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.
Economic Background
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En provenance du cours de Johns Hopkins University
Toxicology 21: Scientific Applications
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Module 7
In this lesson you will learn about integrated testing strategies and how they differ from individual tests or test batteries. Also a wrap-up lesson "beyond chemical" will summaries your knowledge from this course and give a out-look for further directions in the field of alternatives to animal testing.
Rencontrer les enseignants
Lena SmirnovaResearch Associate
Center for Alternatives to Animal Testing
Thomas HartungProfessor
Environmental Health and Engineering
In the second section,
we will expand our thoughts on
the legislative and regulatory needs
to studying the different markets a little bit further.
To highlight what different industries are
needing in order to apply toxicity in 21st century type of approaches.
The economical dimension, if you take the key industry of chemistry, drugs, food,
and cosmetics here as an example of consumer products,
these are big industries and they have to protect
not only the adults but also vulnerable populations like this child here.
So we have to do this.
And these industries are in the rank order of
nine trillion dollar turnover worldwide per year.
And what they're using is traditionally more or less the same set of animal tests.
And we have calculated a few years ago that this amounts to
about three billion dollar of testing costs in animals every year.
Regulatory toxicology is also an industry.
It's not only an aspect of safety of science and of ethics,
it is also something which has an economical dimension.
For example, the you can REACH legislation,
I will show you the calculation in a second,
is an effort of test producing data which over around $13 billion,
and as I said, about three billion of annual testing costs.
But also the In vitro sector,
the use of cell cultures as we are mainly discussing here in this lecture series,
becomes increasingly a market.
This market analysis from July 2006 suggested that by 2021,
the In vitro toxicology testing market would worth $27 billion worldwide.
So, you can see that there is enormous investment in collecting data.
In a series of articles which did originate around a master thesis
at the London School of Economics in Milan by Annamaria Bottini,
we've analyzed a little bit the economical situation.
There is unfortunately no newer data available,
so I have to use this compilation of information to
give you a little bit of an idea about the economy and the basis of testing.
There's quite a few functions of animal testing of the product life cycle.
We are, first of all,
thinking of agent discovery.
This is what pharmaceutical industry's doing.
They're using animals as disease models for drugs.
Then, the sector of regulatory testing,
that's the one we have been addressing in our lecture series,
about safety and the respect of liability.
In Europe at least,
we see that typically,
the liability of the producer is dramatically
reduced after carrying out theories based to testing.
In the US, liability claims have a very different tradition.
But also, animal welfare and the absence
or not use of animal test can become a marketing aspect.
Body Shop was one example very,
well known for their campaign stating,
"We are doing our cosmetics without the use of animals."
And animals can also be trade barriers.
If a certain test is requested before entering the market,
this in fact presents a trade barrier for
those who want to export or import into the respective country,
and for this reason,
it is delaying and producing costs for foreign competitors.
So, we have to keep some of these aspects in mind when discussing the economy.
We also see that the limitations of
animal tests as discussed earlier in this lecture series,
do have some economical consequences.
Toxicities are rare.
Scandals are not observed very often but whenever
we see that a drug is withdrawn from the market,
it can be associated with not only enormous losses in
sales of these often very important products,
commodities, but they are also producing direct cost
in legal payments in compensations to be paid to patients.
And they can sometimes reach 10 of billion of dollars.
We also see that, we have discussed this earlier in the lecture series,
that many of the animal test actually representing outdated technologies.
And this is a lack of innovation which Tox21 actually wants to overcome.
We also have to say that a lot of the toxicity testing originates from the pharma-sector.
In the pharma-sector, people are very precautionary.
Why do they have to be precautionary?
There's no experience with these substances.
These substances have to go for the first time into humans.
People have not been really exposed before.
It is also extremely costly to withdraw something and these substances are
optimized to be not only taken up by the organism but also to be biologically active.
Using the same methodologies,
what is typically done in other sectors for chemicals,
industrial chemicals for existing substances which sometimes are for many decades
on the market is not always appropriate because we get far too many false allegations.
You have to understand that a drug,
during its development process,
has no market value yet.
You can typically change to other substances
quickly which are variants of the molecule as soon as you have a problem,
and with limited losses promote a new chemical.
To replace a chemical which is on the market for many decades is very
difficult as some of them are found in thousands
of different products and are very difficult to replace.
We'd like to talk about a few different industries
just to give you a feel, and as I said,
Annamaria's work was mainly focusing on EU for comparison.
The EU is a conglomerate of around 500 million people,
so almost twice as big as the US,
and in most instances you can simply compare the size of
the population and the economical size by a factor of 1.822.
It's quite interesting if you look for chemicals for example,
how many companies actually are part of a chemical sector?
29,000 companies accounted in
the EU which shows there's a lot of small medium enterprises,
small entities of a hundred or less people.
The official count in the EU is that 250 people and below,
this is small medium enterprise.
And it's an important industry with almost 600 billion Euro,
so this is about $700 billion dollar.
It represents about 35% of the world market.
But it is in comparison a very small use of animals.
Only about 90,000 animals have been used in the year 2005 for example.
At the same time, innovation occurs,
about 300 new substances are registered in
the EU per year at more than 100 kilogram per year.
This is showing you that this is an area where a lot of new substances have to be
evaluated in order to ensure the safety of these new products.
And is also employing, in EU,
more than a million people,
so you can understand that this is a very important industry.
Let's do a rough calculation,
just to show you what it means to actually tackle
properly something like the safety of existing chemicals.
So far, we have been testing about 300 chemicals and
a handful of pesticides per year for which in
Europe about 750 million dollars have been spent.
There's an average of 2.5 million dollars per individual chemical.
If we are now trying to address all of the existing chemicals on the reach,
or possibly all of the substance under the Toxic Substances Control Act,
which is by the way not the intention of the actual legislation,
and we don't do this over two decades let's say,
we're ending up with something between a 1500 to 4,300 chemicals per year.
Let's say we calculate 3,000 on average,
and we have to do testing on nanoparticles,
we have to do some testing on mixtures,
on new endpoints and so on,
and we can come up with such a simple calculation to about 11 billion dollar to be spent,
which means a 15 fold increase over what we are spending at this moment.
And we would use four million animals every year to comply with this.
And this very rough calculation shows you that
the economics do not advance to the use of our traditional methodologist,
they are only suitable for a few substances per year,
not for mass testing of existing chemicals.
The European Reach legislation entered into force in 2007,
and we have the first experiences from this.
We can see the estimates and the reality of this political program,
and it was quite interesting to see that the original estimations
have actually been based only on the view of 12 member states in 1991,
and have not included the five percent annual growth of this industry.
For this reason, we have seen dramatic increases,
almost doubling compared to the expectations
already for the first two deadlines in 2010 and 2013.
In 2018, the last group of chemicals those
between the production volume of 1 to 100 tons will be registered,
and only then we will know exactly how many substances fall under the REACH legislation.
Interestingly, industry has only suggested to do
about 10 percent of the tests which the guidance for industry actually will demand.
And they have been extensively using read across technologies or no test options,
as well as some existing data,
which is of unclear quality.
So the industry is trying to deliver
less data than the legislation has actually acquired.
So for this reason,
especially since no alternative approaches are being used,
it will be of critical importance how the chemical agency does react to these proposals,
and we will have to wait whether the industry suggestions are being accepted over
the tremendous additional testing requirements are being requested by [inaudible].
And once again, the toxicology which is applied here in
this context to industry chemicals was not the products it was developed for,
because more or less identical methodologies used for pharmaceutical developments,
for drug development have been applied and requested from the industry.
And these precautionary approaches are not necessarily suitable for the chemicals.
Let's talk about another sector.
I said already that cosmetics because of a testing done in Europe,
have been a driving force for alternative new approaches on the European side.
About 2,000 companies are producing about 60 billion euro of turn over,
which means they are about one tenth of the size of the chemical industry.
The European cosmetic industry is big,
it has about 50 percent of the world market,
and it has been using hardly any animals.
In 2005 before the ban,
it was just five thousand six hundred animals in total.
So you could say [inaudible] the sector,
which is using 0.03 percent of all animals in Europe.
However, it was a political decision to ban animal use here,
because vanity products seemed not to be an area where animal testing is acceptable.
And though the cosmetic industry might be the wrong victim,
we are very happy to have them.
Because they turned to become a real engine of
change and with their investment over the course of the last decade,
a lot of the new approaches have been brought forward
and moved into validation and international acceptance.
The industry is using about 400 new substances per year,
as we calculated in our studies,
it is a very interesting industry with about 5500 new products in Europe per year.
Worldwide, there's more than 8,000 lipsticks every year,
and we are buying this new stuff.
25 percent of the turnover of cosmetics
is done with products which were not yet on the market six months ago.
So this exchange of substances requests
testing or evaluations of substances and for this reason,
cosmetics where substance come into our eyes,
into our mouth, in our skin,
these substances have to be evaluated properly.
And it's not a small industry including retail as you can see,
it's about half a million people in Europe working in the cosmetics sector.
The food sector is even bigger.
The sales size is about 600 billion euro,
310,000 companies in Europe,
and there are submarkets for food additives
and for pesticides which are obviously used in food production.
Europe has about 29 percent of the world market,
similar size to the U.S..
The animal use is surprisingly high,
with about 500,000 animals in 2005.
And interestingly, the large majority of this was mice used for shellfish toxin testing.
These are allergy toxins which are accumulated by shellfish
and can lead to diarrhea and also to some paralytic problems.
This area has actually been dramatically reduced by new technologies following
2005 but these data are no longer really fully up to date.
But still there is some animal testing which is
often overlooked with regards to the safety of food,
mainly groceries which are using food additives of various kinds.
The number of new food additives or pesticides is in the one to two digit order,
8 pesticides have been calculated for a year,
10 new food additives on average.
So there's not a tremendous number of new substances entering this sector,
which is also the biggest factor with regard to number of employees,
we're talking of millions of people altogether.
But there is some similarity in the dimensions to the US here.
Food is different to chemicals and drugs.
We are going to discuss in a second because it is very much separated,
how food, in this case food additives,
as an example, are being regulated.
In Europe, it is via the European Food Safety Authority EFSA,
which is giving guidance for food additive evaluations.
The Food and Drug Administration here in the U.S. has their own guidance,
which is different in approach and in scope,
and this at the same time also on the level of W.H.O or
for example in Japan Independent Regulation on Food Safety and how to test.
Last I would like to talk about the pharmaceutical sector.
In Europe 2,200 companies sales,
similar size to chemical industry and to the food sector.
28% of the world market.
It is also quite representative or
correlating with the economical share of this industry.
It is using a lot of animals.
About 50 percent of all animals used in Europe are used for pharmaceuticals,
for their development or for their safety assessment.
Safety assessments, it is the smaller part,
but still it is about 50% of
all safety assessments of substances which is here in the drug sector.
An astonishingly large use of animals is for vaccine control.
And the reason is here that while a regular chemical is tested once in this lifetime.
Vaccines is produced from growing bacteria or viruses,
and then inactivating them by extracting substance.
All of them has to be tested each and every time it is going to the market,
a new batch is being produced.
And for this reason, there is a tremendous use of animals for vaccine control.
And the number of substances is not very big.
In Europe, it's on average 12,
in the U.S. up to 20 substances per year.
So, we're not talking about too many substances which have to be tested.
However, they're tested very extensively and this results in their respective numbers.
The evaluation of a substance to become a drug for pharmacology,
for the desired effects and for the undesired effects are not very different.
In the end, it is substance xenobiotic,
which is foreign to the body,
which is impacting on body functions.
But the approaches are very different.
We know in pharmacology very well that 90 percent of our substances fail.
I will come back to this in a second.
Many of them because of lack of efficacy.
Others because of lack of toxicity or
not enough efficacy to warrant for the economical developments.
Most of toxicology does not have the privilege of testing in humans.
So, other sectors have to completely rely on animal tests.
We know that the limitations of animal tests have suicidal effects.
Just to show you how important tracks are for societal progress,
there's two studies done by Lichtenberg about 10 years ago.
Which showed quite impressively that a population in an area where a new drug is being
introduced that each drug for
the entire population raises the life expectancy by about three weeks.
And, he showed that about 63 percent of the gain in
life expectancy we're enjoying from year to
year comes from introduction of new drugs into society.
It also showed in another quite boring study that the prescription of all drugs are
not having everybody enjoy medical progress is actually increasing mortality.
So, another hint that medical progress,
that drug development is actually benefiting society.
The FDA is most important in determining
how drugs are being tested in the U.S. and outside.
And the reason for this is very simple,
The U.S. market for drugs and the patent to the new stuff,
the new things which come out of the medical development.
The U.S.A is 6 percent of the world population represent
66 percent of the U.S. market according to the statistics from 2002-2006.
And though, push the growth in the Asian markets especially,
it is still 61 percent for the period of 2005 and 2009.
Because of this predominance,
this enormous use of drugs and the patents all of
the pharma companies in the world target mainly the U.S. market.
And for this reason, whatever FDA wants FDA gets.
This also puts FDA into a role which is very
important when now new approaches are being discussed
and the FDA has turned in a recent years to
a strong advocate also for advancing Regulatory Sciences.
So the innovation which comes out of
the agency and their programs and collaborations is of
critical importance for toxicity testing in 21st century.
Last but not least,
another sector which we did not discuss with animalia dither work.
The medical device area is also world wide
a 600 million dollar industry and we have most
recently submitted this workshop report soon to be available in our journal.
Our takes on this industry and the possibilities of changing
from In Vivo to In Vitro testing using
thoughts and concepts of toxicity testing at 21st century.
So altogether, we see that economic forces are in play and in our analysis we saw
a quite a few positive effects where economics are
driving us towards replacing traditional tests with noble ones.
One effects discussed separately in one of
the three articles was defect of globalization.
We are dealing with a worldwide industries and
these worldwide industries need world wide harmonized safety controls.
It makes no sense that the same product can only
be sold in different markets if there's an agreement about its safety.
We also see that life science and the informatics revolution are supplying
us economically driven with new technologies which can now be used in Tox21.
We also see that the animal welfare standards need to be harmonized in order to have
open markets to allow the trade partnerships
and by doing so very often they have been improved.
What we've seen for example was the legislation in Europe in 2010.
The consumers and other type of NGOs,
Non-governmental organizations,
who'll risk their advocacy impacting on
players in the economic arena are also putting prejudice
towards the improvement of safety controls of
substances and this means very often revamping legislation.
There's also a very interesting concept put forward by Porter,
discussed in his article which says,
"Whenever you start regulating a certain sector, this creates innovation."
Because the industry can no longer do business as usual.
They have to respond.
They have to innovate and this is often beneficial for the industry.
An interesting thought which I would like to just share with you here.
And there's also movements towards public private partnerships.
So, it is not just the regulator requesting the industry to deliver certain things.
An example of the European partnership for alternative approaches to animal testing EPAA.
Between the European Commission and the almost 40 companies and trade associations is
an example that there is also
interaction and joint developments and promotion of new approaches.
And, the legislative demands,
legislation like post-career authorization,
the Lautenberg Chemical Safety Act for
the 21st century and others on pesticides, on endocrine disruptors.
These demands are actually producing economical resonances.
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