Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
UNITED NATIONS SC 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. Source of Page Chapter Comments Comment 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 2 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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. 3 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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 4 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 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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; 5 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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– 6 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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 7 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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 9 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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. Norway 4 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 10 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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.” Norway 5 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).” Norway 5 1.1 This is partly a repetition. Fuse with the text in the first paragraph of the Chapter (p. 4). Norway 6 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.”. Norway 6 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.” Norway 6-7 1.1 This is fairly basic toxicology. Delete or shorten the text? Norway 8 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 11 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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. Norway 9 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. Norway 9 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.”. Norway 10 2.2 Change title to “Scope and aim of the draft”. Norway 11 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 Norway 11 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. 12 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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. Norway 11-12 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.” Norway 12 2.2 Please delete “Our model approach” and integrate this information in the text in Chapter 3 Norway 12 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. Norway 12-13 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 13 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment (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 Norway 13 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. Norway 13 3.2 It is perhaps possible to fuse 3.2 and 3.3. Norway 14 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? 14 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment Change title to “Relevant information on toxicological and ecotoxicological properties of POPs and their mixtures”. Norway 15 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". Norway 16-17 3.2 To avoid repetitions in the text please delete the consequtive paragraphs of this section. Norway 17 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. Norway 21 4 Move this chapter forward so that it in the revised version becomes chapter 3. Norway 21-22 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.” Norway 22 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. Norway 22 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. Norway 22 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.” Norway 23 4.3 This section should be placed after section 4.4. Norway 23 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. Norway 25 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) 15 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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).” Norway 27 4.6 Please shorten and fuse with "new" b) a)b)Toxic Units (TUs) above. Norway 29 4.6.2 Please delete this chapter and shorten/ change the text and fuse with paragraph b) Toxic Units (TUs) above. Norway 29 4.6.2 Move to the proposed new chapter "3.5 Challenges and limitations of the proposed approach" or a similar chapter Norway 30 4.8 See comments already provided in chapter 3. Please move to the new chapter 3.3. Norway 31 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. Norway 31 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. Norway 31 4.9 This point may be captured elswhere e.g. by movein the information to the proposed chapter 3.3. limitations/ challenges. Norway 32 4.9 Move to chapter 6. conclusion Norway 32 4.10.1 Please delete this section. The point has already been made in previous parts of the text. Norway 32 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. Norway 33 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. Norway 35 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. Norway 36 4.10.5 We do not belive this text to be directly relevant to the topic of mixtue toxicity. Please delete this section. Norway 36 4.11 Please move to Appendix Norway 42 5 Move to the new proposed chapter 3.3 Challenges and limitations of the proposed approach Norway 42 5 The following section (starting “For the toxic interactions assessment we need 16 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment few sets of information:”) may in our view be deleted. Norway 45 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. 17 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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 18 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment (epi. version of toxicological interactions) are also issues for epidemiologic studies. United States 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 13-14 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 17 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 IPEN 19 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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 20 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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 21 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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 22 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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. 23 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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.” 24 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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 25 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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 26 UNEP/POPS/POPRC.8/INF/11 Source of Page Chapter Comments Comment 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 Source of Page Chapter Comments 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 Source of Page Chapter 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