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 of the Fifteenth to Twentieth Centuries
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来自 Johns Hopkins University 的课程
Toxicology 21: Scientific Applications
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从本节课中
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.
与讲师见面
Lena SmirnovaResearch Associate
Center for Alternatives to Animal Testing
Thomas HartungProfessor
Environmental Health and Engineering
[MUSIC]
I would like to come to part three of this lecture.
I would like to talk about the shortcomings of
what I'd like to call 20th century toxicology.
And I've put up on purpose as start of this part of the lecture,
a picture of Paracelsus.
Paracelsus was a Swiss-German researcher from almost 500 years ago
who is praised as the founder of toxicology.
Toxicology, which was not just the art of poisoning somebody else, but
a science which tries to understand how
dangerous effects of substances to the human body do occur.
And he is very well known for this quote which is, all things are poison and
nothing without poison, only the dose makes a thing is no poison.
So very importantly he introduced the concept,
it is all about how much of a substance.
Tiny amount of substance will typically not endanger you becomes or
more likely to do so.
Toxicology comes in the various industries.
You can see here chemistry, pharmaceutical industry,
food industry and consumer products like cosmetic industry, and
we want to protect not only adults but as shown here, we want to protect also
babies, vulnerable subpopulations, the elderly, the immunocompromised.
And to do so in these big industries which are all about 3 trillion
each of commerce, so really very big world wide industries.
In order to protect these, we're employing animal experiments.
These animal experiments are costly.
About $3 billion are spent per year for
animal experiments world wide, only for safety of these substances.
But you can also take from this, that in a global industry of about
10 trillion, this is only 0.03% of their turnover.
So it is a small price to be paid for
decisions on safety of substances which are in commerce, but you'll hear
in the next lecture already that this is not applied in a very uniform way.
We have very different standards for
the safety testing of various type of products.
Drug and drug evaluation, drug safety
has actually been the area where most of our toxicology has been developed.
And toxicology is often seen as the sister science to pharmacology.
It is both about the effects of normally small molecules.
Pharmacology's interested in the good effects and
toxicology's interested in the bad, undesired effects.
In pharmacology, they're actually quite critical about animal experiments.
This is for the very simple reason that far more than 90% of all
substances which go into human trials fail
despite all of the favorable results we get in our animal experiments.
And this is 20% because of toxicity, which we did not predicted.
And for about 40% because like of efficacy which was promised by the animal and
did not hold true.
Interestingly in toxicology they almost completely rely on animal test without
controls if it is about industrial chemicals, pesticides and
other substances because we simply don't have clinical trials to tell us the truth.
It is already should give you an idea about difficulties in applying
only animal experiments for safety assessment of non-drug substances.
So I would like to illustrate some of the problems of toxicology with this example.
This is a breakfast, it is a very nice breakfast with a glass of sparkling wine.
I use it for the purpose of illustrating some of the discrepancies we
are facing when dealing with toxicology.
You might have heard of dioxin, TCDD, a very prominent contaminant
because of a big scandal in Seveso in the late 70s.
Dioxin is a very prominent toxicant for which we are protected, for
example, by foot thresholds in these eggs.
Still, in my mother country, Germany, some 300 million eggs have been destroyed 4
years ago, when these thresholds were exceeded 3 fold.
So a lot of eggs destroyed to protect us against dioxin.
Where does this numbers come from?
They come from animal experiments which were then calculated
to derive a safe threshold for humans.
If we would run the very same animal experiment on alcohol, and
we would do the very same calculation, we also can derive a threshold and
you can continue drinking this glass of sparkling wine.
You can drink 1 glass per 345 years.
And this shows you I think that we're not dealing substances as same.
Alcohol is very acceptable, dioxin is not.
And this is not based on the actual risk, the actual problem it is generating, but
it is about our perception and acceptance of different classes of substances.
We have more on this breakfast here.
For example, salt, kitchen salt.
It shows up in some genotoxicity essays as damaging to the genes.
So it is something we could not easily develop as a drug.
It would typically be sorted out because of such findings.
The same holds true for sugar, regular sugar.
It is genotoxic in some essays and
it would be difficult to develop as a pill or as a food additive
if we did not know better from our traditional experiences with this.
Yeah, you're protected against pesticides.
For example, on these cucumbers, there's minute amounts left,
because the pesticides are applied long before harvest and
they are actually degrading, spontaneously.
But these plants have developed their own pesticides.
A co-evolution with insights they have developed substances which are fighting
insects, and these natural pesticides are found in sometimes
10,000 times higher concentrations than our synthetic pesticides.
And guess, if you test these in standard animal tests, for example for cancer,
they are very often carcinogenic, they end using cancer in animals.
So 63 of them have been tested, 35 of them were actually carcinogens.
So substances we could not add to the food, are found in the food, and
are producing carcinogenic effects.
And the same for coffee, 23 ingredients of coffee have been tested for
their carcinogenic effect in rats and 23 of them were positive.
So we're enjoying a brew of carcinogens in our breaks.
So you can see, these animal experiments would have been misleading,
it is only the traditional use of the substance that we do not
challenge them as possible carcinogens, we don't apply the same measures.
Another problem of toxicology I would like to illustrate with this mock product,
it doesn't exist.
It reads here, 7-in-1.
It has various properties including
being a glue on a toilet bowl cleaner.
But this is a mock product.
But I put it up here because I want to just make the case.
If we want such new innovative product, we permanently need new chemistry.
And this is what chemists have been doing.
85 million chemical abstracts, which is 85 million descriptions
how to synthesize a new molecule have been published by chemists so far, and
more than 100,000 of them have made it into consumer products.
And this is creating the permanent challenge of safety assessments for
these substances entering consumer products.
So if you imagine that this screen
represents 100,000 chemicals in consumer products,
all these nasty chemicals here, how many of them have actually been tested?
Only about 8%.
Most of the substances have not undergone any type of testing or
at least data are not publicly available.
If you ask how many of them have been built tested, its only about 3%.
These are mainly the drugs and pesticides for
which we spent a lot of money in order to have intense characterizations.
And we can go step further as different species as we will learn in this
lecture series are predicting each other only by some 40 to 60%, this is what we
should know about human toxicity of these 100,000 chemicals, a lot to be desired.
If this gives you headache, why don't you take an aspirin?
I'm using aspirin as an example because this is the oldest synthetic
chemical on the market, it was introduced in 1897 by Bayer
and it is still almost a blockbuster with almost $1 billion of sales per year.
But if you would run today's toxicology on this substance, it would actually have to
be labeled as harmful if swallowed because it kills rats.
The lethal dose 50%, so 50% of rats die at 150-200mg/kg.
Interestingly, this is exactly the maximum allowed daily dose in patients.
So we are treating our patients with doses of aspirin,
which would kill half of the rats.
No safety factor of 100 or 1,000 which we typically require for new substances.
It is also irritant to the eye, the respiratory irritant, the skin irritant.
The good news, it is not a carcinogen.
But it is a co-carcinogen.
It is promoting the carcinogenic effect of other substance which are applied at
the same time.
Has unclear mutagenicity findings, so damage to the genes.
And it also is producing embryonic malformations in essentially
any animal species tested.
Cat, dog, rat, mice, rabbit, and monkey data are very clear.
Aspirin is damaging the fetal development but not in humans.
89,000 pregnancies had been analysed that there's no evidence
of aspirin impacting on fetal development.
So you could say, it is quite unlikely to bring the subs like aspirin to the market
today, or we can be lucky that there was no regulatory toxicology 1897.
But I don't want to argue against regulation.
And I want to use the very same example.
This is an advertisement from Bayer from the turn of the last century,
where aspirin was advertised but there's also very interesting second product here
which is heroin, a sedative for coughs.
It became very successful but not in the pharmacies.
On two weeks after Felix Hoffmann acetylated salicylic acid to
derive aspirin her acetylated morphine to derive heroin, and
as you saw, this was being marketed as a sedative for coughs.
So there's good reason to look what companies want to bring to the market.
Not everything they put out is necessarily beneficial.
Another aspect which I think is very important,
toxicology is the only area of science where we are using methodologies which
are often 40, 50, 60 years old and have not been changed in essence.
The early 50 test,
which I mentioned earlier, was developed in the 20s of the last century.
The chronic toxicity in the 30s, skin and eye irritation in the 40s.
In the 60s, we developed reproductive toxicity testing, and in 1970,
the standardized cancer bioassay is one of the youngest assays actually.
So I am 52 now.
Most of the assays we are working with have been developed when I was not yet
born or I was in kindergarten.
Very unusual for science, and very unusual that
exactly in an area of our safety we are using some outdated methodologies.
Another thing is, science is moving but
it has been moving mainly because of scandals.
You see Carson's famous book,
Silent Spring, which impacted very much on pesticide regulation.
You see here scandals of dead fishes, of even burning rivers in
the late 60s, which have led to environmental legislation and
have led to changes in how we assess substances.
But it has not been the scientists,
it has been pressure from policy in public in order to introduce these things.
At the same time, we are continuously increasing our life expectancy.
This is a very interesting slide from nature
in 2008, it is shown that since 1850,
we are continuously increasing our life expectancy.
Every year born, lives one month longer on average than the year before.
And this is a process which does not seem to stop.
So while we were introducing more than 100,000 chemicals into our life,
we are permanently increasing life expectancy.
And this shall be a little bit of a balance to the chemophobia, the fear
of chemicals, which all of these scandals have introduced over the last years.
And many people fear chemicals more than they fear other diseases.
Though obviously there is at least not on the level of life expectancy,
a strong correlation.
