Conclusions and recommendations
A. E. Fischli,
IUPAC President 1996-97
T. Godfraind, IUPHAR President
I. F.H. Purchase, IUTOX
For the majority of scientists and the average member
of the public, the first time that the issue of disruption of the endocrine
system from chemical exposure became a subject of public discussion was in
1993. Richard Sharpe and Nils Skakebak had published a paper in Nature proposing
that the decrease in sperm count and the increase in testicular cancer and
hypospadia believed to have occurred in humans could be due to a mechanism
involving the exposure of individuals very early in life to chemicals which
perturbed the endocrine system. This paper was the focus of a television programme
('Assault on the Male' transmitted by BBC in the UK on 31 October, 1993 and
subsequently internationally), which provided the public with an insight into
the hypothesis put forward by Sharpe and Skakebak. The public debate on the
link between oestrogenic chemicals found in the environment with these reproductive
diseases in humans and with a variety of diseases in wildlife (alligators,
birds, frogs) had begun. The common link was that the diseases were all potentially
caused by perturbation in the endocrine system, but particularly by disruption
of hormones controlling sexual reproduction and the development of sex organs.
As is common with such programmes, attention was focused on the hazard
(that is the observation of adverse effects) without proper attention being
paid to proof of causation and risk (which together provide
an assessment of the probability that these effects were due to chemical exposure).
Paracelsus' observation in 1538 is still relevant today: 'What is there that
is not a poison ? All things are poison and nothing is without poison. Solely
the dose determines that a thing is not a poison'.
These events fuelled a debate about whether the epidemiological
observations could be considered proven and about the likelihood that chemicals,
such as pesticides and industrial chemicals which might enter the food chain
through contamination, were the cause of the events. These concerns were the
subject of a book 'Our Stolen Future' by Theo Colbourn which asserted that
the presence of oestrogenic chemicals was affecting humans and wildlife to
the extent that the future of the human species was at risk. The question
of whether such chemicals (and particularly polychlorinated biphenyls and
DDE) were the cause of breast cancer was also the subject of debate particularly
in the USA.
On the other hand, there were reports of beneficial
effects of oestrogens - particularly phytooestrogens from sources
such as Soya - on human health. That chemicals with the same
oestrogenic activity could be both harmful and beneficial is
Inevitably with an issue as important as this, there
was and continues to be considerable media and public interest. Much of the
scientific understanding of the cause of these symptoms was in its infancy.
Thus there was uncertainty and controversy. In the face of this situation
actions were taken at the national and international level to provide framework
within which the scientific understanding of these issues could be expanded
- such as the formation of the Endocrine Disrupter Screening and Testing Advisory
Committee (EDSTAC) in the USA and activities undertaken by the World Health
Organisation through its International Programme of Chemical Safety.
There are remarkable similarities between the current
situation with endocrine disrupters and the situation with chemical carcinogens
in the late 1970s soon after the Ames' test for detecting carcinogens became
available. In both cases there was concern about the cause of serious diseases,
about whether a continuing increase in the diseases was occurring and how
much chemicals contribute to the causation of the diseases. The resolution
then was to improve understanding of the scientific basis for the concerns
and collect data which has helped to reduce the areas of disagreement. A similar
approach is unfolding with endocrine disrupters.
In the meantime, the science has developed
remarkably quickly. At the level of the molecular structure
of the cell, a new oestrogen receptor has been identified in the last year.
The fact that there are three receptors (a,b1 and b2) provides an opportunity
for understanding the variation in effects between organs and between species
of some oestrogenic chemicals. Methods of testing have been developed or older
methods evaluated for regulatory utility. Some of the concerns - for example
that breast cancer may be associated with xeno-oestrogens - has been studied
in more detail and this has helped to reduce the level of concern. However,
much still remains to be done before a understanding
of the science is sufficient to reduce the uncertainty about the association
between exposure to oestrogenic chemicals and disease or about the reliability
of risk assessment.
This volume provides a view of the current state of scientific
knowledge underpinning the assessment of the risks of exposure to
endocrine disrupting chemicals. It is contemporary, having been prepared in
a short period of time, and has been subjected to peer review. We believe
that the thorough peer review process through which the manuscripts
have been put provides the best safeguard for the quality of the scientific
content of the chapters.
Inevitably the scientific knowledge will advance rapidly
in the next few years, particularly with the attention being paid to the issue
on a world wide basis. However, a review of this volume allows us to make
recommendations which are relevant and based on an our assessment of the state
The International Council for Science (ICSU) and the
three Scientific Unions IUPAC, IUPHAR, IUTOX, which have supported the preparation
of this book, should:
- make the book widely available;
- work through the established links with international
and supranational organisations to disseminate the scientific information
which it contains.
The appropriate approach to these problems,
given the scientific uncertainty about the epidemiological observations and
the causal link with chemical exposure, must be prudent. In particular this
- careful checking of experimental results
must be undertaken before decisions and actions derived from
them are implemented;
- all scientific contributions should
be peer reviewed;
- care should be taken not to exaggerate
the likely consequences of particular scientific observations.
It is our contention that the resolution
of many of the uncertainties will only be achieved
by the conduct of high quality scientific investigations
which are rigorously peer reviewed. We believe that it is vitally important
that the scientific veracity of the epidemiological observations and the scientific
understanding of the causation of the adverse effects seen must be pursued
with vigour. In particular this means that:
- The basis of confidence in assessing the risks of
exposure to chemicals with endocrine effects will be a better understanding
of the mechanisms by which the chemicals produce their effects.
Thus, knowledge of the metabolic fate and the mechanisms of action at the
molecular, cellular and whole organism levels is an urgent research priority.
This will provide the platform for understanding differences in the response
of different species both in a qualitative and quantitative sense. For the
environment, an understanding of the effects of such chemicals on sentinel
species and the consequences for the environment as a whole is also an urgent
- Methods of measuring the actual exposure
of individuals and populations to chemicals with potential for producing
endocrine diruption is a critical requirement for proof of causality and
for assessing risk. Development of data on exposure should receive high
- Considerable further scientific examination
is required before a definite conclusion can be drawn about any
causal association between chemical exposure and most of the adverse effects
in humans and wildlife reported in this volume.
- Better methods of screening and testing
chemicals to provide the information necessary to carry out robust risk
assessment must be developed, standardised and validated.
The results of the mechanistic research work outlined above will be of considerable
value in this endeavour.
- Risk assessment methods, based on the well tested approaches for other toxic
events, should be refined and validated so that the risks
of potential adverse effects due to endocrine disruption can be placed in
context with other risks which are inherent in the environment in which
we live. These approaches must be capable of dealing with endocrine disrupting
chemicals whether they are synthetic or natural and of placing both the
beneficial and adverse effects due to the influence of such chemicals on
the endocrine system into context.
We recognise that the Scientific Unions (IUPAC, IUPHAR,
IUTOX) do not have the resources to provide the massive investment
in research necessary to support these recommendations. However,
we believe that the international community through national research
initiatives and international co-operation through existing organs,
such as the International Programme of Chemical Safety of the World
Health Organisation, have the capacity to make significant progress
in understanding the scientific issues which are currently unresolved.
The International Scientific Unions have a role to play in developing
scientific opinions, providing the resources for peer review and in
disseminating the information from research, a task which has already
begun with the publication of this volume with the sponsorship of the
International Council for Science (ICSU).
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