology and safety assessments are being done.
For me, this evidence-based toxicology business,
and my personal interest,
in quality assurance of science in reproducibility,
and validation started is my very first experiences.
During my master in PhD,
I tried desperately to reproduce a paper,
actually cell culture paper not an animal study,
and this cell culture paper despite the fact that I wrote several
times the group which were publishing this was simply not reproducible.
And this started me to get interested in aspects like,
good cell culture practice and validation,
heading later the European validation body,
and you will hear a lot about the quality of science,
in this lecture which is going beyond toxicology,
because all areas of life sciences benefit from this type quality controls.
And this is a very interesting book,
one of my favorites actually is
"Follies and Fallacies" in all life sciences are described here,
because all tools have limitations and we are pretending far too often in science.
So this would be something, this is already a little bit of an appetizer for
the evidence-based toxicology collaboration and the lecture series for you.
This is one of the best quotes from this book, it says,
"Learning from experience may be nothing more than
learning to make the same mistakes with increasing confidence."
So what does it mean?
We might far too often in toxicology be using methodologies now for 40, 50,
60 years and we've forgotten about the problems,
the shortcomings because we've always been doing like this,
and we do it with increasing confidence,
in their value and we're not addressing their shortcomings anymore.
In the next lecture,
you will hear much more about the shortcomings of this.
Because there's a continuum between belief,
empirical, evaluations, evidence, and truth,
and you can argue but I placed the various scientists I have been studying here,
and I will show you that regulatory toxicology was based on a lot of belief systems.
And by moving regulatory toxicology towards evidence,
towards a better mechanistic understanding
using the in silico tools and the in vitro tools,
the biochemistry, the cell biology.
I hope that we are actually creating an evidence-based toxicology,
which is using mechanistic knowledge
and is a marriage with biometry,
and bioinformatics and that is what Tox21 and evidence-based toxicology are about.
So it is moving away from an expert-driven science
which is looking into the animal experiment like the crystal ball
predicting the future towards molecular science which is evidence-based,
which is using whatever modern science has to offer to us.
And this is my strong belief that all of the life sciences should move to.
And just for fun,
to show you that it's not only toxicology that
whatever controversial discussion is you can find some evidence.
I took the example of climate change,
you can find clear-cut evidence,
that there is global warming if you only look for it properly.
Evidence-based toxicology is also prompted by the fact
that far too much is published,
far more than you can possibly read and understand.
Sir William Osler from Hopkins is known for this quote,
"It is astonishing with how little reading a doctor can practice medicine,
but it is not astonishing how badly he may do it."
If you give it a look here there are some facts on reading
of medical literature and this was the starting point for evidence-based medicine.
Somebody has to help physicians to get
a high quality assessment of the scientific literature for a given question.
And for this reason,
systematic reviews of the literature have been introduced,
and you will learn more about it if you decide
to choose also the evidence-based toxicology class.
And in toxicology or health sciences we have a similar problem,
perhaps we need to say,
it is astonishing just how little reading we can practice public health sciences.
If you look into the most important database for scientific literature,
for Environmental Health Sciences in the last 10 years there were 40,000 articles,
there's almost a hundred thousand for toxicology and 270,000 wishlist exposure.
So nobody can possibly read this all.
You need processes of quality assurance and
condensing this information and this is what evidence-based toxicology wants to do.
And I think that all of this quality assurance,
validation, evidence-based medicine approaches,
good practices, all of this is a gift to the life sciences that is
about making our scientists better,
and this is the foundation of Toxicology for the 21st Century.
You will learn more about the evidence-based toxicology movement,
which started only in 2006 was our first publications and the first conference in 2007.
We have the evidence-based toxicology collaboration
for which we're hosting here in Hopkins,
the secretariat, and you will learn more about all of this.
But this is as I said the course in the fourth-term only.
So let me come to the conclusion for this introduction.
You will see that alternative approaches,
alternative to the traditional toxicology,
the toxicology of the 21st,
or 20th century have become one of the most dynamic areas of toxicology.
It is 3Rs Plus,
the 3Rs concept of replacing, reducing, and refining animal experiments,
will be introduced to you but it is more than this.
It is embracing latest technologies,
it is emerging new concepts,
it is harmonizing internationally,
how we do safety assessments and collaborating between the different continents,
it is spanning cross industrial sectors.
So pharma, chemical industry,
consumer product industry, they all work together in order to develop a new science.
And by its quality aspects it is I think a role model for most of the life sciences.
So let me close with a quote from an economist,
not a natural scientist or a physician,
John Maynard Keynes he said very wisely,
"The difficulty lies, not in the new ideas,
but in escaping from the old ones."
And this is what we are going to discuss,
new ideas and strategies to implement them,
so how to escape from the old ideas.
And I'm looking forward to seeing you again in one of our lectures. Thanks a lot.
Is there anything else that need to do?
Nope.
All right. Great.Thank you.
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