Committee report November 18-19, 2015 - Chemicals Management Plan Science Committee

Chemicals Management Plan Science Committee

The Science Committee (the Committee) was requested to address the following Charge Questions:

  1. Are proposed ecological and health approaches for determining cumulative risk for the phthalates grouping appropriate?
  2. When conducting a screening assessment under the Canadian Environmental Protection Act, 1999 (CEPA 1999), what are the considerations for determining when a cumulative risk assessment (CRA) is appropriate?

In providing their responses to these questions for consideration by the Departments, the Committee has reordered and reframed the Questions as follows:

  1. When conducting a screening assessment under CEPA 1999, what are the considerations for determining when a CRA is necessary?
  2. Are proposed ecological and health approaches for determining cumulative risk for the phthalates grouping appropriate?

1) When conducting a screening assessment under CEPA 1999, what are the considerations for determining when CRA is necessary?

1.1) A major scientific driver for holistic chemical evaluation is the fact that multiple-chemical exposure is a reality. There is a global aspiration to move risk assessments in the following direction: the public is motivated to ensure that we live in a "non-toxic" environment and this concern is encouraging regulatory innovation across jurisdictions, including Canada, to assess substances in groups when co-exposures of the assessed chemicals are likely. The Committee expressed enthusiasm about the long-term goal of moving risk assessment closer to the public and ecosystem health aspirations of an "exposome" approach in which all exposures are considered. However, they were also aware that this is a future aspiration that awaits the development of well-evaluated approaches and the availability of necessary data. Thus, this Report is based on the achievement of more proximate goals, and focuses on whether decisions that need to be made within the Chemicals Management Plan (CMP) in the next few years would benefit from the performance of a CRA. That is, would a CRA evaluate health and environmental risk in a better manner (for example, more accurately predict actual risks) and be more appropriate than a single-substance risk assessment? Would performing a CRA increase efficiency within CMP, Phase 3 (CMP3)?

Conceptually, the option to conduct a CRA will be informed by numerous factors, predominantly specific to the substances under consideration; examples are summarized in Figure 1.

Figure 1. Outline of Possible Factors for Conducting a CRA

A diagram illustrating possible factors for conducting a CRA.

For substances that are subject to the provisions of the Canadian Environmental Protection Act, 1999, the first question Health Canada and Environment and Climate Change Canada should consider is whether or not their decision on a predefined class is crucial. The second question the Departments should consider is whether there should be a similar level of protection for the substances (for example, all reprotoxic substances versus a chemical class).

Departments should then consider the type of CRA that needs to be conducted:

  1. a chemical-class CRA (for example, phthalates or hindered phenols);
  2. a source-based CRA (for example, textile mill effluents);
  3. an endpoint-based CRA (for example, androgen insufficiency); and,
  4. a holistic-based CRA (organism/ecosystem level) (for example, aquatic system in the Ottawa River).

From these different CRA options, the Departments should then determine if the same or a different decision tree applies, depending on the type of CRA chosen.

The Departments should then use the appropriate decision tree, and determine if there is the same or different conclusion.

Based on the conclusion from the decision tree, there will be either:

  1. Group A of substances for which a CRA is relevant;
  2. Group B of substances for which a CRA is relevant;
  3. Group C of substances for which a CRA is relevant; and,
  4. Group X of substances for which a CRA is relevant, etc.

Explanation of Figure 1:

The first row of clouds comprises examples of questions to be asked when deciding which type of CRA is more appropriate.

The meaning of "Is the Health Canada/Environment Canada decision on a predefined chemical class crucial?" is "Is the Health Canada/Environment Canada decision on the selection of a predefined chemical class crucial for the final conclusion?"

The box "Decision Tree" and its associated cloud indicates that the decision tree could be different depending on the type of CRA that is selected and whether the anticipated cumulative risk is significantly greater than the individual risks from the component substances.

The last row of boxes comprise the outcome of the decision tree, and its cloud contains an open question: How does the choice of the type of grouping affect the final conclusion?

1.2) Within the confines of undertaking a CRA under CMP3, a focus will be on chemical class assessments, as these are typically the type of assessments being conducted under the second phase of the CMP and those that are proposed for the remaining priorities under the third phase, if necessary and appropriate; phthalates or hindered phenols (illustrated on the left side of Figure 1) are examples. Therefore, the Committee's deliberations were predominantly based on a chemical class CRA, and addressed the specific considerations for the use of such a CRA to support the decisions made under CEPA 1999. Having initially determined that co-exposure of the substances included in the chemical class can reasonably be expected, the considerations could include the following:

  1. the substances under consideration are anticipated to share an adverse outcome or endpoint signal that is of concern in either a human or ecological population;
  2. an improved understanding of risk(s) associated with co-exposures relative to single chemical exposures is gained; and
  3. the added Value of Information of a CRA in terms of a more efficient CEPA decision and/or an improved risk management decision/action is obtained.

1.3) The Committee agreed that the Problem Formulation aspect of an assessment is a critical opportunity to initially identify whether a CRA is appropriate. To provide a logic sequence for the discussion, the Committee posed a series of questions along the lines of "Should we/Can we/How do we conduct a CRA?" The results are summarized in Table 1 and the associated notes.

Table 1. CRA Problem Formulation
Should we conduct a CRA? How do we conclude that CRA is not needed? Can we conduct a CRA? (Do we have the appropriate technical knowledge and data in hand?) Link to How do we conduct the CRA? How do we conduct the CRA?
Value added by a CRA: Potential for the CRA to influence/inform a different regulatory outcome than a single substance decision:
  • Substances are in commerce
  • Evidence for potential co-exposure
  • Readily identified risk of regrettable substance substitution
  • "Severity" of effects
Availability of sufficient data (exposure/hazard) Tier 0 (see new CMP3 Assessment Framework) - analysis of Hazard Quotients (HQs): If the sum of the HQ is ≥ 1, move to Tier 1
Public/international mandate Is there any prior experience for this type of CRA? Tier 1:
  • Same/similar effects
  • Ecosystem - population health
  • Health - similar health outcome same/similar physical-chemical properties
  • Evidence of co-exposure
  1. The default assumption in Table 1 under "Should we?" is that there is a likelihood of co-exposure to the chemicals considered for the assessment group. The Committee strongly endorsed this concept.
  2. Under "How do we?" in the Tier 0 assessment of hazard, cumulative risk is determined using a dose-addition method. Thus, the HQs for each individual chemical in the group are summed to calculate the Hazard Index (HI). It is recognized that while compounds of an assessment group may have similar target organs or modes of action, there may be an absence of information for some of the compounds. On occasion, these HQs may be based on different data sets with different critical effects, but nevertheless, this approach would provide an appropriate first estimate (for example, Backhaus & Faust 2012; Environ Sci Technol 46: 2564-2573). Under the scheme in Table 1, an HI of ≥ 1 results in a Tier 1 evaluation, or a more refined analysis of hazard with additional information on the dose-response relationship for critical common effects, if additional information is available.

Having confirmed the importance of an initial and carefully conducted Problem Formulation step, the Committee proceeded to identify other important considerations:

  • 1.3.1) There are circumstances in which dose addition is not appropriate, such as when data analysis reveals that there are alternative response interactions (antagonism, synergism) or when some of the individual substances have divergent pharmacodynamic profiles; these may make the conduct of a dose-addition-based CRA either impractical or meaningless. Specific approaches need to be developed for mixtures of interacting substances, and the "response addition" concept might provide an approach for compounds having dissimilar Modes of Action.
  • 1.3.2) The Committee discussed the issue of whether individual HQs, based on different Modes of Action, could or should be summed to create an HI and did not come to an agreement. This subject is recognized to be important and needs to be further discussed as the CMP evolves; it may be determined that different approaches are applicable for human versus environmental risk assessment.
  • 1.3.3) When conducting a CRA, there is a basis for increasing concern as the HI approaches 1. The Committee discussed the "comfort" associated with a sharp "cut-off" value with respect to the margin of safety and the possible impact on the proportion of the population that might be affected. At what point near 1 might this occur? The level of ambiguity may be such that quantitative treatment of uncertainty is necessary, but the overall level of conservatism in terms of how components are averaged is not clear. On the other hand, the impact of high uncertainty factors for specific chemicals will be decreased by adding HQs to obtain an HI in a CRA; this impact depends in part on the value and robustness of individual HQs. Last, the issue of "cut-off" has a policy component. The Committee concluded that no general guidance can be provided at this time; a case-by-case approach must be adopted until sufficient experience with CRAs has been gained such that some guidelines can be developed.

1.4) Additional comments were made within the framework of Table 1:

  1. The exposure assessment considerations for NOT doing a CRA include the following:
    • There is not enough information to quantify co-exposure (no added Value of Information versus individual assessments).
    • There is sufficient evidence that co-exposure risks are negligible or will be negligible in future.
    • The potential for a "regrettable substitution" is low (that is, there are no commercially available substances with similar chemical, toxicological, and use profiles which are being excluded from the CRA).
  2. The hazard assessment basis for NOT conducting a CRA includes the following:
    • Insufficient hazard or mode of action data on individual compounds; if so, individual assessments need to be implemented prior to a CRA.
    • Obtaining an HI of ≤ 1 after a Tier 0 assessment (how much less? - see above).
    • Different or dissimilar effects/endpoints/dose-response curves or modes of action in a Tier 1 assessment (note: in some circumstances, this might emphasize the need for a CRA).
    • Evidence for non-additive responses or non-monotonic dose-response curves (but this may also increase the need for a CRA or direct a detailed individual assessment).

A decision tree formulating this approach is presented in Figure 2. This is not intended to be an alternative decision tree to be used by the Departments. Note that the Committee struggled with this decision tree because some of the steps are somewhat circular. For example, it is difficult to confirm whether one should perform a CRA without doing some of the work associated with a Tier 0 assessment. The Tier 0 assessment cannot be effectively conducted without having a working Problem Formulation which includes a (provisional?) list of substances under consideration and the approximate concentrations associated with co-exposures.

Figure 2. CRA Decision Tree

A diagram illustrating a proposed cumulative risk assessment decision tree. This decision tree is not intended to be an alternative decision tree to be used by the Departments.

When there is a chemical class of substances for human health and ecological assessments, the first step to consider is whether or not there would be value added in conducting a CRA. If the answer is no, then either no CRA is needed or there is a need to consider new relevant information.

If new relevant information is considered, and there is value added in conducting a CRA, then the next step is to complete a Tier 0 - HQ screen which would consider conservative exposure(s).

Information from individual assessments may contribute to the Tier 0 - HQ screen. The results from the Tier 0 - HQ screen would be either: no concern for cumulative risk (no further CRA work required); or, yes, there is concern for cumulative risk.

If there is a concern for cumulative risk, this is a decision point and refinement is required on hazard and exposure.

The next step in the decision tree after the refinement is completed is problem formulation. As part of this step, consider if there is evidence of the same/similar effect/properties and sources/uses. Both human specific and eco specific information needs to be considered in the problem formulation step. Another consideration is whether or not there is sufficient data. If there is insufficient data, more data need to be collected and considered in the problem formulation step (if possible).

The reason a CRA is appropriate/required should be explicitly stated in the Problem Formulation. A consideration specific to a CRA, but not necessarily an individual risk assessment, is the availability of relevant and complete hazard data for most of the compounds under consideration. In a Tier 1 CRA, the Problem Formulation phase must clearly state the specific "endpoint" that is the subject of the exercise. If it is not expected to be the most sensitive endpoint (for example, a specific life stage in human development or a specific taxon for ecological risk - which may be the case if the available data for the CRA do not fully relate to the most sensitive endpoint), the basis for conducting a CRA requires additional justification. When the decision has been made that it is appropriate to conduct a CRA, the efficiency of the CMP will be increased, because this will lead to the possibility that it is not necessary to perform single-substance assessments.

1.5) Some of the approaches/tools for an effective CRA are outlined in Table 2. The development of a more complete version of such a table may be helpful in making a decision about the appropriate approach for doing a CRA for a specific group of chemicals.

Table 2. Considerations on Possible Approaches for the Conduct of an Effective CRA
Approach Preconditions Remediation Advantages Disadvantages/ weaknesses
Toxic unit method Exposure data available for all substances in the assessment group. Read across can be used to fill data needs. For environmental assessments, RQ based on most sensitive trophic level. ECx preferred over NOEC/LOEC (not a disadvantage, but a likely issue with many environmental CRAs).
Assumption: no toxicodynamic or toxicokinetic interactions.
Toxicity data for the same organism for each substance.
Same endpoint and exposure duration for all toxicity data.
Internal toxic unit method All of the above. Additional modelling of BAF (may be highly uncertain). N/A Requires BAF for each substance.
BAF or internal tissue concentration required for each substance.
Summation of PEC/PNEC or HI's Exposure data available for all components. N/A DNELs and PNECs that are documented from single-substance assessments can be directly used for CRA (that is, no specific data collection is necessary). PNEC or HI can be based on hazard data from different tissues, organs, or organisms.
PNEC response and HQ available for all components. No need to specifically consider different assessment factors. Consequently, the resulting HI and PEC/PNEC sums may be difficult to interpret.
Assumption: no toxicodynamic or toxicokinetic interactions. Conservative, but not excessively overprotective.
Response addition (independent action) Exposure data available for all components. N/A The scientifically valid concept for assessing the joint action of compounds with dissimilar modes of action (target sites, tissues, organs, organisms) that still impact the (eco) toxicological endpoint of interest. Highest demands in terms of available (eco) toxicity data for each compound.
Assumption: no toxicodynamic or toxicokinetic interactions. NOECs/NOAELs cannot be used.
Complete concentration-response curves for each component available for the (eco) toxicological endpoint of interest.
Abbreviations used in Table 2:
Bioaccumulation Factor
Derived No-Effect Levels or the level of a substance above which humans should not be exposed
Concentration of a substance causing x% effect
Hazard Index
Hazard Quotient
No-Observed Effect Concentration/Lowest-Observed Effect Concentration
No-Observed Adverse Effect Level
Predicted No Effect Concentration
Cumulative Risk Quotient

The considerations listed in Table 2 could be used as an aid in selecting the most appropriate CRA approach for environmental assessments. Each CRA approach has necessary preconditions and/or information elements needed for success; if the listed preconditions are not satisfied, there may be assessment techniques (such as quantitative structure-activity relationships) which can "remediate" the data gaps. The advantages and disadvantages of each approach should be considered in light of the information and resources available, degree of certainty required based on Tier 0 evaluation, and so forth.

The Committee noted that the use of the approaches outlined in Tables 1 and 2 might assist assessors in the determination of the utility associated with conducting a CRA.

1.6) The Committee spent some time in reviewing two versions of a proposed decision tree prepared by the Departments. They did not conclude which one was better, nor did they develop an alternative tree for the Departments. They agreed that the concept was sound and that a decision tree would provide assessors a useful tool in early discussions about whether or not to conduct a CRA, and it would assist in communication of the concept as part of the Problem Formulation statement within the risk assessment report.

1.7) The hindered phenols Case Study was more difficult to discuss than the CRA for phthalates because:

  1. there is no precedent for this group of chemical structures,
  2. there is a high degree of structural diversity, and
  3. this is an example of a data-poor chemical grouping where much of the data are modelled.

In particular, information on the modes and mechanisms of action of the substances in the standard test organisms is scarce. The Committee noted that this might be typical of many attempted CRAs in the near future and therefore it provides a good example of how difficult it might be in practice to decide whether or not to conduct a CRA. It seems entirely possible that a substantial effort is required in order to determine if the CRA is feasible and, if feasible, whether it provides additional value over a conventional assessment.

Given the data-poor situation for many hindered phenols, early agreement on a critical Mode of Action (MOA) would be of assistance (for example, non-polar narcosis versus endocrine disruption). Nevertheless, one could "mix" HI values derived from various MOAs for individual members of the group to create a Tier 0 realistic worse-case assessment or an HQ (see discussion in Backhaus and Faust 2012, Environ Sci Technol 46: 2564-2573). This approach might be very useful in order to check whether there is a "case to answer", that is, whether even under conservative assumptions there is a possibility of a risk to the environment or human health. If so, a more detailed assessment is needed. If not, the CRA can stop. The HI method (Predicted Effect Concentration/Predicted No Effect Concentration summation) therefore facilitates action in situations of considerable uncertainty. It should, however, be emphasized that the overall validity of such a Tier 0 assessment hinges on a valid exposure assessment, which will often be more complex than a single assessment. If successful, a Tier 0 assessment also enables an initial ranking and prioritization of the assessment group components for gathering additional experimental data, or even for risk management and mitigation. The Committee could not provide any further advice to the Departments on this Case Study, nor, by extension, for other potential CRAs where there is a serious lack of required data—except to observe that these would be good examples of "learning by doing", even if it proves impossible to complete a CRA in some circumstances.

2) Are Proposed Ecological and Health Approaches for Determining Cumulative Risk for the Phthalates Grouping Appropriate?

The Committee recognized that the CRA for health risk associated with phthalate exposures represented a major effort. In addressing the specific Charge Question, and with respect to the phthalates grouping of substances, the Committee suggested that co-exposure, rather than target or action, be the primary determinant in deciding which chemicals constitute an appropriate grouping for a CRA. Under this scenario, all 28 phthalates would be subjected to the exposure filter to assess co-exposure. When chemicals are removed from the group on the basis of insufficient information on co-exposure, it is important to distinguish between those for which there are no data versus those for which there are data indicating that there is no co-exposure. The current CRA has "removed" 10 short- and long- chain phthalates from the group based on a lack of evidence for androgen insufficiency as a mode of action common with other members of the group.

The Committee suggested that the data for all phthalates for which there is co-exposure be screened under Tier 0 using dose addition as a worst-case scenario, regardless of the critical endpoint. Under this scenario, all 28 phthalates would be included in Tier 0, adding in all parameters and taking into account the lowest Point of Departures regardless of the specific mode of action. Further action would then depend on the outcome of this first step. Should Tier 0 indicate a possible risk for human health or the environment, more detailed analyses would need to follow, including MOA-oriented assessments (which could entail the use of Response Addition as an alternate approach for assessing the combination effects of compounds with dissimilar MOAs, or a combination of Dose Addition and Response Addition). Because higher-tier assessments might require the investment of considerable resources, it would be advisable to analyze the potential gain in assessment efficiency (in particular, in comparison to the uncertainties in the exposure estimate) prior to embarking on such activities.

Further, some Committee members suggested that because CRA methodology is relatively new, in moving forward it may be advisable not to depend on the traditional "one critical effect, one vulnerable group" approach generally adopted for single-substance assessments, but to broaden both the endpoints considered and the vulnerable population groups/taxa (see our earlier comments in the context of Problem Formulation). We recognize that this approach may be very challenging to apply in practice.

The methodology/approach for ecological health, the Internal Toxic Units method, included all phthalates and used narcosis as the common MOA. This method was proposed because phthalates have a solubility cut-off, whereby the longer chain-length phthalates do not show effects at concentrations below their solubility limits in water. No toxicity data may be available for some of the substances because ecotoxicological testing was conducted at concentrations exceeding their solubility. It was suggested that approaches to doing a CRA in this instance might involve the use of such tools as the Organisation for Economic Co-operation and Development toolbox to estimate a more sensitive endpoint (perhaps estrogenicity). Additionally, the use of read-across from toxicological studies should be explored for the MOAs of the phthalates. This is particularly important, as narcosis is the baseline mechanism of ecotoxicity, and overlooking other, more specific MOAs might underestimate the ecotoxicological potential of certain phthalates and, consequently, might underestimate the cumulative ecotoxicity.

3) General Conclusions

The Committee found responding to the Charge Questions to be very challenging, with several issues warranting further in-depth evaluation. The Committee recognized the motivation to conduct a CRA in recognition of human and ecosystem exposures to multiple chemicals. In the context of the CMP, the specific motivation would be evidence of co-exposure to a group of chemicals. Given the limited history of CRA in regulatory risk assessment, the process of attempting to conduct a CRA will allow assessors to gain valuable experience. Phthalates are one of the few substance groups within the context of the CMP that have a well-justified basis (including sufficient data) for such an approach, whereas hindered phenols are a more difficult group to assess in this way. Valuable experience will be gained by the exercise of conducting a CRA, with ensuing enhancements made to the knowledge base of "regulatory science"; but, decisions will have to be made on when a focus on CRA provides improved ability to meet the health and environmental protection goals of the CMP given the timelines associated with delivering CMP3.

Respectfully submitted on behalf of the CMP Science Committee. The Committee wishes to thank ad hoc member Thomas Backhaus for his valuable contributions.

Barbara Hales and Geoff Granville (Co-Chairs)

January 8, 2016

Page details

Date modified: