Background
In the
framework of Council
Regulation (EEC) 793/93 on
the evaluation and control of
the risks of existing
substances, the CSTEE is
requested to give its opinion
on the results of the risk
assessments. The terms of
reference are the
following:
1. Does
the CSTEE agree with the
conclusions of the Risk
Assessment Report?
2. If the
CSTEE disagrees with such
conclusions, the CSTEE is
invited to elaborate on the
reasons for this divergence
in opinion.
In
developing the present
Position paper The CSTEE has
focussed its attention on
human health. The issues
concerned with ecological
risks are somewhat different,
but as we shall indicate
there are analogous problems
that will need separate
consideration.
The
conclusions concerning human
health consider workers,
consumers and man indirectly
exposed via the environment,
and are based on a comparison
(setting the Margin Of Safety
- MOS) between the estimated
exposure for each of the
three mentioned population
groups and the identified
N(L)OAEL for those toxic
effects for which information
is available. According to
the Technical Guidance
Document (TGD) on risk
assessment for existing
chemicals, there are three
options for the
conclusions:
i. there
is need for further
information and/or
testing
ii. there
is at present no need for
further information and/or
testing and no need for risk
reduction measures beyond
those which are being applied
already
iii. there
is a need for limiting the
risks; risk reduction
measures that are already
applied shall be taken into
account
However,
the TGD offers very little
advice on how to arrive at
each of the different
conclusions (page
143-144):
"Where the
exposure estimate is higher
than or equal to the
N(L)OAEL, this indicates that
the substance is "of concern"
with regard to the exposure
of the human population
considered.... Where the
exposure estimate is less
than the N(L)OAEL, the risk
assessor will need to decide
which of the possible results
applies. For this step, the
magnitude by which the
N(L)OAEL exceeds the
estimated exposure (i.e. the
"margin of safety") needs to
be considered taking account
of the following
parameters:
- the
uncertainty arising, among
other factors, from the
variability in the
experimental data and
intra-and interspecies
variation;
- the
nature and severity of the
effect;
- the
differences in exposure
(route, duration, frequency
and pattern);
- the
dose-response relationship
observed;
- the
overall confidence in the
database
Expert
judgement is required to
weigh these individual
parameters on a case-by-case
basis. The approach used
should be transparent and a
justification should be
provided by the assessor for
the conclusion
reached."
So far (7
March 2001, date of adoption
of the Position Paper by the
CSTEE), the CSTEE has given
its opinion on 17 Risk
Assessment Reports. As the
calculated margins of safety
(MOS values) vary from
compound to compound, a
principal question has been
raised within the CSTEE on
how the Committee should look
upon low MOS values with
regard to the conclusions,
especially concerning the
choice between conclusions
ii) and iii). A working group
was set up in order to
identify the issues. Two
short meetings were held
before the plenary meetings
on October 9 and November 9
in 2000, and a more extended
meeting took place on January
9, 2001. There were also
short discussions at plenary
meetings.
The views
and recommendations expressed
in this Position paper need
to be set in the context of
the Scientific Steering
Committee's (SSC) report on
"the harmonisation of risk
assessment procedures in the
EU" and the new WHO/IPCS
document "Guidance document
for the use of data in
development of
chemical-specific adjustment
factors (CSAF) for
inter-species differences and
human variability in
dose/concentration response
assessment"
(CSTEE/20000/19-Add.2).
Summary of the
discussions
The main
question has been on how far
the responsibility of the
CSTEE goes in relation to the
conclusions in the risk
assessment reports. The CSTEE
should clearly concentrate on
scientific issues, and be
less concerned with risk
management. The wording of
the conclusions, especially
iii), can be interpreted as
being close to a risk
management issue.
There is
agreement that the CSTEE
should comment on the
confidence in the MOS with
regard to the reliability of
the NOAEL and the reliability
of the exposure assessment.
According to the terms of
reference, the CSTEE should
also give an opinion on the
conclusions of the risk
assessment reports. The
critical question then
appears when there is a low
calculated MOS. If the CSTEE
finds the MOS to be too low,
it should provide an
explanation of its opinion.
This should be expressed in
terms of scientific concerns,
but in a way that can be
understood and interpreted
for risk management. The
CSTEE was of the view that
this should be described in
terms of "cause for concern",
meaning "scientific concern".
There should be an attempt to
standardise terminology based
on an expanding base of case
histories in the CSTEE.
Guidance will also be
available in a report from
the SSC on harmonisation of
terms in risk
assessment.
In only
one of the risk assessment
documents, the one on
1,4-dichlorobenzene, did the
CSTEE disagree with the
conclusion ii) in favour of
conclusion iii), although a
need for further information
and testing (conclusion i)
instead of ii) was recognised
for some of the other
substances (see the attached
table). Below are citations
from the CSTEE opinion on
1,4-dichlorobenzene:
GENERAL
COMMENTS:
Due to a
limited or not adequately
conducted discussion of
available toxicological data
together with the fact that
the calculated MOS are to
small to be acceptable to
this committee, conclusion
(ii) of the risk assessment
for consumer health is deemed
not acceptable by the
CSTEE.
Human
Health:
Margins of
safety of 13, 35, 14, 14 and
43 that are discussed on page
94 are lower than those that
are usually thought to
provide full protection to
the public. As a consequence,
it is the CSTEE understanding
that they all indicate a
conclusion (iii) there is a
need for limiting the risk.
These low values for MOS
should not be accepted unless
there are special, well
documented and discussed
reasons to do so.
SPECIFIC
COMMENTS.
Human
Health:
A
realistic worst case scenario
for inhalation exposure is
set at 3,3 mg/m
3, corresponding
to an oral dose of 0.69 mg/kg
bw/d with a ventilation rate
of 0.7 m
3/h, bodyweight of
60 kg and 75% absorption from
the lungs. The lowest NOAEL
for the critical effect
(hepatotoxicity) is 10 mg/kg
bw/d in the dog. In the
mouse, hepatoxicity is also
seen (but at higher doses),
as well as liver
carcinogenicity which could
have liver toxicity and
secondary proliferation as an
underlying mechanism. No
sound arguments are presented
for discounting the endpoint
liver toxicity as being
relevant to man. Since a MOS
value of at least 100 is
generally considered to be
protective, a MOS value of 14
(10/0.69) for
1,4-dichlorobenzene raises
some concern.
Interestingly
the MOS approach is not used
in ecological risk assessment
1
.
How large should the MOS be, then, in order not to "raise concern"? The CSTEE has just started to discuss this. As already mentioned, risk assessment must be done on a case-by-case basis using expert judgement based on the scientific information. The commonly used uncertainty factor of 100 (based on the NOAEL from long-term animal studies) is thought to be a useful default value. However, it is difficult to say what is scientifically justified, both generally and in the specific case. It is agreed that a MOS of at least 100 should be used as a starting point, taking into account factors such as the type, incidence, magnitude and severity of the toxicological effect/response, the duration and administration schemes in the animal experiments, dose-response relationships, sensitive subgroups within the human population, the quality of the underlying database and the quality of the exposure assessment. As the future direction in human health risk assessment will probably involve chemical-specific and/or default assessment factors to a larger extent, this development must be followed and discussed further.
Examples
of factors that would require
a higher MOS than 100
are:
- the
NOAEL is based on
less-than-chronic exposure,
while exposure has a chronic
duration
- only a
LOAEL but not a NOAEL was
identified
-
uncertainties regarding the
quality of the available
data. This is particularly
the case in situations where
the most sensitive effect
detected is a lesion regarded
as serious, e.g.
teratogenicity or
carcinogenicity, or where the
statistical information is
inadequate.
- there
are sensitive subgroups
identified within the exposed
population not properly
addressed in the risk
assessment
- in
situations where co-exposure
to other chemicals with
similar mechanisms of
toxicity is likely
-
probability for
underestimation of
exposure
Examples
of factors that would justify
a lower MOS than 100
are:
- there
are documented and validated
scientific data showing that
for mechanistic reasons,
humans are less sensitive
than the experimental animals
used in the critical
study
- there is
strong evidence that the
internal target dose(s) in
humans is markedly lower than
in experimental animals due
to e.g. metabolic or
toxicokinetic
differences
- the
N(L)OAEL is based on human
data, and these are
adequate
- the
human population considered
is less heterogeneous, e.g.
occupationally exposed
workers
- the
critical effect is due to
local irritation
- the
exposure estimate is clearly
an unrealistic worst case
scenario.
Consistency of the CSTEE
opinions
As the
CSTEE agreed that it should
concentrate on the scientific
data in its opinions on the
risk assessment documents,
and comment on the confidence
in the MOS with regard to the
reliability of the NOAEL and
the reliability of the
exposure assessment, it was
decided to check the
consistency between the
different opinions that have
been delivered. In the
attached table there is a
compilation of which parts of
the risk assessment documents
that the CSTEE has commented
upon in their
opinions.
Although
there are relatively few
compounds that have been
covered this far, some
inconsistencies can bee seen
from the table. The exposure
estimates are only seldom
questioned, whereas the
toxicological effects are
commented upon in most cases.
Sometimes a comment is given
on the reliability of the
NOAEL. The magnitude of the
MOS has been mentioned mostly
in the later opinions. The
CSTEE has commented on the
conclusions in all opinions.
Only in one case
(1,4-dichlorobenzene) was it
explicitly said that the MOS
was regarded as too small for
conclusion ii).
It should
be noted that the CSTEE, in
two early opinions (on
methoxy- and
buthoxyethoxyethanol), did
not agree on the use of
assessment factors in the
risk assessment report for
establishing health based
occupational recommended
values (HBORV), which is the
responsibility of the SCOEL.
The CSTEE has also pointed
out the limitations in the
scientific basis for
developing minimal margins of
safety (minimal MOS) for
occupational exposure that
were calculated in the
documents on acrylaldehyde,
hydrogen fluoride and
dioxane
In only
two of the opinions did the
CSTEE discuss possible
sensitive subgroups of the
population:
- dioxane
: the preferential uptake of
1,4-dioxane in the milk of
lactating women should lead,
at least in the workplace, to
measures limiting exposure of
the breast feeding
women
-
anisidine : because young
children are of concern, the
CSTEE would recommend further
testing regarding
reproductive and
developmental
toxicity.
The
outline of the CSTEE opinions
is somewhat different,
depending on the responsible
CSTEE WG
rapporteur.
In
conclusion, the consistency
of the CSTEE opinions could
be improved. A difficult but
important improvement would
be to more carefully
scrutinize the exposure
assessments, which in turn
would necessitate to weigh
the relative importance of
the exposure part of the MOS
in each risk
characterisation.
A further
exercise to check on
consistency would be to go
through the risk assessment
documents to check which
conclusions that have been
drawn in the documents from
the MOS values for different
population groups and
different toxicological
effects. There is a need to
review how the MOS are being
used, if they are being used
consistently, the rationale
behind them, and if they can
be improved. However, this is
a fairly big task that has
been done only once by the
ECB (« Margins of safety
for human health. Overview of
conclusions agreed at
Technical meetings in
1997 ». Doc. ECB
4/34/97).
Probabilistic methods in
risk assessment
Some CSTEE members have mentioned the importance of introducing new techniques in risk assessment, especially the use of probabilistic methods that are currently not recommended explicitly in the TGDs. We believe that a fundamental shortcoming of the MOS approach is that it promotes a false deterministic impression of risk assessment; that if we have an exposure concentration (x) and an effect (no-effect) concentration (y) then the MOS is precisely specified by the difference between x and y. Yet in reality both x and y are associated with variability (x +/- v and y +/- w), some of which is due to irreducible stochasticity (spatial and temporal variability in x) and some of which is due to uncertainty (extrapolations between taxa in y). The MOS approach, by using single numbers (x and y), tends to obscure the variability. However, increasingly, techniques are available which take the variability into account and which make use of it to calculate objective probabilities of y (+/- w) being exceeded (or not) by x (+/- v). Moreover, techniques are also being developed that can make explicit the "confidence" that scientists associate with various elements of risk assessment (e.g. endpoint in one species being representative of others) and that can be used in calculating subjective probabilities of x exceeding (or not) y. We believe that these probabilistic techniques need to be given serious consideration for incorporation in the EU's risk assessment procedures, as a refinement and improvement of the MOS approach. Probabilistic risk assessment is no substitute for scientific judgement, but informs that judgement by making the underlying variability more explicit.
The CSTEE procedure for
reviewing the Risk
assessment documents
Besides
appointing a
rapporteur for each
document, there are
« progress
chasers » for the
following subjects:
1.
Terrestrial
environment
2.
Environmental exposure
assessment
3.
Carcinogenicity
4.
Modelling
5. Water
environment
6.
Endocrine disruption
7.
Allergenicity
Conclusions and
recommendations
- In
reviewing the existing
substances risk assessment
documents, the CSTEE should
concentrate on scientific
issues, including the
reliability of the NOAEL and
the reliability of the
exposure assessment. The
latter is less well covered
by the CSTEE today. More
attention should be given to
the exposure assessment
element of each report. The
committee has to consider
whether it has enough
expertise in this
area.
- In the
terms of reference, the CSTEE
is asked to give an opinion
on the conclusions of the
risk assessment documents.
This means that a value
judgement must be given in
some cases whether a MOS is
large enough not to raise any
concern. The working group
agrees that the estimated MOS
values should be discussed on
a case-by-case basis before
an opinion is given. It will
often be useful to start with
a default value of
100.
- The
CSTEE should come to a common
interpretation of the
standardised phrasing of
conclusions ii) and iii),
especially iii). The
interpretation of the working
group is that in case ii) the
estimated exposure caused by
the existing substance is so
low that it raises no
concern, but in case iii) the
estimated exposure is so high
that it raises concern. If
one regards the exposure as
being too high it is obvious
that there is a need for
limiting the risks. Which
risk reduction measures are
or should be applied is a
risk management issue that is
the responsibility of others.
However, the phrase "risk
reduction measures that are
already applied shall be
taken into account" is
ambiguous. It could also be
interpreted to mean that one
should look scientifically at
the data that are available
in order to assess whether
such measures are applicable
and effective. The CSTEE
recommends that the ambiguity
of this phrase be
remedied.
- The
CSTEE recommends the adoption
of a framework for making a
judgement on the adequacy or
otherwise of a particular MOS
value. Parameters for this
framework are set out in page
4 - 5 of this paper. The
framework should be updated
regularly in the light of
evolving experience of the
CSTEE with the Existing
substances Risk assessment
reports.
- The
CSTEE considers that there
would be value in the ECB
initiating a review of all
the Risk assessment reports
that have been prepared to
date, in order to assess how
the MOS values have been used
in developing the
conclusions.
- The
CSTEE should be proactive in
the area of probabilistic
methods in human and
environmental risk
assessment.
- The
CSTEE recommends that in
order to improve the
consistency of its opinions
on the Risk assessment
reports a common outline
should be applied.
- The
CSTEE recommends that a
procedure is adopted for
regular review of the
consistency in its opinions
on the Risk assessment
reports. This could be
performed after the review of
10-15 reports.
- The
CSTEE recommends that
clarification be sought on
the role that the committee
has in discussing protection
of the health of workers, and
the relevance of calculating
minimal MOS for occupational
exposure.
- There
would be a virtue in CSTEE
members contributing to the
revision of the TGD on risk
assessment for existing
chemicals.
- The
CSTEE needs to consider its
organisational arrangements
for dealing with the risk
assessments in the light of
its experience and the recent
changes in the committee
membership.
Specific comments from
the CSTEE on different
parts of the Existing
substances Risk assessment
documents
In the
table below, √ means that
there is a discussion on this
specific subject in the CSTEE
opinion. Concerning the
conclusions of the risk
assessment report, a√ means
that the conclusion has been
discussed by the CSTEE. If
the CSTEE has disagreed on
the conclusion, the reason is
given in the Comments
column
----------------------------------------
1
In
ecological risk assessment,
fixed application factors are
applied to endpoints, the size
of which depends on the quality
and quantity of available data.
The application factors give
less flexibility in making
judgements about the
relationship between effect
thresholds and environmental
concentration. As with the
default values used with MOSs,
however, the application
factors should be subject to
scientific scrutiny and should
not be applied without
question.