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UNITED
NATIONS
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UNEP/POPS/POPRC.8/INF/11
Distr.: General
17 August 2012
Stockholm Convention
on Persistent Organic
Pollutants
English only
Persistent Organic Pollutants Review Committee
Eighth meeting
Geneva, 15–19 October 2012
Item 5 (d) of the provisional agenda**
Technical work: intersessional work on toxic interactions
Comments on the first draft of an approach to the consideration
of toxicological interactions in the evaluation of chemicals
proposed for listing in the annexes to the Stockholm Convention
Note by the Secretariat
The annex to the present note contains a table listing comments received from members of the
interesessional working group on toxic interactions on the first draft of an approach to the
consideration of toxicological interactions in the evaluation of chemicals proposed for listing in the
annexes to the Stockholm Convention, which is set out in the annex to document
UNEP/POPS/POPRC.8/INF/10. The annex has not been formally edited.

**
K1282355
060912
Reissued for technical reasons on 6 October 2012.
UNEP/POPS/POPRC.8/1.
UNEP/POPS/POPRC.8/INF/11
Annex
Comments on the first draft of an approach to the consideration of
toxicological interactions in the evaluation of chemicals proposed for
listing in the annexes to the Stockholm Convention
Minor grammatical or spelling changes have been made without acknowledgment. Only
substantial comments are listed.
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Australia
General
The report presents a good overview of the available methodologies to assess
the impacts from chemical mixtures as well as the available regulations to
control this issue.
In general terms, Australia considers the proposed methodology is acceptable
and provides a good starting point for assessing the impact of mixtures of
POPs. The proposed methodology is based on the best available information
(and the most commonly used methodology) to undertake risk assessment of
chemicals and assess the impact of chemical mixtures (i.e. concentration
addition and independent action method).
Australia
General
The author proposes a method (concentration addition and independent action
method) to estimate the impacts from a mixture of POPs, but also indicates the
lack of chronic data for POP chemicals. We believe that only using acute
endpoints to estimate the impact of POP mixtures may not represent chronic
effects, which could reasonably be expected to form the majority of effects in
environments distant from sources of release. Therefore, conclusions from
this approach could be incorrect if based on an endpoint that is not
representative of the likely impacts. Accordingly, Australia suggests any
limitations in the approach would need to be clearly and explicitly recognised
throughout.
Australia
General
The proposed methodology (concentration addition and independent action
method) should be applicable to endocrine disruption, which may have a
different mode of action and different target organs. It would be highly
desirable for the guidance document to specifically discuss how the lack of
suitable endpoints (i.e. ECx, NOEC, PNEC) for endocrine disruption effects
will be considered (we understand that there are not much data available on
this issue due to the complexity of the impact). This will have a bearing on
how accurate and representative the final outcome will be.
Australia
General
Further consideration of the technical discussion is needed in many parts of
the report as some are weak or not quite correct.
Australia
General
It would be helpful if the English is improved as several sections are difficult
to understand.
Colombia
Comments on the document “Guidance for the Committee’s approach to its
consideration of toxicological interactions when evaluating proposed
chemicals.
It is convenient to define what the scope of the document is, if it corresponds
to an assessment of human health effects from exposure to a mixture of
chemical compounds, according to established by the ATSDR as Assessment
of the joint toxic action of chemical Mixtures, however with the information
requested in the title "the model approach" can make a risk assessment,
considering the following:
The International Programme on Chemical Safety - IPCS defined that
human health risk assessment is a process intended to estimate the risk to a
given target organism, system or (sub) population, including the identification
of attendant uncertainties, following exposure to a particular agent, taking into
account the inherent characteristics of the agent of concern as well as the
characteristics of the specific target system (IPCS, 2004). The risk assessment
process begins with the problem formulation and includes four additional
steps: 1) hazard identification, 2) hazard characterization, 3) exposure
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assessment and 4) risk characterization (IPCS, 2004).
Likewise the IPCS Harmonization Project goal is to improve chemical risk
assessment globally, through the pursuit of common principles and
approaches, and, hence, strengthen national and international management
practices that deliver better protection of human health and the environment
within the framework of sustainability.
The EPA notes that a risk assessment includes a group of interconnected
processes that include hazard identification, dose-response assessment,
exposure assessment, and risk characterization. Integrating step in the risk
assessment process that summarizes assessments of effects on human health
and ecosystems and assessments of exposure from multiple environmental
media, identifies human subpopulations or ecological species at elevated risk,
combines these assessments into characterizations of human and ecological
risk, and describes the uncertainty and variability in these characterizations.
Considering the work of Persistent Organic Pollutants Review Committee
(POPRC), which should establish the effect of simultaneous exposures to
mixtures of persistent organic compounds for human health and the
environment, this document should refer to the risk assessment, consistent
with the work done by other multilateral institutions like the International
Programme on Chemical Safety - IPCS.
According to the above, it is proposed that the document be called “Guidance
for Risk Assessment of Chemical Mixtures in the framework of the Stockholm
Convention on Persistent Organic Pollutants”.
In consideration to the above is suggested the following model approach:
1.Problem formulation.
2.Hazard identification.
a.Identification of the chemicals of interest in the mixture;
b.Composition to the mixture and class of mixture;
c.Physical-chemical properties;
d.Fate and behavior under given environmental conditions;
3.Hazard characterization
a.Exposure the humans and animals to a mixture or to single compounds;
b.Epidemiological information;
c.Toxicological and ecotoxicological effects to a mixture or single
compounds;
d.Concentrations en drinking – water, river, sea water, soil, air, food, human
and animal tissues and others;
e.Cancer risk associated;
f.Information about compound’s interactions.
4.Exposure assessment.
a.Routes and pathways of exposure;
b.Estimating of the exposures: modelling or measurement approaches;
c.Exposure duration ;
d.Concentration and rate of exposure;
e.Biomarkers of exposure;
f.Enviromental fate and transport;
g.Model organisms living in the Polar region, if they exist.
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5.Risk characterization
a.Type and magnitude of potential adverse effects;
b.Risk management;
c.Limitations, interpretation/des-interpretation, uncertainties,
strengths/weakness;
d.Effects of sources – model situation – surroundings of source – nearby,
shorter and longer distance from?;
e.Contributionof the results in the effects (synergistic, antagonistic or none).
6.Selection of the assessment method
a.Data quality assessment;
b.The additive Approach;
c.Other Approachs;
d.Advantages and disadvantages of these approaches.
7.Model case studies.
Norway
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A. General comments to the concept note and the draft approach on
toxicological interactions

Our understanding from the discussions at POPRC7 and the final
decision taken at POPRC7 to establish an ad hoc working group to
develop a draft approach for the consideration of toxicological
interactions when evaluating chemicals proposed for listing (see
UNEP/POPS/POPRC.7/CRP.15, Decision POPRC7/9) is that the
draft approach should be of a general character and should not only
be limited to SCCP i.e. the draft approach should provide a general
guidance to POPRC on how it should consider toxicological
interactions involving multiple chemicals in its work.

Our understanding is also that the draft approach should draw on the
main conclusions and experiences from the two case studies and the
discussion paper on toxicological interactions of POPs presented at
POPRC7 i.e. documents UNEP-POPS-POPRC.7-INF-15, UNEPPOPS-POPRC.7-INF-16 and UNEP-POPS-POPRC.7-INF-17.

The work on toxicological interactions that has been undertaken by
POPRC in the past has centered on toxicological interactions
between POPs. We therefore believe that the draft approach also
needs to draw attention to the fact that humans and wild organisms
are exposed to a complex mixture consisting not only of POPs but
also other types of hazardous chemicals and that POPRC in its work
may have to consider toxic interactions between POPs and other
types of pollutants i.e. where such data exist and where it may be
considered relevant for the evaluation of new chemicals.

The draft approach moreover needs to highlight in which particular
step(s) of the evaluation of a new chemical POPRC should consider
toxicological interactions. The draft approach should moreover,
where possible, provide practical examples or case studies that
illustrate the how and what type of data POPRC may consider under
each of these particular steps.

In the draft approach it should in particular be emphasized that
Article b) of Annex E of the Convention clearly states that POPRC
should consider toxicological interactions involving multiple
chemicals when assessing the hazard of chemicals undergoing
evaluation for listing in the Convention. It should also be
highlighted in the draft approach that toxicological interactions may
be relevant to other parts of the evaluation process. In our view it
may be relevant to consider/ take into account toxicological
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interactions also under Annex D paragraph 1 e) and paragraph 2,
Annex E paragraph d), e) and f) and Annex F paragraph b) iv). As
noted above, case examples that explain how and/ or what type of
information POPRC may consider under each of these criteria
should be provided.

With reference to the case studies presented at POPRC7, other work
undertaken by the POPRC on toxic interactions and the WHO report
on toxic interactions the draft approach should give a concise/
summary overview of the most recognized methods for predicting
mixture toxicity. It should also give a general recommendation on
the most suitable default approach and highlight its potential
weaknesses and limitations and also indicate in which cases an
alternative approach if any should be used. In this regard we would
like to highlight that the case studies and also the comprehensive EU
report on mixture toxicity by Kortenkamp et al. from 2009 (see
references below) have indicated that our current status of
knowledge may justify the general use of concentration addition as a
pragmatic default approach to the predictive hazard assessment of
chemical mixtures but that the final decision on what approach to
use will have to be considered on a case by case basis. In the text the
reader should be referred to/ provided with references to original
literature where he/ she may get more comprehensive information
on the different approaches to predict mixture toxicity etc.

Besides the above the draft approach should contain an introduction,
objective and/ or a scope that amongst other things should explain
how and why toxicological interactions are relevant to the practical
work of POPRC
B. Suggestion for outline; Draft approach for the consideration of
toxicological interactions when evaluating proposed chemicals
As a thought starter for further work and to clarify our comments more in
detail we would like to propose the following outline for the draft approach;
Outline
1. Introduction - the “history” behind the draft approach;
 The importance of toxicological interactions to the work of
the POPRC – humans and wildlife are simultaneously
exposed to multiple chemicals - both POPs and other
hazardous substances
 Introduction to POPRC history/ obligations of considering
toxicological interactions;
- Article b) of Annex E states that POPRC should
consider toxicological interactions involving
multiple chemicals when assessing the hazard of
chemicals undergoing evaluation for listing in
the Convention.
- Toxicological interactions may be relevant for
other also for other parts of the POPRC
evaluation of new chemicals e.g. the
consideration of toxicological interactions may
be relevant also under Annex D e) , Annex E d),
e) and f) and Annex F b) iv).
- Overview of work on toxicological interactions
undertaken by the POPRC in the past with
emphasis on two case studies on toxicological
interactions of POPs presented at POPRC7 and
their outcomes/ conclusions.
2. Aim/ objective and/ or scope of the draft approach
3. Approaches for assessing effects of chemical mixtures and a
general recommendation for their use by POPRC;
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 Concentration or dose addition (CA); may be used when
mode of action is unknown or when mode of action for
different chemicals is known to be the same
 Independent action (IA); an approach that should only be
used when it is known that two chemicals or more
chemicals have different modes of action.
 Limitations, uncertainties, strength/weakness of the
approaches
 Conclusion and recommendations
4. Considerations and examples on how the POPRC should/ may
consider toxicological interactions in the evaluation of new
chemicals under;
 Annex D, 1. e) and 2.
 Annex E b), d) e) and f).
 Annex F b) iv).
Under each of the above criteria/ subcriteria describe;
-
Relevance of toxicological interactions
-
Considerations to keep in mind
-
Relevant examples and/ or types of information to be
considered
C. Some relevant scientific publications that may be used as case studies
or as supporting references when developing the draft approach on
toxicological interactions
1. Literature documenting mixed chemical exposure in humans and wildlife;
Science of the Total Environment. Special Issue. Levels, trends and effects of
legacy and new persistent organic pollutants in the Arctic: An AMAP
assessment. Volume 308 Number 15, July 2010.
Sagerup K, Helgason LB, Polder A, Strøm H, Josefsen TD, Skåre JU,
Gabrielsen GW. Persistent organic pollutants and mercury in dead and dying
glaucous gulls (Larus hyperboreus) at Bjørnøya (Svalbard). Sci Total Environ.
2009 Nov 15;407(23):6009-16. Epub 2009 Sep 6. PubMed PMID: 19735935.
Halogenated organic contaminants (HOCs) and mercury in dead or dying
seabirds on Bjørnøya (Svalbard). Report TA-2222. SFT 2007. See
http://www.klif.no/Tema/Miljoovervakning/Statligmiljoovervakning/Kartlegging-av-nye-miljogifter/Rapporter/41168/
Weihe P, Grandjean P, Debes F, White R. Health implications for Faroe
islanders of heavy metals and PCBs from pilot whales. Sci Total Environ.
1996 Jul 16;186(1-2):141-8. Review. PubMed PMID: 8685706.
Schecter A, Colacino J, Haffner D, Patel K, Opel M, Päpke O, Birnbaum L.
Perfluorinated compounds, polychlorinated biphenyls, and organochlorine
pesticide contamination in composite food samples from Dallas, Texas, USA.
Environ Health Perspect. 2010 Jun;118(6):796-802.
2. Literature on effects of mixed exposure to POPs and methods
Andreas Kortenkamp, Thomas Backhaus and Michael Faust State of the Art
Report on Mixture Toxicity. Final Report to the European Commission, DG
Environment 2009
Roze E, Meijer L, Bakker A, Van Braeckel KN, Sauer PJ, Bos AF. Prenatal
exposure to organohalogens, including brominated flame retardants,
influences motor, cognitive, and behavioral performance at school age.
Environ Health Perspect. 2009 Dec;117(12):1953-8.
Fischer C, Fredriksson A, Eriksson P. 2008. Coexposure of neonatal mice to a
flame retardant PBDE 99 (2,2’,4,4’,5-pentabromodiphenyl ether) and methyl
mercury enhances developmental neurotoxic defects. Toxicol Sci 101:275–
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285.
Sagerup K, Helgason LB, Polder A, Strøm H, Josefsen TD, Skåre JU,
Gabrielsen GW. Persistent organic pollutants and mercury in dead and dying
glaucous gulls (Larus hyperboreus) at Bjørnøya (Svalbard). Sci Total Environ.
2009 Nov 15;407(23):6009-16.
Halogenated organic contaminants (HOCs) and mercury in dead or dying
seabirds on Bjørnøya (Svalbard). Report TA-2222. SFT 2007. See
http://www.klif.no/Tema/Miljoovervakning/Statligmiljoovervakning/Kartlegging-av-nye-miljogifter/Rapporter/41168/
3. Method
Andreas Kortenkamp, Thomas Backhaus and Michael Faust State of the Art
Report on Mixture Toxicity. Final Report to the European Commission, DG
Environment 2009
Toxicity and Assessment of Chemical Mixtures. Preliminary Opinion
approved for Public Consultation. Scientific Committee on Consumer Safety
(SCCS), Scientific Committee on Health and Environmental Risks (SCHER),
Scientific Committee on Emerging and Newly Identified Health Risks
(SCENIHR), DG Health and Consumer Protection. European Commission
2011
Norway
General
The document is now 53 pages long and very detailed in its deliberations on
the topic of mixture toxicity. While the amount of work and effort put into this
is impressive we believe that much of this detailed information is already
captured in the two studies on exposure to multiple chemicals that were
prepared for POPRC7 in accordance with the work programme on
toxicological interactions and that it does not need to be repeated in such detail
in the guidance document considering what has been the common work
practice- and approach when POPRC evaluates new substances for listing.
There are also several repetitions/ overlaps in the text that should be removed/
dealt with to make the document more concise and to the point.
Norway
General
As stated also in our comments previously, our understanding is that the draft
approach should draw on the main conclusions and experiences from the two
case studies and the discussion paper on toxicological interactions of POPs
presented at POPRC7 i.e. documents UNEP-POPS-POPRC.7-INF-15, UNEPPOPS-POPRC.7-INF-16 and UNEP-POPS-POPRC.7-INF-17 as well as other
sources of information discussed by the POPRC in the past such as the
documents on mixture toxicity prepared by the WHO/ IPCS and the EU
(Kortenkamp et al. 2009).
Norway
General
In our view the guidance needs to be simplified and adapted to the practical
approach used by POPRC in its evaluation of new candidates for listing
taking into account the guiding principles set by the text of the Convention,
in particular paragraph b) of Annex E. To be more specific;
o
The text should practically applicable to the Committee in its work; we
believe that this guidance document should reflect that POPRC in
developing risk profiles and risk management evaluations largely draw
on information from other sources such as reports, risk assessments
and peer-reviewed scientific publications rather than generating new
information themselves. The risk profiles and risk management
evaluations prepared by POPRC have an upper limit of twenty pages
and are in many ways similar to scientific review papers. This puts
certain constraints on the evaluations and the level of detail of the
work that POPRC itself contributes with. Based on what has been the
common work practice POPRC in the past the Committee can be
expected to be down-stream users of literature on mixture toxicity,
they are however less likely to generate their own data and do their
own calculations on mixture toxicity when developing risk profiles for
new chemicals. This should be mirrored in the draft guidance which
should put particular emphasis on explaining what types of existing
data/ literature is relevant and how it should/ may be considered/ taken
into account. In our view, the guidance document should contain
information of a more general and practical character that can be
applied by POPRC in their work/ when evaluating new substances for
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listing according to the Annex D-F criteria of the Convention.
8
o
The text should be simplified and shortened; mixture toxicity is a
complicated topic and a lot of detailed information can cause
confusion, particularly if there are repetitions in the text. We therefore
propose to keep the text relatively simple, straight forward and to the
point and to only extract/ use information that may be deemed relevant
to the practical work of POPRC and the text of the Convention from
the above mentioned references. There are also repetitions in the text.
To deal with this some text may have to be deleted from the present
draft and the document may have to be partially rearranged. See
detailed comments in the draft text.
o
The guidance and the proposed approach should reflect and be true to
the text of the Convention; the text of the Convention puts certain
constraints on the work of the Committee. This need to be reflected in
the guidance for the Committees approach to its consideration of
toxicological interactions when evaluating proposed chemicals. What
constraints the text of the Convention puts on the Committee needs to
be highlighted in the text e.g. that paragraph b) of Annex E specifies
that "hazard assessment for the endpoint or endpoints of concern,
including a consideration of toxicological interactions involving
multiple chemicals" should be conducted as part of the risk profile (i.e.
not a risk assessment).
o
POPRC conducts hazard assessments not quantitative risk
assessments; a full risk assessment is outside the scope of the
convention and beyond the work of the Committee. According to
paragraph b) of Annex E a "hazard assessment for the endpoint or
endpoints of concern, including a consideration of toxicological
interactions involving multiple chemicals" should be conducted as part
of the risk profile (i.e. not a risk assessment). We therefore do not
consider section 3.3. "Risk assessment" of the present draft to be
relevant to the work of the Committee and propose that this section
should be deleted to avoid any confusion on this issue. In line with this
we also suggest that the proposed title "Guidance for Risk Assessment
of Chemical Mixtures in the framework of the Stockholm Convention
on Persistent Organic Pollutants" is changed to "Guidance for Hazard
Assessment of Chemical Mixtures in the framework of the Stockholm
Convention on Persistent Organic Pollutants".
o
The guidance document should be more like a manual; in its finished
form the guidance document should be more like a manual that can
help POPRC understand when and how they, in a practical and
concrete way, should address mixture toxicity when evaluating new
substances for listing according to the Annex D, E and F criteria.
Questions that need to be addressed in this context are in particular: In
relation to which parts of the evaluation process/ Convention text
should toxicological interactions be taken into account? What types of
data are relevant, how may/ should the data, in each particular context,
be considered? Why are toxicological interactions relevant to the
Annex D, E and F evaluations in general? With reference to the text of
the Convention and by providing practical examples how may
evidence of toxicological interactions affect the conclusions of the
Committee?
o
The text should in a concrete/ practical way explain how the
committee should take mixture toxicity into account; the draft
approach should give a brief and simple introduction to the main
approaches for assessing toxicological interactions. It should also in a
simple way summarize the main findings and conclusions from UNEPPOPS-POPRC.7-INF-15, UNEP-POPS-POPRC.7-INF-16 and UNEPPOPS-POPRC.7-INF-17 as well as other sources of information
discussed by the POPRC in the past. Based on this information it
should provide a concrete recommendation to POPRC on a possible
approach. The draft guidance should highlight in which particular
step(s) of the evaluation of a new chemical POPRC should/ may
consider toxicological interactions. The draft approach should where
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possible, provide practical examples or case studies that illustrate the
how and what type of data POPRC may consider. Practical examples
should also as far as possible be used illustrate how mixture toxicity
may affect the decisions made by POPRC in relation to the Annex D,
E and F evaluations. General limitations/ challenges with addressing
mixture toxicity according to the proposed method should also be
addressed. E.g. with chemicals what you measure is what you "see"
hence to get the most complete picture of the exposure situation
POPRC should consult multiple studies and not only rely on one or a
few studies*, the available studies does not necessarily take into
account the most relevant endpoints as risk is calculated based on what
limited information on toxicity and environmental levels that was
available at the time, the mixture toxicity of chemicals with non-linear
dose response curves and strongly time-dependent action such as
endocrine disrupters which are highly effective at low concentrations
during early developmental phases may not be adequately addressed
unless the study design specifically takes these endpoints and factors
into account, the endpoints used in the case studies may not be
representative enough of long-term effects that are relevant to wild
populations of organisms such as neurotoxicity, changes in
reproduction because they are derived from controlled lab-studies,
which takes place with model organisms typically of a different
species and are conducted at a much higher temperature than in the
Arctic etc.
* It would perhaps be useful for POPRC in collaboration with e.g. AMAP,
IPCS/WHO and others to start working on an "exposure database" e.g. for the
Arctic and humans to ensure the best possible starting point for assessing
mixture toxicity.
o
The guidance should provide a short list of fairly simple conclusions
and recommendations; To help guide the committee we believe that
the guidance document, based on the above sources of literature,
should provide a fairly short list of rather simple and practical
conclusions/ recommendations. However, to avoid over simplifying
the issue references to more detailed information should also be
provided. Based on the present knowledge of mixture toxicity we
believe that is possible to make simplified conclusions
recommendations along the lines of:
1. How to evaluate and predict the toxicity of chemicals is a major
challenge in toxicology, but our understanding of such effects has
grown considerably in the past ten years and is still growing as new
scientific findings are being published. The present guidance should
therefore be considered as a living document that must to be up-dated
at regular intervals.
2. Data on toxicological interactions should be considered by POPRC
and included in the risk profile when such data are available e.g. from
peer-reviewed scientific publications, but may also be
considered/taken into account when such data are not directly available
but there is reason to assume that toxicological interactions may occur
based on existing data documenting the presence of multiple hazardous
chemicals (such as other POPs) in environmental matrices and/ or
biota.
3. While the multi-component mixtures such as environmental samples is
composed of a heterogeneous mix of dissimilarly or similarly acting
chemicals whose effects may be additive or interactive the currently
available scientific evidence, pragmatic considerations as well as the
precautionary approach set forth in Article 1 of the Convention support
dose (concentration) addition as the preliminary default concept for the
assessment and prediction of mixture effects.
4. Where available data strongly/ clearly suggest that the effects are not
additive POPRC should, on a case-by-case basis, consider interactive
effects and employ other explanation models such as independent
action when taking mixture toxicity into account in their Annex D, E
and F evaluations. For example: Even if there is good evidence that
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endocrine disrupting chemicals in general produce combination effects
in a dose additive manner (Kortenkamp et al. 2009), synergistic effects
have been observed for certain classes and combinations of chemicals
with endocrine disrupting activity (e.g. Christiansen et al. 2009, Mu
and Le Blanc 2004).
Norway
General
Norway
General
It could be useful to introduce a list of commonly agreed definitions for key
terms and concepts. Though not all of these may be equally relevant for this
guidance document the IPCS agreed on the following list at a workshop held
in 2007 (Kortenkamp et al. 2009) that may be used as a starting point to
explain key concepts mentioned in the text:
o
Exposure to the same chemical by multiple pathways and routes
should be described as “Single Chemical, All Routes” (sometimes also
referred to as “aggregate exposure”).
o
Exposure to “Multiple Chemicals by a Single Route” should be
distinguished from “Multiple Chemicals by Multiple Routes”.
o
Chemicals that act by the same mode of action and/or at the same
target cell or tissue display “Dose Additive” combination effects.
o
Where chemicals act by diverse modes of action or at different target
cells or tissues, the combined effects are “Effects Additive” or
“Response Additive”.
o
Synergy and antagonism are defined as departures from dose
additivity, not response additivity.
o
“Mode of Action” is a biologically plausible sequence of key events
that lead to an observed effect.
o
“Mechanism of Action”, in contrast, involves a sufficient
understanding of the molecular basis for an effect so that causation can
be established.
References
Christiansen S, Scholze M, Dalgaard M, Vinggaard AM, Axelstad M,
Kortenkamp A, Hass U. Synergistic disruption of external male sex organ
development by a mixture of four antiandrogens. Environ
Kortenkamp A, Backhaus T, Faust M. State of the Art Report on Mixture
Toxicity. Report to the European Commission 2009. Study contract
070307/2007/485103/ETU/D.1. 391 pp.
Mu X, LeBlanc GA. Synergistic interaction of endocrine-disrupting
chemicals: model development using an ecdysone receptor antagonist and a
hormone synthesis inhibitor. Environ Toxicol Chem. 2004;23(4):1085-91.
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1.1
This text is a good startingpoint but may need some refinement. Please try to
shorten the text and make it more to the point. The text should in our view
answer why POPRC needs to consider mixture toxicity in their work and in
doing so provide information on the history and development of mixture
toxicity. See Kortenkamp et al. 2009 for inspiration.
Change first paragraph to: “The Due to the industrial revolution the number of
chemicals to which humans and other living organisms are exposed has
increased dramatically in the past 100 years (Carpenter et al., 2002). While
Mankindmankind has always been exposed to various metals, which as natural
elements are present throughout the environment, in drinking water, and in
food., the industrial revolution and the emergence of synthetic chemistry
introduced a new class of substances into many parts of our lives and the
environment - the synthetic chemicals. Many natural chemicals are in the
foods that we eat, and many of these act at a variety of sites in different organs
and cells. It is estimated that more than 65,000 chemicals have been
manufactured for commercial use in industrialized countries () Intentionally or
not, humans come into contact with these chemicals during manufacture,
handling, or consumption. Exposure to a vast array of synthetic chemicals can
occur when a person ingests food or drink, works in an agricultural setting
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with pesticides, or lives in a home among solvents, paints, plastics, and fuels.
Through industrial production, consumption and use these chemicals are also
released to our surrounding environment whereby also wild organisms are
exposed. Although many of the chemicals greatly benefit us, some are
hazardous substances that are toxic to humans and wild organisms. From an
environmental- and health perspective persistent organic pollutants which are
toxic, highly persistent, bioaccumulating substances that may undergo longrange environmental transport are of special concern.”
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1.1
This information is very general please delete paragraph “Persistent Organic
Pollutants (POPs) are a diverse group of organic chemical substances with
number of environmentally hazardous properties that include (i)
environmental persistence; (ii) global distribution in environmental matrices
including soil, water, air, biota; (iii) tendencies for accumulation in soil or
sediments and for bioaccumulation in living organisms including humans and
biomagnification in the food chains; (iv) high toxicity to both humans and
wildlife. With respect to their global environmental distribution and impacts,
an international treaty was adopted by the United Nations in 2001 and entered
into force 2004 the Stockholm Convention (SC) on Persistent Organic
Pollutants. Production and use of most of the POPs listed under the SC was
banned in the past decades but due to their persistence and other hazardous
features, POPs still represent a serious global problem (Bláha and Holoubek,
in press).”
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1.1
This is partly a repetition. Fuse with the text in the first paragraph of the
Chapter (p. 4).
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1.1
Please also include this point/ paradox from Kortenkamp et al. 2009 which
highlights how chemicals are assessed and managed today in the text.
Add “Given the current knowledge of mixture toxicity it is a paradox that,
with a few exceptions, chemical risk assessment as conducted by most
regulators and others today only considers the effects of single substances in
isolation, an approach that is only justified if the exposure to mixtures does
not bear the risk of an increased toxicity. This would be the case, for example,
if only one chemical of the mixture is toxic while the others are biologically
inert, or if empirical evidence showed that the joint action of chemicals is
typically not larger than the effect of the most toxic compound.”.
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1.1
Please also include this information from Kortenkamp et al. 2009 which
highlights the developments in our understanding of mixture toxicity
Add “During the last ten years, mixture toxicology has undergone a
remarkable and productive development. Whilst earlier experimental studies
have focused mainly on combinations of only two chemicals, a significant
number of well-designed and decisive studies have been carried out that
involve multi-component mixtures. Ecotoxicology has played an important
role in advancing mixture toxicology, with human and mammalian toxicology
slowly catching up. The planning, conduct and assessment of multicomponent mixtures is possible, with clear results. This has extended from in
vitro assays to in vivo studies and even to analyses of mixture effects on
biological communities. Multi-component mixtures were composed of both,
unspecifically and specifically, acting chemicals, with similar, and to a lesser
extent, dissimilar modes of action. The compounds in the mixtures belong to
several chemical classes. Among the most frequently studied groups are
pesticides, heavy metals, endocrine disrupters, PAHs and general industrial
chemicals.”
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1.1
This is fairly basic toxicology. Delete or shorten the text?
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2.1
Change first paragraph to “Toxic interactions and evaluation of potential
effects of complex environmental mixtures of chemicals has been on the
agenda of several POPRC meetings in the past. As Paragraph (b) of Annex E
of the Convention lists “hazard assessment for the endpoint or endpoints of
concern, including a consideration of toxicological interactions involving
multiple chemicals” as an element of the risk profiles to be prepared by the
Committee the objective of the discussions and the ensuing activities on this
topic has been to provide the Committee with a framework and an approach
for how they should assess and take such effects into account when evaluating
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new substances for listing in the Convention. Mixture toxicity has also been
on the POPRC following an invitation to provide comments on a draft
framework for risk assessment for combined exposures developed by the
WHO IPCS The toxicological interactions are subject of many parts of the
Stockholm Convention. For example Article b) of Annex E states that POPRC
should consider toxicological interactions involving multiple chemicals when
assessing the hazard of chemicals undergoing evaluation for listing in the
Convention. Toxicological interactions are may be relevant for other also for
other parts of the POPRC evaluation of new chemicals e.g. the consideration
of toxicological interactions may be relevant also under Annex D e) , Annex E
d), e) and f) and Annex F b) iv). “.
Please explain in the text which meetings and refer to the relevant documents.
This may be written even shorter/ simpler and may be captured in more detail
elswhere in the text. See comments and new proposed structure for Chapter 3.
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2.1
Change paragraph to “This work has mainly centered on toxicological
interactions between POPs, although as mentioned humans and wild
organisms are exposed to a complex mixture consisting not only of POPs but
also other types of hazardous chemicals.”
The sentence “Thus and that POPRC in its work may have to consider toxic
interactions between POPs and other types of pollutants i.e. where such data
exist and where it may be considered relevant for the evaluation of new
chemicals.” should be captured elswere in the text. Please move to chapter 3.
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2.1
Delete the sentence “The key was to select an endpoint or endpoints generally
acceptable for the potential multiple exposure and description of synergistic
and additive effects.”.
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2.2
Change title to “Scope and aim of the draft”.
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2.2
Add “Additivity, antagonism and synergism are three of the possible effects
that may have to be considered by the POPRC in their evaluation of new
substances under the Annex D, E and F criteria.
Based on the intersessional work on toxicological interactions contained in
documents UNEP/POPS/ POPRC.7/INF/15 and UNEP/POPS/
POPRC.7/INF/16 and the possible conclusions in document UNEP/POPS/
POPRC.7/INF/17 POPRC7 decided to establish an ad hoc working group to
develop, intersessionaly, a draft approach to consideration of toxicological
interactions when evaluating chemicals proposed for listing in the annexes to
the Stockholm Convention on Persistent Organic Pollutants (Decision
POPRC-7/9 on toxic interactions). The objective is to establish a framework
within which toxicological interactions may be considered with the aim of
develop a more systematic approach for addressing toxicological interactions
of nominated chemicals.”
Some of the points here are taken from UNEP/POPS/POPRC.4/INF/3
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2.2
Please fill inn according to your understanding of the discussion in the
working group.
Our suggestions:
The working group on the basis of their discussion decided to pursue the
following approach:
 The guidance document should reflect the guiding principles set by the text
of the Convention
 The guidance document should be developed as a manual that can assist
POPRC in identifying situations where toxicological interactions may be
relevant to their work.
 The guidance document should be developed as a manual that can assist
POPRC in understanding how toxicological interactions may be taken into
account.
 The guidance document should help increase the general awareness and
the knowledge of toxicological interactions among Committee members.
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 The guidance should be considered a "living" document that must be
updated at regular intervals.
Add “In this work the following broad issues were addressed identified:” and
please fill in according to your understanding of the discussion in the working
group.
Add “In this work the following challenges were identified:” and fill inn
according to your understanding of the discussion in the working group.
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2.2
Please delete the following to avoid unneccessary repetition in the text. This
information is already captured elsewhere:
“There are essentially two main approaches that can be used to estimate the
toxicity arising from simultaneous exposure of more than one chemical. These
are known as concentration (or dose) addition and independent action. The
selection of the appropriate method for assessing the effects or risks from
combined exposure depends to a large extent on whether the component
substances of the mixture exert their toxic effects by the same mode of action
or not.
Overall, basic methods are currently available for assessing or predicting the
effects from simultaneous exposure to multiple chemicals. These are
concentration (dose) addition and independent action. The choice of method is
dependent on the mode of action of the chemicals and the relevant physicalchemical, environmental, eco-toxicological and toxicological properties of
evaluated substances.”
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2.2
Please delete “Our model approach” and integrate this information in the text
in Chapter 3
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3
Move this chapter after the chapter "Methods for prediction of effects from
compined exposure" and rewrite. Please simplify and adapt the text to the
practical approach used by POPRC in its evaluation of new candidates for
listing taking into account the guiding principles set by the text of the
Convention, in particular paragraph b) of Annex E. See also separate
document with general comments for further information on this topic.
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3
Proposal for new outline for this chapter:
3.1. Guiding principles for the Committees work based on the present day
knowledge of mixture toxicity
This chapter should in a simplified way present the general conclusions and
the most appropriate approaches whereby POPRC may assess/ take into
consideration mixture toxicity based on the present state of knowledge with
reference to UNEP-POPS-POPRC.7-INF-15, UNEP-POPS-POPRC.7-INF-16
and UNEP-POPS-POPRC.7-INF-17 and other relevant studies such as
Kortenkamp et al. 2009, WHO 2009 etc. Important points to cover are the
following:
 Humans and animals are constantly and simultaneously exposed to a
complex mixture of chemicals consisting of persistent organic pollutants
and other classes of chemical substances.
 How to evaluate and predict the toxicity of chemicals is a major challenge
in toxicology, but our understanding of such effects is constantly growing
as new scientific findings are being published and has developed
significantly in the past ten years.
 Combined effects of POPs present in remote areas may be of extremely
high concern for the biological community, particularly for top predators.
 The effects of chemicals in a mixture may be additive or interactive
 Additive effects occur when chemicals have a similar mode of action
(concentration addition) or when their mode of action is different but the
substances elicit the same response (response addition).
 Interactive effects arise when two chemicals have the opposite effect of
each other (antagonism) or when they potentiate each other and produce a
stronger effect than each of the chemical produces independently
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(synergism).
 There is decisive evidence that mixtures composed of chemicals with
diverse modes of action also exhibit mixture effects when each component
is present at doses equal to, or below points of departure (Kortenkamp et
al. 2010).
 Taken together both the currently available scientific evidence as well as
pragmatic considerations support the idea of adopting dose (concentration)
addition as the preliminary default concept for the assessment and
prediction of mixture effects.
 The composition of environmentally relevant mixtures of chemicals such
as those found in Arctic biota and environment are highly complex and
vary both in time and space depending on release/ emission patterns and
are best understood by consulting a broad spectrum of scientific peerreviewed literature, reports and risk assessments.
 The methods for assessing mixture toxicity employed by POPRC needs to
be revised/ updated regular intervals to reflect the current scientific
development in the field.
3.2 Approaches for assessing mixture toxicity available to the POPRC
This chapter should contain an introductory text that describes the work
process in the POPRC and that highlights that POPRC in developing risk
profiles and risk management evaluations largely draw on information from
other sources such as reports, risk assessments and peer-reviewed scientific
publications rather than generating new information themselves. This text
should in our view emphasise that the main objective of the guidance is to
provide the POPRC with a manual that can help them understand when and
how they may consider toxicological interactions when a) such data are
available for the chemical in question from scientific peer-reviewed
publications, reports risk assessments and 2) what basic approaches to employ
when available data suggests that mixture toxicity may be a concern but no
predictions have yet been made. The text from section 4.8 largely and the final
conclusion in chapter 6 captures this.
3.3 Practical consideration of mixture toxicity in the evaluation of new
chemicals
This chapter should describe the guiding principles/ framework set by the text
of the Convention and identify where in the evaluation process POPRC
should/ may/ have to consider mixture toxicity and by using practical
examples from already listed POPs what types of available data may be
considered in each step/ circumstance. In our view these parts of the text of the
Convention may be relevant:
Article 1
Annex D, paragraph e) and section 2)
Annex E, in particular paragraph b), but mixture toxicity may also be relevant
d), e), f) plus the final conclusion/ statement of reason for concern on "whether
the chemical is likely, as a result of its……"
Annex F, paragraph a) ii), c)
3.4 Challenges and limitations of the proposed approach
This chapter should capture the main challenges and limitations of the current
approach and mixture toxicity in general
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3.1
We belive that the text on each topic should be highly informative and rather
short and and consise. Preferably ¼ - ½ page or shorter. References for
further information and reading may be provided.
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3.2
It is perhaps possible to fuse 3.2 and 3.3.
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3.1
This information is useful, but may fit better somewhere else in the text. Move
to Chapter 1 i.e. the general introduction or somewhere else?
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Change title to “Relevant information on toxicological and ecotoxicological
properties of POPs and their mixtures”.
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3.2
Please move this section/ capture the points covered by this section in the new
chapter "Challenges and limitations". See also suggested point under 3.1
"Guiding principles for the Committees work based on the present day
knowledge of mixture toxicity".
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3.2
To avoid repetitions in the text please delete the consequtive paragraphs of
this section.
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3.3
It is our view that a full risk assessment is outside the scope of the
Convention. Please delete this section. It is not relevant to the evaluations
undertaken by POPRC.
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4
Move this chapter forward so that it in the revised version becomes chapter 3.
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4.1
Not directly relevant in this context. The information may also confuse the
reader. Please delete the following two paragraphs: “Traditionally, the
legislation for the control of chemical substances focuses on the assessment of
the hazard and the risk of individual chemicals. Procedures for setting
chemically based Environmental Quality Criteria or Objectives (EQO), as well
as the Environmental Quality
Standards (EQS) are usually developed for individual chemicals. However, in
the real environment, living organisms – human and wildlife - are seldom, if
they are, exposed to individual chemicals. For instance, surface water bodies
as well as terrestrial environments are usually contaminated by chemical
emissions of different origin (industrial, agricultural, urban, etc.) and nature.
In many cases, chemicals are used as formulations or technical mixtures of
congeneric or non-congeneric substances.”
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4.1
Use ” . Chemicals used as commercial formulations” instead of ”Chemicals
used as technical mixtures”
Be consistent with the terminology and use the terminology that best describes
all types of industrially produced prefabricated chemical mixtures.
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4.1
Change paragraph C to “C. Chemicals likely to be present in the environment
as the result of emissions/ releases from multiple anthropogenic sources and
activities: An environmental system may be exposed to complex mixtures of
chemicals resulting from the combination of all the emissions of human
activities (e.g. mixture present in a river as a result of the emissions in the
hydrographic basin). These kinds of mixtures results from local, regional and
global emissions of chemical. Although they may be characterized based”
Please delete “in a given territory” to make it clear that the emissions are not
only local.
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4.1
Change paragraph E to “E. Metabolites and degradation products. Complex
mixtures of products of abiotic and biotic transformations of chemicals
emitted and released to the environment.”
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4.3
This section should be placed after section 4.4.
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4.3
This may have been true in the early days ecotoxicology but things have
changed and ecotoxicologists now consider the death of endangered species or
keystone species as unacceptable from a prespective of ecosystem health.
Please modify the statement accordingly.
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4.5
Replace “Assessing effects of POP mixtures” with “Commonly employed
methods for assessing additive effects”.
These approaches are general and not specific to POPs
Norway
Reforumalte beginning of 4.5.1 as follows:
a) “Toxicity Equivalence Factors
The concept of TEF (Toxicity Equivalence Factors) is a pragmatic approach
for comparing and combining the effects of the PCDD/F and the so-called
“dioxin-like” PCBs that act via a common mechanism by binding to the aryl
hydrocarbon receptor (AhR)
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It is based on the hypothesis of concentration (or dose) additivity, referred to
the effects of 2,3,7,4-TCDD (TEF=1). However, it should be understood that
the TEF concept is based on a number of assumptions and has many
limitations the first being that it is only applicable for predicting combined
effects of chemicals that are AhR agonists
Secondly, the approach only covers one endpoint of toxicity. In reality the
toxic response of these chemicals is extremely complex, involving dermal
toxicity, immunotoxicity, carcinogenicity, adverse effects on reproduction,
development and endocrine functions. Information on these effects are not
captured.,
TEF values have been developed for mammals, birds and fish (Table 1; Van
den Berg et al., 1998). TEFs represent a low-confidence interim approach to
describe the highly variable toxicities of dioxins and dioxin-like compounds.
They are set using single compound studies, therefore, they have a
comparative value, but the scientific bases for using them for predicting
combined effects are weak.
As stated above, the comparison is only based on the Ah receptor response
and does not account for the extreme complexity of toxicological response to
POPs. Therefore caution must be excerted when including new compounds
into TEF assessment. Possible deviations from additivity require further
investigation in order to assess the extent to which they undermine the
usefulness of the TEF concept (Van den Berg et al. 1998).”
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4.6
Please shorten and fuse with "new" b) a)b)Toxic Units (TUs) above.
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4.6.2
Please delete this chapter and shorten/ change the text and fuse with paragraph
b) Toxic Units (TUs) above.
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4.6.2
Move to the proposed new chapter "3.5 Challenges and limitations of the
proposed approach" or a similar chapter
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4.8
See comments already provided in chapter 3. Please move to the new chapter
3.3.
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4.9
This chapter in our view provide too detailed and too much information.
Please extract the most important information and fuse with previous sections.
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4.9
This point e.g. that the currently available methods assessing mixture toxicity
today may fail to predict the real impact of toxic exposure because they only
refer to to a single toxicological end-point i.e. one effect and one organism
may be moved to the proposed chapter 3.3. limitations/ challenges.
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4.9
This point may be captured elswhere e.g. by movein the information to the
proposed chapter 3.3. limitations/ challenges.
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4.9
Move to chapter 6. conclusion
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4.10.1
Please delete this section. The point has already been made in previous parts
of the text.
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4.10.2
The text in this section specifically refer to one of the case studies and does
not contain information of such a general character that it should be included
in this document. Please delete.
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4.10.3
The text in this section specifically refer to one of the case studies and does
not contain information of such a general character that it should be included
in this document. Please delete.
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4.10.4
The key points higlighted in this section may be captured in a simpler and
more consise manner in the conclusions in chapter 6.
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4.10.5
We do not belive this text to be directly relevant to the topic of mixtue
toxicity. Please delete this section.
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4.11
Please move to Appendix
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5
Move to the new proposed chapter 3.3 Challenges and limitations of the
proposed approach
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5
The following section (starting “For the toxic interactions assessment we need
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few sets of information:”) may in our view be deleted.
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Sweden
6
The information provided in this section is good and is along the lines of what
we envisage for the recommendations made in Chapter 3 i.e. simple and
straight forward. We therefore propose to move most of this text to the present
Chapter 3 "Approaches for assessing effects of chemical mixtures and a
general recommendation for their use by POPRC". The conclusion of the final
version of this document may be much shorter and could perhaps highlight a
few main points e.g. that the available methods and the current development in
the field will/ may allow POPRC to consider mixture toxicity in future
evaluations of chemicals for listing, but that there still are some challenges
when assessing mixture toxicity (such ad e.g......) and that this guidance
should be considered a "living" document that needs to be updated at regular
intervals considering the development in the field of mixture toxicity.
General
Our main concern is that the description on page 11, regarding effects from
mixed exposure of substances with different MoA in levels under their
individual effect levels, should be revised. Kortenkamp et al., 2009 „State of
the art report on mixture toxicity“ displays several examples were chemicals
with different MoA are co-exposed below their NOEC causes adverse effects
(Table 6.4, p. 146, Part 1).
United States
The concept note document is a reasonable starting point for further
developing the chlorinated paraffins case study. However, it is unclear from
the note whether or not the document being drafted applies only to the
chlorinated paraffins or whether it is intended to apply to other chemical
groups as well. If the note is intended to apply to any potential group, then
note lacks in meaningful details --- particularly on how the science assessment
will inform the listing process.
United States
5
Introduction
“Little investigation” >> compared to humans, there is a vast amount of
literature on chemical mixtures in animal studies - “little investigation“ is not
a good characterization of those studies.
United States
6
Introduction,
last paragraph
This line of reasoning is difficult to follow and we suggest this discussion be
expanded. Why only two? Further, the document should define REACH and
the Water Framework Directive -- or at least provide references for these
programs for those who are unfamiliar with them.
United States
7
2.1
“The toxic interactions, evaluation of potential effects” >> The document
needs to clearly define what is meant here. The meaning that is becoming
common-place is that toxicological intereactions are effects or reponses
greater or less than expected under some definition of additivity. Is that the
definition intended here? Or is the document inteded to also discuss
additivity? If so, we would use the term “joint toxic action“ to encompase
both additivity and toxic interactions. The document should be very clear
about this.
United States
7
2.1
“It was mentioned above that drawn attention have to be given to the fact that
human and wild organisms are exposed to a complex mixture consisting …”
>> In general, the text here seems to need technical editing.
United States
7
2.1
“based on the framework developed” >> What framework? Please elaborate.
United States
8
2.1
“(ii)
Information on effects of complex chemical mixtures” >>
For truly complex mixtures of hundreds of chemicals, component-based
approaches such as additivity or departures from additivity (e.g., synergism)
may not work well. In those cases, we need whole mixture studies with
“sufficient similairty“ analyses to evaluate the extrapolation to tox results on a
tested mixture to another environmental mixture of concern. See, for
example, the group of 6 papers [below] on sufficient similairty of drinking
water disinfection byproducts.
Bull, R.J., L.K. Teuschler, G.E. Rice. 2009a. Determinants of Whether or Not
Mixtures of Disinfection By-Products are Similar. J. Toxicol. Environ. Health.
Part A. 72(7): 437- 460.
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Bull, R.J., G.E. Rice, L.K. Teuschler, and P.I. Feder. 2009b. Chemical
Measures of Similarity among Disinfection By-Product Mixtures. J. Toxicol.
Environ. Health. Part A. 72(7): 482 – 493.
Feder, P.I., Z. Ma, R.J. Bull, L.K. Teuschler, K.M. Schenck, J.E. Simmons,
and G.E. Rice. 2009a. Evaluating Sufficient Similarity for Disinfection ByProduct (DBP) Similar Mixtures via Multivariate Statistical Procedures. J.
Toxicol. Environ. Health. Part A, 72(7):468 — 481.
Feder, P.I., Z. Ma, R.J. Bull, L.K. Teuschler, G.E. Rice. 2009b. Evaluating
Sufficient Similarity for Drinking Water Disinfection By-Product (DBP)
Mixtures with Bootstrap Hypothesis Test Procedures. J. Toxicol. Environ.
Health. Part A, 72(7):494 — 504.
Rice, G.E., L.K. Teuschler, R.J. Bull, J.E. Simmons, and P.I. Feder. 2009.
Evaluating the Similarity of Complex Drinking Water Disinfection ByProduct Mixtures: Overview of the Issues. J. Toxicol. Environ. Health. Part
A, 72(7):429 — 436.
Schenck, K.M., M. Sivaganesan, and G.E. Rice. 2009. Correlations of Water
Quality Parameters with Mutagenicity of Chlorinated Drinking Water
Samples. J. Toxicol. Environ. Health. Part A, 72(7):461 — 467.
United States
9
2.2
“Overall, basic methods are currently available for assessing or predicting the
effects from simultaneous exposure to multiple chemicals. These are
concentration (dose) addition and independent action.” >> Although these are
commonly used, there are other appraoches including integration of these 2
methods. e.g., Rider and Leblanc, 2005; Teuschler et al., 2004 and the
Interaction based hazard index in U.S. EPA 2000 mixtures supplementary
guidance and Hertzberg and Teuschler , 2002
United States
9
2.2
“Our model approach:” >> also need “summary measures“ that characterize
the whole mixture, not just selected components (see 6 papers referenced
above on sufficient similarity for examples)
United States
11
3.2
“common mode of action” >> The document needs to define common mode
of action as opposed to common “mechanisim of action“ and “common
adverse outcome“ – the latter being coined in the National Academies of
Science 2008 publication on phthalates. Reference to NAS 2008 is important
here as its influence is significant in the chemical mixtures field. If using
common adverse outcome, regardless of pathway of toxicity, then the dose
addition method may provide a conservative estiamte. The other way
additiivty has been“verified“ is by using empirical data – e.g., look at Earl
Grey’s studies on phthatlates.
United States
11
3.2
“critical exposure” >> The document should define this term – the reader
might assume the meaning is a health based toxicity value, e.g., the U.S.
EPA’s Refernce Dose (RfD) which is used in the equation below but not
defined and referenced.
United States
12
3.2
“In spite of the lack of scientific foundation, Eq. (1) offers a practical way to
account for an increased risk when more contaminants are present” >> Based
on dose addition theory, so does have a scientific foundation. See e.g.,
Finney, 1971.
United States
12
3.2
“assumed to be additive” >> evaluated using response addition
United States
12
3.2
“For the evaluation of human risks and toxic interactions in human body is
very important to know the results from well designed epidemiological
studies.” >> although not usually available.
United States
12
3.2
“Some of the limitations of these studies include the limited sensitivity of
some study designs and the difficulty in the detection of small effects.” >> We
think the biggest problem is the exposure assesement, including the potential
for exposure mis-classification. Confounding factors and effect modification
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(epi. version of toxicological interactions) are also issues for epidemiologic
studies.
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12
3.2
“Seveso, Italy, PCB contamination” >> Should be Seveso, Italy, TCDD
contamination. This was primarily a TCDD exposure, not PCBs. Provide a
citation, e.g., Mocarelli, et. al. papers. Also need citations for the other
examples in this sentence.
United States
12
3.3
“joint toxic action”>> Again, we don’t know the definition here. If greater or
less than additive toxicological interactions, then use ATSDR 2004 along with
numerical interaction based hazard index in EPA 2000 and Hertzberg and
Teuschler 2002.
United States
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3.3
“In consideration to the above is suggested the following model approach:” >>
This whole section needs alot of work so that the approach is well laid out.
The document seems to bar “reinventing the wheel“ with this document.
“b.
Estimating of the exposures: modelling or measurement
approaches”>> The document will need discussions of the application of
kinetic models to POPs.
United States
United States
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4.1
“risk for man” >> risk for humans
United States
17
4.1
“chemicals that cause similar effects” >> chemicals that cause common
adverse outcomes regardless of the toxicity pathway
United States
20
4.5
“Table 1; Van den Berg et al., 1998” >> Update this to the new WHO 2005
TEFs and other updated information in his 2006 paper.
United States
20
4.5
“additivity” >> dose addition
United States
21
4.6
“Vighi and Villa, 2011” >> expand here.
United States
22
4.6
“by equation 7” >> by equations 6 and 7
United States
25
4.9
“Very important question is how many component of the mixture should be
considered. Theoretically, a POP mixture of global concern could be
composed by thousands of chemicals. However, most of them could be
present at toxicologically negligible concentrations” >> We don’t understand
how you can not include whole mixture methods in this document.
United States
25
4.9
“Therefore, a threshold of concern should be set up as a function of the actual
toxic potency (TUs or HQ) in the mixture instead of simply related to toxicity.
A TU value of two orders of magnitude lower than the most dangerous
chemical in the mixture could be a reasonable proposal for a threshold of
concern.” >> In some cases, chemicals with less than 0.1 Hazard Quotient are
dropped from a Hazard Index calculation (ATSDR, 2004).
United States
25
4.9
“(Crofton et al., 2005). For example, the effect of acethycolinesterase
inhibitors (e.g. organophosphorous insecticides) is increased in presence of
DDT (Thompson, 1996). Other potential synergistic effects need to be
investigated more in depth and must be studied case by case.” >> See the
Boobis, et. al. 2011 paper that looks at low dose synergy and shows that from
the few data available,synergy would be less then 4-fold larger than expected
under additivity.
United States
32
4.11
“Boobis et al (in press).” >>Published in 2011
United States
34
5
Add “- kinetics, e.g., elimination rates, partition coefficients such as fat:blood
ratios, etc.”
United States
35
5
“Probably the most serious effect of environmental pollutants/chemicals or
any mixtures of chemicals is the immunotoxicity,” >> This should be restated.
Personal judgment is likely not shared universally.
United States
35
5
“Key question of this assessment is what is the maximum extent to which
additive models would underestimate the toxicity of a mixture at exposure
levels of interest?”>> See the Boobis, et. al. 2011 – shows factor of 4-fold or
less.
General
The extensive limitations of all the methodologies reinforce the need to design
the document as a summary of the present concepts around assessing
mixtures, and rely on peer-reviewed studies for the relevant topics at hand in
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the operational process of the POPRC evaluation.
IPEN
General
The current document is inappropriate as a guidance doc which should look at
the tasks of POP RC and then propose where and how the issue of
toxicological interactions should be considered. This could include:
- improving the risk profile with available information on toxicological
interactions. Here the clear purpose for POP RC would be to get more detailed
information in the context of deciding on a potential future POP.
- monitoring the effectiveness of reducing exposures to current POPs, e.g.
mixture effect investigations in environmental matrices to decide if further
efforts in elimination and reductions are needed
IPEN
2
3.3
This is inappropraite in the context of POP RC and should deleted
IPEN
2
4
This chapter should be deleted as it does not provide any real guidance for
POP RC and is therefore inappropraite for a guidance document.
IPEN
3
4.8
This is not a worst case
IPEN
3
5
In the title, replace “Assessment” by “Evaluations”.
IPEN
3
Appendix 2
This was an informal workshop hosted by the european chemical industry, it is
inappropriate to include in this document.
IPEN
4
1.1
Pesticides is the generic term that incldues insetcidies, herbicides,fungicides,
nenaticides, miticides and others
Use of nitrate fertilisers can increase the levels of nitrates and nitrites in food.
Please thus rephrase the sentences as follows: Many of our food crops are
produced using pesticides and synthetic chemical fertilisers.. We produce meat
products through extensive use of antibiotics and in some countries growth
stimulants as well. [….]Most of these compounds have not been adequately
tested for human toxicity.
IPEN
4-5
1.1
Please rephrase the sentences as follows: With respect to their global
environmental distribution and impacts, the Stockholm Convention (SC) on
Persistent Organic Pollutantswas adopted by the United Nations in 2001 and
entered into force in 2004.Production and use of most of the POPs listed under
the SC was banned in the past decades. However, in recent years, more
substances in current use or recent use have been added to the treaty and there
are other POPs still in use that have not yet been added. All together, POPs
still represent a serious global problem due to their persistence and other
hazardous features (Bláha and Holoubek, in press).
IPEN
5
1.1
Please rephrase the sentences as follows: However, iIn the real environment,
living organisms are seldom, if they areat all, exposed to individual chemicals
(Vighi and Villa, 2011). For instance, surface water bodies as well as
terrestrial parts of environment are usually regularly contaminated by
chemical emissions of different origin (e.g., industrial, agricultural, urban,
etc.) and nature. Food items often contain multiple pesticide residues. In many
cases, synthetic chemicals are used as formulations or technical mixtures of
congeneric or non-congeneric substances.
IPEN
6
1.1
Please delete “and little investigation of this question even in animals.” – it is
not correct see examples of synergy studies.
IPEN
6
1.1
“ […] health outcomes are not specific to route of exposure” is not correct for
all contaminants.
IPEN
7
1.1
Replace “The first and major policy fact is: there are two lines of tackling
mixture problems: regarding sources (in short: like REACH) and regarding
compartments (like” with “The first and major policy fact is: there are two
lines of tackling mixture problems: regarding sources of exposure from
manufacturing, downstream use and use of products (which are addressed in
chemicals laws such as REACH and other legislation concerning production
and products) and regarding the “receiving” compartments such as the
environment as well as wildlife and humans ( which are addressed in
environmental legislation e.g. in the EU’s”. Not sure the policy comment is
useful in this document. It seems out of place and irrelevant. Policy options
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should not be presented here.
IPEN
7
1.2
Add “Harold I. Zeliger, Human Toxicology of Chemical Mixtures, Toxic
Consequences Beyond the Impact of One-Component Product and
Environmental Exposures, 2nd Edition July 7, 2011” to references.
IPEN
8
2.1
Add “if data is available” to the title of bullet point 2.
IPEN
9
2.1
Replace “Availability of relevant information for decision making process”
with “Data supporting interactive effects between a candidate substance and
another POP (or another substance) should increase the likelihood of
exercising the precautionary approach in Committee decision-making”
IPEN
9-10
2.1
Replace “In general, guidance for evaluation of toxic effects and interactions
will be very useful tool for the Committee members and its work. The
Guidance can be prepared based on the use of the approaches mentioned and
summarized in both Case studies and can be focused on the summary of
relevant approaches and methods available for the evaluation of toxic
interactions (WHO, OECD, EU, etc.).” with “(i)
The Committee
consideration of interactive effects depends on the existence of appropriate
and adequate data. Considering the current state of the field, it may not be
possible to develop a detailed guidance document. Instead, a document can be
prepared that summarizesthe concepts and approaches in both Case studies
along with relevant approaches and methods available for the evaluation of
toxic interactions (WHO, OECD, EU, etc.).”
IPEN
10
2.2
This conceptual approach describes how investigators might approach this
topic. However, it seems far beyond the scope of the POPRC.
IPEN
10
2.2
As so much depends on data availability to answer the questions above
including data on real world mixtures. As this is not available for the vast
majority if not all species inclding humans how is the POPRC to assess even
the scope of the mixtures it should consider.
IPEN
10
2.2
The selection of these models is not the key question in the work of POP RC.
Given that the knowledge on the mode of action is often missing the CA is
often accepted as default approach. However, in practice the information (dose
response curves, exact composition of mixtures) will simply not be available
to carry out these calculations.
IPEN
10
2.2
Add “Both approaches have severe limitations and currently there is
considerable disagreement over the various methodologies to assess mixtures.
While methodologies for assessing/estimating the combination effects of
chemicals are being developed and used, as yet there is no systematic,
comprehensive and integrated approach. This is confounded by the severe lack
of data available on real world mixtures, their chemical effects, and species
exposure, as well as the growing dissatisfaction with the reliance on NOELs
and NOECs in regulatory risk assessment
Professor Kortenkamp, author of the 2010 report for the European
Commission notes regulators are minimizing risks of the ‘toxicity of mixtures’
as they depend on NOELs and NOECs and that these are not suitable for use
for risk assessments and regulatory guidelines. He notes ‘they do not describe
a “safe” concentration and differ fundamentally from true No Effect
Concentrations, although they are frequently equated with the latter.’ (State of
the Art Report on Mixture Toxicity Final Report Executive Summary 22
December 2009 p19)
The use of NOEC and LOEC data has been severely criticised since the 1990s
(Chapman et al 1996, Warne& van Dam 2008, Landis & Chapman 2011,
Jager 2012) yet these data continue to be generated and deemed acceptable by
regulatory authorities nationally and internationally. The problems associated
with NOEC and LOEC data include the misleading nature of their names; the
inappropriateness of the method by which they are calculated; and the validity
of the statistical methods used.”
IPEN
10
2.2
The conceptual approach needs to acknowledge limitations and disagreement
over methodologies and the data on which they are based.
Add following Referemces: “Warne M & van Dam R 2008. NOEC and LOEC
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data should no longer be generated or used. Australasian Journal of
Ecotoxicology 14(1), 1–5. (published October 2009)
Jager T. Bad habits die hard: The NOEC's persistence reflects poorly on
ecotoxicology. Environ Toxicol Chem. 2012 Feb;31(2):228-9. doi:
10.1002/etc.746.
Chapman, P. M., Cardwell, R. S. and Chapman P.F., 1996, A warning:
NOECs are inappropriate for regulatory use. Environmental Toxicology and
Chemistry, 15, 77-79.
Landis, W., G. and Chapman, P. M., 2011, Well Past Time to Stop Using
NOELs and LOELs. Integrated Environmental Assessment and Management,
7 (4), vi-viii.
Fox DR. A Bayesian approach for determining the no effect concentration and
hazardous concentration in ecotoxicology. Ecotoxicol Environ Saf. 2010
Feb;73(2):123-31.”
IPEN
11
2.2
I not understand how this will actually work in practice.eg Much of the data is
not available for the contaminants involved.
Does this mean the Arctic? What organism?
This is out of the scope of POPRC’s work. If countries submitting dossiers for
new nominations include work on mixtures, the POPRC needs to understand
how this was developed and the limitations of the methodology but it is highly
unlikely POPRC would undertake this work itself.
IPEN
11
2.3
These need to be identified.
IPEN
12
3.1
Replace “long life” with “chronic or transgenerational” and add “Some types
of toxicities such as neurodevelopmental and endocrine, may depend on the
timing of the exposure, which is particularly relevant for exposure to the
foetus and children. Other factors include age and developmental status, sex,
health, nutritional and hormonal status.”
IPEN
13
3.1
Add “Remobilization of POPs as a consequence of climate change is already
apparent and raising additional concerns.”
IPEN
13
3.1
Add “and metabolic disorders” and “Codru et al 2007.”.
IPEN
13
3.1
Add “(REF : Codru N, Schymura MJ, Negoita S, The Akwesasne Task Force
on the Environment, Rej R, Carpenter DO. 2007. Diabetes in relation to serum
levels of polychlorinated biphenyls and chlorinated pesticides in adult Native
Americans. Environ Health Perspect 115:1442-7.)”.
IPEN
13
3.2
What if they are metabolites of other components with different physical
properties?
IPEN
13
3.2
Delete “Although the exposure ratediffers for each contaminant, the impact of
this combined exposure must be assessed in a human healthrisk assessment.”.
The treaty gives equal weight to environmental impacts.
IPEN
13
3.2
It seems to important to note that this assumes chemical pairs or two-chemical
combinations only. That is an important limitation/assumption to be clear
about, particularly as both humans and wildlife carry a wide range of chemicsl
cotaminants in their bodies.
IPEN
13
3.2
It seems that it would be helpful to explain that this is essentially combining
the results of two separate evaluations. This means that the uncertainty in each
evaluation is also combined. How is this handled? It seems it should also be
noted that there is minimal supporting data from actual mixtures which would
enable some sort of comparison and support for the various assumptions
employed.
IPEN
14
3.2
Replace “In contrast, the combined effect of contaminants showing response
additionwill not exert a negative health risk appraisal when the separate
exposures do notexceed the critical exposure (Wilkinson et al.,2000), “ with
“However, disagreement exists over the combined effect of contaminants
showing response addition, while some argue that this will not exert a negative
health risk appraisal when the separate exposures do not exceed the critical
exposure (Wilkinson et al.,2000), others (Kortemkamp 2009) stress there is
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evidence that dissimilarly acting agents, when combined at doses below their
NOAELs, may also produce significant mixture effects.”
Kortemkamp 2009: „There is evidence that dissimilarly acting agents, when
combined at doses below their NOAELs, may also produce significant mixture
effects” Cites a variety of studies that directly contradict the conclusion cited
in the text
What about cases of toxicity overlap where there is joint toxicity but no
simultaneous exposure? This is clearly relevant to carcinogenicity: promotion
and initiation...
IPEN
14
3.2
It is essenial to provide examples of studies demonstrating additive and
synergistic interractions,
Add “Yet, there are many studies demonstrating synergistic action of real
world contaminants. For example;
 Zhou et al assessed toxicities for a pyrethroid (cypermethrin) and an
organophosphate insecticide (chlorpyrifos) individually and in
combination. A series of tests were conducted on different responses
(acute, chronic, behavioral) of earthworms of species Eisenia fetida
andrei in the ecological risk assessment of these pesticides. The results
showed that the toxicity of the mixture of cypermethrin and chlorpyrifos
was significantly higher than either of these pesticides individually,
especially on the earthworm’s chronic responses.
REF: Zhou S P, Duan C Q, Michelle W H G, Yang F Z, Wang X H, 2011.
Individual and combined toxic effects of cypermethrin and chlorpyrifos on
earthworm. Journal of Environmental Sciences, 23(4): 676–680
 Christiansen et al examined the effect of combined exposure to the
selected chemicals on malformations of external sex organs and
observed the responses were greater than would be predicted from the
toxicities of the individual chemicals. When the four chemicals were
combined at doses equal to no observed adverse effect levels estimated
for nipple retention, significant reductions in AGD were observed in
male offspring. They concluded that because unhindered androgen action
is essential for human male development in fetal life, these findings are
highly relevant to human risk assessment. Evaluations that ignore the
possibility of combination effects may lead to considerable
underestimations of risks associated with exposures to chemicals that
disrupt male sexual differentiation.
REF: Sofie Christiansen, Martin Scholze, Majken Dalgaard, Anne Marie
Vinggaard, Marta Axelstad, Andreas Kortenkamp, and Ulla Hass, Synergistic
Disruption of External Male Sex Organ Development by a Mixture of Four
Antiandrogens Environ Health Perspect 117:1839–1846 (2009)
 Laetz et al examined mixtures of organophosphate and carbamate
pesticides commonly detected in freshwater habitats that support
threatened and endangered species of Pacific salmon (Oncorhynchus
sp.). They measured brain AChE inhibition in juvenile coho salmon
(Oncorhynchus kisutch) exposed to sublethal concentrations of
individual organophosphates and carbamates. They observed addition
and synergism, and noted several combinations of organophosphates
were lethal at concentrations that were sublethal in single-chemical
trials.
REF: Cathy A. Laetz, David H. Baldwin, Tracy K. Collier, Vincent Hebert,
John D. Stark, and Nathaniel L. Scholz The Synergistic Toxicity of Pesticide
Mixtures: Implications for Risk Assessment and the Conservation of
Endangered Pacific Salmon Environ Health Perspect 117:348–353 (2009)
 Silva et al tested multicomponent mixtures of xenoestrogens at
concentrations below individual NOEC or EC01 level and concluded that
estrogenic agents are able to act together to produce significant effects
when combined at concentrations below their NOECs. They note that
hazard assessments that ignore the possibility of joint action of estrogenic
chemicals will almost certainly lead to significant underestimations of risk.
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REF: Silva, E., Rajapaske N., & Kortenkamp A., Something from “Nothing” –
Eight Weak Estrogenic Chemicals Combined at Concentrations below NOECs
Produce Significant Mixture Effects Environ. Sci. Technol. 2002, 36, 17511756
 Hayes et al (2006a) examined the effects of four herbicides (alachlor,
atrazine, metolachlor, nicosulfuron), three insecticides (cyfluthrin,
cyhalothrin, tebupirimphos), and two fungicides (metalaxyl and
propiconazole) alone or in combinations, on metamorphosis, time to
metamorphosis, and gonadal differentiation in northern leopard frogs.
They found that the mixtures had much greater effects than individual
pesticides in inhibiting larval growth and development..
REF : Hayes TB, Case P, Chui S, Chung D, Haefele C, Haston K, Lee M, Mai
VP, Marjuoa Y, Parker J, Tsui M. 2006a. Pesticide mixtures, endocrine
disruption, and amphibian declines: are we underestimating the
impact? Environ Health Perspect 114(suppl 1):40-50.
IPEN
15
3.2
If synergy is ignored, then that should clearly be stated in assumptions... and
clearly justify ignoring the peer-reviewed studies that demonstrate it using
listed POPs. A range of exmples of studies demonstratig synergy is needed in
this section.
IPEN
15-16
3.2
Delete “As a simplified approach to dose addition, the different Risk indices
(ratio of exposure to critical exposure value) are added up, while the criterion
for ‘possibleunacceptable human health risk’ is:
(exposure1/ RfD1) + (exposure2/ RfD2) + . . . + (exposuren/ RfDn) = 1 [1]
Where:
exposure1, exposure2,...., exposurenis exposure to contaminant 1, 2, . . ., and
n[mg.kgbw−1·d−1];
RfD1, RfD2 , . . ., RfDnis Critical Exposure of contaminant 1, 2, . . ., and
n[mg·kgbw−1·d−1].
From a quantitative human health risk assessment perspective, this
procedureis not correct, since it falsely assumes that the risk is linearly related
to the RiskIndex (e.g., that a Risk Index of 0.6 is two times worse than a Risk
Index of 0.3). Inspite of the lack of scientific foundation, Eq. (1) offers a
practical way to accountfor an increased risk when more contaminants are
present.“
IPEN
16
3.2
This is another deviation from reality and should be explicited stated as an
assumption when these methods are used.
IPEN
16
3.2
Add “Yet, as Kortenkamp points out, there has been a ‘dearth of mixture
experiments with mutagenicity and genotoxicity as the endpoints for
evaluation that allow clear assessments of the usefulness of concentration
addition (CA) or independent action (IA) as prediction concepts. Some
publications show that genotoxic and mutagenic agents, combined in
sufficient numbers, can work together at very low concentrations to produce
mixture effects.’
(REF : Prof. Dr. Andreas Kortenkamp (ULSOP), Assoc.-Prof. Dr. Thomas
Backhaus (UGOT) Dr. Michael Faust (FBEC), State of the Art Report on
Mixture Toxicity Final Report Executive Summary 22 December 2009)”.
IPEN
16
3.2
Replace “For the evaluation of human risks and toxic interactions in human
body is very important to know the results from well designed epidemiological
studies” with “For the evaluation of human risks and toxic interactions in the
human body it is highly beneficial to know the results from well designed
epidemiological studies, although, unfortunately these are rarely available.”
IPEN
17
3.2
Replace “The draft approach should provide a general guidance to POPRC on
how it should consider toxicological interactions involving multiple chemicals
in its work.“ with “The draft approach should provide a general summary of
the principal issues involved in toxic interactions to the POPRC and provide
some ideas on how it should could consider toxicological interactions
involving multiple chemicals in its work.”
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IPEN
17
3.3
Section 3.3 is not required. The guidance document only needs to provide a
summary of the discussions around assessing mixtures and provide some
guidance on how POPRC could consider data provided to it. Attempting to
undertake a risk assessment of real world mixtures is both out of the terms of
reference for the POPRC and simply an impossible task.
POPRC should not be asked to undertake a risk assessment of real world
mixtures in their consideration of toxicilogical interactions involving multiple
chemicals. This is simply beyond the scope of the committee.
IPEN
17
3.3
Replace “Risk assessment approach” with “Some approaches to the evaluation
of risk”.
Note that the Convention does not ask the Committee to conduct a risk
assessment, but a risk profile.
IPEN
17
3.3
Replace “Possible useful approach is the using the assessment of human health
effects from exposure to a mixture of chemical compounds, according to
established by the ATSDR (ATSDR, 2004, Castañeda, 2011) as Assessment
of the joint toxic action of chemical mixtures.” with “The ATSDR (ATSDR,
2004, Castañeda, 2011) has established an assessment of the joint toxic action
of chemical mixtures.”
IPEN
18
3.3
Replace “Considering the work of Persistent Organic Pollutants Review
Committee (POPRC), which should establish the effect of simultaneous
exposures to mixtures of persistent organic compounds for human health and
the environment, this document should refer to the risk assessment, consistent
with the work done by other multilateral institutions like the International
Programme onChemical Safety –IPCS” with “Considering the work of
Persistent Organic Pollutants Review Committee (POPRC), which should
consider the effect of simultaneous exposures to mixtures of persistent organic
compounds for human health and the environment, this document refers to
approaches, by other multilateral institutions like the International Programme
onChemicalSafety -IPCS in so far as they relate to the mandate of the
Stockholm Convention. The Convention does not provide for risk assessment
as described above, but rather for the development of a risk profile based on
the assessment of hazard.”
IPEN
18
3.3
Replace “According to the above, it is proposed that the document be called
“Guidance for Risk Assessment of Chemical Mixtures in the framework of the
Stockholm Convention on Persistent Organic Pollutants”.” with “According to
the above, it is proposed that the document be called “Guidance on the role of
Chemical Mixtures in Hazard Assessment for Endpoints of Concern in the
framework of the Stockholm Conventionon Persistent Organic Pollutants”.“.
This language more closely matches Annex E text. Risk assessment is not in
accordance with the mandate given
IPEN
18
3.3
This is way beyond the scope of the Committee. The POPRC can and should
incorporate information on toxicological interactions from appropriate peer
reviewed studies. Given the current state of the field, it seems beyond the
scope of the Committee to begin applying a multitude of assumptions and
technical work to get a grasp of the topic and how it might apply to the
evaluation at hand.
THIS IS TOTALLY UNREALISTIC FOR THE POPRC
IPEN
20
4
This section could be simplified simply listing and describing in summary the
approaches. Much of the detailed section starting in 4.3 is not needed for this
document. The need is to simply present concepts in the summary document
and rely on peer-reviewed studies for the relevant topics at hand in the
operational process of the POPRC evaluation.
According to the Convention, the POPRC members are NOT undertaking a
risk assessment.
IPEN
21
4.1
There is a lot of repetion of earlier material here.
IPEN
22
4.1
Add “Cbis Chemicals likely to be present in the body as the result of
intergenerational transfer and ongoing exposure A living organism is exposed
to complex mixtures of chemicals resulting from the combination of all the
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emissions of human activities.”.
IPEN
22
4.1
These limitations reinforce the need to simply present concepts in the
summary document and rely on peer-reviewed studies for the relevant topics
at hand in the operational process of the POPRC evaluation.
IPEN
23
4.1
I think you would find many ecotoxicologists find these sort of comments
highly offensive. While death of an individual is accepted, it is not accepted
that the death be caused by contaminants. .
IPEN
23
4.1
This is simply not true. Ecotox endpoints incldue LD50s for certain birds, fish,
bees, earthworms. Ecotox concepts incldue the disruption of the ecological
system. This document appears to have a strong bias against effects on
wildlife.
IPEN
23
4.1
Tumour formation in fish seems quite relevant to population dynamics; The
method should not ignore the impact of carcinogens on ecosystems. There is
published literature on testicular tumors that result in death during spawning.
Carcinogenesis is of extreme relevance to endangered species such as the
Tasmanian Devil, whose population has been decreased by 90% in ten years
due to cancer in the form of Facial Tumors. Moreover, how can this reasoning
be protective for sensitive subpopulations in certain regions?
IPEN
23
4.1
Note that this method also contains some important assumpations. For
example, a determination of protecting 95% of the species present also needs
to take into account the statistical confidence level of the statement. There
may in fact be significant % chance that a large number of species may be
harmed if confidence levels are not high enought.
IPEN
23
4.1
This does not appear to be relevant to the document and could be removed.
IPEN
25
4.5
Add “For example, the TEF concept assumes parallel dose response curves
and that the TEF is the same for all exposure scenarios and all endpoints.”.
EPA/100/R-10/005 December 2010;
Recommended Toxicity Equivalence Factors (TEFs) for Human Health Risk
Assessments of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Dioxin-Like
Compounds
IPEN
25
4.5
Replace “TEF values have been developed for mammals, birds and fish (Table
1; Van den Berg et al., 1998).” with “TEF values have been developed for
some common mammals, birds and fish from the northern hemisphere (Table
1; Van den Berg et al., 1998).”
IPEN
27
4.6
Replace “The major advantage is the possibility of characterising the risk from
mixtures with a single value.” with Despite these limitations, it is used
because of the possibility of characterising the risk from mixtures with a
single value.”
IPEN
28
4.6
However, low levels are still a concern for POPs evaluation since the
substances bioaccumulate, are transgenerational, and many are endocrine
disruptors, exerting effects at very low levels of exposure.
IPEN
29
4.7
Add “No information could be gleaned for impacts of the mixture on other
endpoints.”.
IPEN
29
4.8
The CA approach is not the most conservative or “worst case” approach.
Instead a method that takes synergistic effects into account would be a “worst
case” approach method.
IPEN
30
4.8
Add “However, it does not reflect the complexity of real world mixtures and
the complexity of different modes of action for one substance as well as the
option of synergistic behaviour of the mixture.”
IPEN
30
4.8
This comment is simply opinion ...what is realistically acceptable is a personal
view.
IPEN
30-31
4.9
Add “However, both have added effects and other modes of action as well,
which may not be taken into account using this method. This includes
significant neurodevelopment effects of organophosphates, resulting from
exposure in utero, that do not occur via the inhibition of
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acetylcholinesterase.”.
IPEN
31
4.9
Replace “However, most of them could be present at toxicologically
negligible concentrations.” with “However, some of them could be present at
toxicologically negligible concentrations.”.
Our lack of data and information on low level impacts of all POPs particularly
their endocrine dsruption potential makes this statement of concern.
IPEN
32
4.10
These discussions and conclusions may be appropriate for a risk assessors
workshop but we do not consider that they assist the POPRC in its task.
Suggest deletion.
IPEN
32
4.10.1
Add “However, both have significant limitations and do not consider
synergistic or antagonistic effect, which are known to occur.”.
IPEN
32
4.10.2
This may also reflect failure to measure chemicals that are in fact present.
IPEN
32
4.10.2
This seems overly confident considering all the assumptions and
uncertaintities
IPEN
32
4.10.2
The dataset is far from complete for the Antarctic.
IPEN
32-33
4.10.2
The sentence “For fish this is fully irrelevant for risk assessment: the
contribution of all chemicals estimated to the total TUs of the mixture is very
low and even an approximation of one order of magnitude would not affect
substantially the final result indicating negligible risk. “ is not clear.
IPEN
33
4.10.2
There is no evidence presented why the assumptions are actually worst-case;
Using LC50 data ignores impacts at lower concentrations; as seen elsewhere,
low dose response cannot always be estimated from high dose. See earlier
comments about the use of NOAELS.
IPEN
33
4.10.2
There is no justification for labeling them highly protective.
IPEN
33
4.10.2
This is debatable since many are based on old data and numerous assumptions
that seem to be ignored when they are used further.
IPEN
33
4.10.2
This does not seem like a comprehensive list of assumptions that have been
stated in the paper and that exist in reality.
IPEN
33
4.10.2
Considering the large number of uncertainities and assumptions,
„proved“ seems overly strong.
IPEN
34
4.10.3
The large number of assumptions seem to make it questionable
IPEN
34
4.10.4
Please see comments above regarding uncertainties and assumptions; if this
statement is true, then it reinforces the idea that the paper should act as an
informative summary and the Committee should use appropriate peerreviewed studies when available.
IPEN
34
4.10.4
See comments above. The exposure assessment is limited to one aspect of the
global environment. There is a significant lack of data for nearly all ecological
systems other than the Artic.
IPEN
34-35
4.10.4
This justifies the statements about the utility and nature of the paper.
IPEN
35
4.10.5
This comment ignores the findings of the report by UNEP &AMAP on
climate change impacts on POPs releases, mobilisation and toxicity.
IPEN
36
4.11
There is no reference for this publication; it does not exist on PubMed; there is
no trace of it on any internet search; It seems inappropriate to spend time in a
paper highlighting concepts from a publication that no one else has access to...
Delete rest of chapter 4.11.
This is simply inappropriate for substances which bioaccumulate.
Furthermore, “small contributors” or substances in low concentrations may
have large effects depending on the timing of exposure or over long exposure
times. This concept may, in fact, invalidate the entire exercise for use by the
Committee. Finally, ILSI has been cited by WHO as an organization used by
tobacco companies to avoid tobacco control policies under a cover of “sound
science”; completely inappropriate for a POPRC paper...
27
UNEP/POPS/POPRC.8/INF/11
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Comment
IPEN
40
5
Replace “WHAT WE NEED FOR THE TOXIC INTERACTIONS
ASSESSMENT?” with “WHAT WE NEED FOR THE TOXIC
INTERACTIONS EVALUATION ?”.
IPEN
41
5
Replace “toxic interactions assessment” with “toxic interactions evaluation”.
IPEN
42
5
It is difficult to pick a most serious“ effect. Other equally important effects
include endocrine disruption and those chemicals with epigenetic potential.
IPEN
42
5
Not appropriate for substances which bioaccumulate
IPEN
43
5
Inappropriate; see comments above regarding ILSI and the TTC concept.
TTC is completely inappropriate for POPs as it cannot be used for
bioaccumulative substances
This sentence and the scheme should be deleted from the document as it
assumes safe thresholds for chemicals, which do not apply to POPs
NOTE : Even EFSA who is generally favourable of the TTC approach
clarified that this can NOT be applied to substances that are bioaccumulative!
See page 5
http://www.efsa.europa.eu/fr/consultationsclosed/call/110712a.pdf
IPEN
44
6
The conclusion chapter should be rewritten, focussing more on the role of
POP RC and how to consider the issue of toxicological interactions in their
work.
IPEN
44
6
It seems to important to note that this assumes chemical pairs or two-chemical
combinations only. That seems like an important limitation/assumption to be
clear about.
IPEN
44
6
It seems that it would be helpful to explain that this is essentially combining
the results of two separate evaluations. This means that the uncertainty in each
evaluation is also combined. How is this handled? It seems it should also be
noted that there is minimal supporting data from actual mixtures which would
enable some sort of comparison and support for the various assumptions
employed.
IPEN
44
6
This statement cannot be justified in the conclusions. Kortemkamp 2009:
„There is evidence that dissimilarly acting agents, when combined at doses
below their NOAELs, may also produce significant mixture effects” Cites a
variety of studies that directly contradict the conclusion cited in the text.
IPEN
45
6
If synergy is ignored, then that should clearly be stated in assumptions.
Add “despite clear evidence that synergies exist”.
IPEN
45
6
Add “However, it must be noted that there are significant limitations to the use
of these methods due to the limitations of the use of NOAELs and LOELS on
which they are based.”.
IPEN
46
Appendix 1
Is this section a critique or a description of what is happening in the regulatory
arena.
IPEN
52
Appendix 2
This was an informal workshop hosted by the european chemical industry, it is
inappropriate to include in this document. The appendix should be deleted.
It is unclear what the purpose of this appendix is and it seems random to
include a result from a workshop in Brussels. Moreover, it relates to risk
assessment approaches in general, whereas the guidance should be about
POPs, which are dealt with in a different policy approach.
IPEN
World Chlorine
Council
28
58
Appendix 3
A summary of these concepts should be sufficient for the document; suggest
deletion
I think the note is a useful thought-starter to kick off the development of
guidance for considering toxic interactions in the context of Annex E risk
profiles. For an initial stage document it is sufficiently broad to cover the large
range of potentially important toxics to be covered. However, I would already
at this stage like to specify a key element of the fate and behaviour which is of
key importance to assess realistic mixture effects. This is ‘bioavailability’ of
UNEP/POPS/POPRC.8/INF/11
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Comments
Comment
substances and mixtures under realistic conditions, which warrants specific
detailed consideration in my view.
In the following steps of the guidance development there will be a need to
provide further clarification of what is precisely meant with 3-other approach;
5: ‘effects of sources-model situation etc.’ topic 6 and some other statements,
but I assume this will be part of the further drafting process.
POPRC member
General
I have a very small observation on the key questions as per the POPRC7, in
question one(1) which reads ..What additional information is needed to assist
the committee.........................toxic interations? I propose phara (i) to read:
• Understanding of toxicological and eco-toxicological effects of lessexplored new compounds and their corresponding isomers;
POPRC member
Suggest the following addition to the information necessary for the evaluation:
1) Structure of chemicals in the mixture;
2) Their physical-chemical properties
3) Their fate and behaviour under given environmental conditions;
4) Their environmental levels;
5) Toxicological and ecotoxicological effects;
6) Effects of metabolites and residues when they are present
7) Mode of actions;
8) Which approach we can use for the assessment;
9) Uncertainties.
3. The additive or other approach will be used for the evaluation:
1) Advantages and disadvantages of these approaches;
2) Limitations, interpretation/des-interpretation, uncertainties,
strong/weakness.
4. Model case studies
5. Effects of sources – model situation – surroundings of source – nearby,
shorter and longer distance from?
6. What contributed to result in the effects?
_________________________
29