Consideration of cumulative effects in risk assessment of existing chemicals

Fact sheet series: Topics in risk assessment of substances under the Canadian Environmental Protection Act, 1999 (CEPA)

Introduction

Exposures to chemicals can occur through environmental media such as air, water, sediment and soil. Additionally, exposures can come from food, household dust, manufactured items, and products available to consumers (such as cosmetics, cleaning products and textiles). When combined exposure (co-exposure) to multiple chemicals occurs, the cumulative effects may be greater than effects resulting from exposure to each individual chemical.

Canadian regulatory context

Amendments in 2023 to CEPA included new requirements when the Government of Canada conducts risk assessments of existing chemicals. One of these requirements is to consider available information about the cumulative effects on the environment and health that may result from exposure to a chemical in combination with exposure to other chemicals. This requirement is specific to chemicals already in commerce in Canada (“existing substances”). While it may be considered when appropriate, the consideration of cumulative effects is not required by CEPA for risk assessments of new substances, which are assessed on a substance-by-substance basis as notifications are received.

In the context of activities undergoing federal impact and environmental assessment processes outside of CEPA, the term “cumulative effects ” includes a broader scope of environmental, social, economic and health effects. Under CEPA, the term is limited to the context of existing chemical assessments. In this case, the term “cumulative effects” means the analysis, characterization and possible quantification of the combined hazards (adverse effects) to humans or other species in the environment from exposure to multiple chemicals. Information on the combined hazards and co-exposures of multiple chemicals can be used to determine the potential for cumulative risk. For practical considerations, including data availability, assessment of cumulative risk under CEPA may be conducted with groups of structurally similar substances prioritized for assessment .

Cumulative risk assessment of chemicals

A cumulative risk assessment (CRA) explores the possibility that co-exposure could lead to different risks relative to exposure to chemicals individually. Chemicals with similar adverse effects or that affect the same target organs may be considered for cumulative effects (for example, see the Phthalates Substance Grouping assessment). The resulting effects can be:

additive, where the effect of the mixture (or combined effect) is the sum of the effects of the individual chemicals
synergistic, where the combined effect is greater than the sum of individual effects, or
antagonistic, where the combined effect is less than the sum of individual effects

Given the toxicological data and assessment approaches available to date, an assumption of additive effects is most commonly considered when assessing the cumulative risk of chemicals. Refinement to consider synergistic or antagonistic effects requires more chemical-specific data than are usually available.

Consideration of cumulative effects in a risk assessment involves the same key components as those considered for a single substance, such as a hazard assessment, exposure assessment and risk characterization. However, it also includes the following additional considerations:

Determining which chemicals are likely to have co-exposures that may increase risk
Determining whether co-exposures to two or more chemicals will occur through single or multiple sources or routes; and
Determining which chemicals have common adverse effects or act through the same mode of action

Problem formulation and group definition

As described by the Organisation for Economic Co-operation and Development (OECD), to determine whether a CRA may be required, a problem formulation is first conducted, in which the data available are considered to examine the potential for relevant co-exposure of people and the environment to multiple chemicals from one or more environmental media, food or products. Information that indicates potential for co-exposure may include monitoring or biomonitoring data showing the presence of two or more chemicals from the identified group of chemicals in the same sample or information about a common use. Information on co-exposure to chemicals exhibiting the same or similar adverse effects or acting through the same mode of action would also be considered.

Chemicals included in a group for CRA may have evidence of co-exposure and common characteristics based on chemical structure (such as a common functional group), physical and chemical properties, and hazard characteristics.

Assessments of existing substances might not include a CRA if data are not available to determine whether co-exposures could lead to greater human health or ecological risk than single chemical exposures. There are also instances when consideration of cumulative effects could lead to a decision to not conduct a CRA even though there is evidence of co-exposure and sufficient data are available. For example, when all chemicals in the mixture are already known to pose a concern individually, then there may not be a need to further assess their cumulative risk unless considered helpful to inform potential risk management actions.

Cumulative risk characterization approaches

For human health CRAs, there are multiple different tiers for assessment of both co-exposure and common hazard, as described by the World Health Organization (WHO)/International Programme on Chemical Safety (IPCS) framework. In this framework, approaches used for risk characterization are applied to chemicals with similar modes of action and more chemical-specific data may be required with higher tier assessments.

Similarly, for ecological CRAs, a tiered framework can be used. An initial assessment of cumulative risk may involve a simple summation of the individual risk quotients for each of the co-occurring chemicals. If this initial calculation indicates a potential concern, further investigation using higher tier approaches, which can include refinement of hazard and exposure characterization, may be considered if data are available.

An assessment of the risk posed by co-exposure to multiple chemicals can be conducted using different approaches. For example, it may consider the whole mixture or it may be component-based.

The whole mixture approach considers a group of chemicals as if they were a single unit and the assessment relies on toxicity studies conducted on that mixture. This approach identifies effects of exposure to the whole mixture, including any unidentified components and any interactions between components, but it does not rely on the information of individual chemical(s) or the specific interactions responsible for any associated effects.

In a component-based approach, all implicated chemicals are considered as separate components, and the effects of the chemical group are assumed to be based on the combined effects of the individual components. When applying this approach, it is necessary to determine the relative proportion of the components (through monitoring, product composition data, or modelling) and their contribution to the overall toxicity of the chemical group. Sufficient data on both effects and exposure for each of the implicated chemicals in the potential mixture must be available to consider a component-based approach. A read-across approach to use data from one chemical to inform data-poor chemicals within the same group may be used, but this can result in higher uncertainty.

The choice of method used in a CRA will be influenced primarily by the available data. Some risk assessments, for example, of inorganic chemicals (such as metals) can use a moiety approach. Risk is evaluated for the common moiety of potential concern. Groups of chemicals with the same moiety have the potential to release the same component, which may lead to similar adverse effects in the exposed species.

There may be additional or compounded uncertainties when conducting a CRA (such as the evidence supporting the co-exposure or common hazard), in addition to those considered in a risk assessment of single chemicals. These uncertainties are considered in the overall weight of evidence for the assessment.

Advancing the science of cumulative risk assessment

The assessment and management of cumulative risks of chemicals in a regulatory context are ongoing areas of discussion both internationally and in Canada. The use of different co-exposure assessment approaches, including a mixture allocation factor approach, may be a way to account for cumulative effects when it is unknown what other chemicals might be co-occurring. Real-world case studies may also help to refine approaches for considering cumulative risk. For example, the Integrated Chemical Mixtures Project was established to support implementation of the modernized CEPA. It is a research and monitoring project that aims to generate knowledge on real-world exposure to, and effects from, chemical mixtures in the environment. The Government of Canada’s approach to CRA under CEPA continues to evolve as scientific tools and methodologies to address cumulative risk advance.

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2026-06-26

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