Scientific Issues in Quantitative Cancer Risk Assessment


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The assessment follows a four-step process: 6 1 hazard identification, 2 dose-response assessment, 3 exposure assessment and 4 risk characterization. The main source of information for identifying hazards toxic end points or adverse health or environmental effects and for determining the relationship between dose and response are animal toxicity studies.

These are considered to be well understood predictors of toxicity in humans. With few exceptions, i. These differences must be taken into account and as a result the PMRA is using two different approaches for assessing the acceptability of risks from pesticides to human health: a margin of safety approach for "threshold" effects and a quantitative risk assessment for non-threshold effects, such as cancer. For toxic end points that have a threshold, the PMRA establishes a reference dose, taking into account both the acute and the chronic nature of the toxic effects.

The lowest level of exposure in test animals that causes no adverse effects, the no observed adverse effect level NOAEL , is the starting point for calculating the reference dose. The NOAEL is selected for a toxic end point observed in animals that is relevant to humans, and it is usually from a study in which animal exposure is representative of the route, frequency and duration of human exposure. Furthermore, the establishment of reference doses must take into account uncertainties arising from the extrapolation of effects observed in animals to potential effects in humans.

It also considers that some humans in the population are more sensitive to potential effects than others. Therefore, the reference dose incorporates two safety factors: a fold factor to account for extrapolation from animals to humans i. In this way, the calculated reference dose for humans is a minimum of fold lower than the dose that caused no adverse effects in animal studies.

In addition to these two fold safety factors, additional safety factors are applied to the reference dose to address severity of toxicology end point, sensitive sub-populations and any concerns or uncertainties about the precision of toxicity and exposure estimates. Increased sensitivity of the young and exposure of infants and children, as well as pregnant women, to a pesticide are considered during the risk assessment process, with the goal of providing additional protection where warranted, consistent with the practice established by the U.

Food Quality Protection Act of Where reliable scientific data are available, a case specific determination as to the size of the additional factor is used. This approach is consistent with that of the U. The determination of whether the exposure is acceptable is made by comparing the estimated human exposure to the reference dose. Exposures that fall below the reference dose are considered to provide sufficient margins of safety and are unlikely to be associated with unacceptable risk to health. The assessment of a chemical's potential to cause cancer requires a different kind of assessment and expression of risk.

Cancer risk assessment for pesticides is based on evidence from cancer studies in at least two species, usually the rat and the mouse, together with evidence from in vitro and in vivo genotoxicity studies. The cancer studies are evaluated on the basis of the number and type of lesions elicited in test animals. They are typically carried out at dose levels that are much higher than expected human exposures.

These studies are in many cases complemented with studies that shed light on the mechanism by which the pesticide causes the carcinogenic effect. The outcome of the animal studies together with mechanistic considerations are used in a weight-of-evidence approach to decide if a pesticide is likely to pose a cancer risk to humans.

This type of approach is used by the International Agency for Research on Cancer in identifying agents that may pose a cancer risk to humans. The quantitative assessment of cancer risk requires the use of sophisticated statistical models to estimate potential cancer risks at the lower levels of exposure seen in humans. A model used widely for regulatory purposes is the linearized multistage LMS model. The acceptability of cancer risk is a risk management decision that cannot rely exclusively on a numerical standard, but needs to take into consideration all the factors that influence the risk.

Quantitative Approaches in Use to Assess Cancer Risk

Given historical actions of regulatory agencies such as the EPA , it is recognized that areas of regulatory concern for lifetime cancer risk are in the neighbourhood of 10 -4 to 10 These risk ranges are used by the PMRA as a guide in reaching decisions about the acceptability of lifetime cancer risk. Both types of risk assessment, the margin of safety approach and the quantitative cancer risk assessment, provide estimates of risk arising from defined exposures.

Usually the estimate reflects a "typical" exposure and use situation taking into consideration whether exposure is occasional or frequent and of short or long life-time duration. The PMRA currently aggregates exposure for a single pesticide active ingredient by combining exposures from all food residues and drinking water. The Agency will also take into account exposure from residential activities.

It should be noted that the aggregation of exposure is a concept only recently introduced by regulatory agencies. There are only a few chemical groups that are toxicologically well enough understood to allow estimation of cumulative risk the combined risk from several pesticides on the basis of a common mechanism of toxicity. The development of a standardized approach and appropriate methods to conduct cumulative risk and aggregate exposure assessments for pesticides with a common toxic mechanism are still under development. The assessment of environmental risk requires the integration of information on environmental exposure and effects.

Although the environmental risk assessment is in principle similar to human health risk assessment, it poses a very different challenge. It requires identification of the potential toxic effects to a vast number of organisms in the environment, and is focussed on potential effects on individuals, but can also include potential effects on species, ecosystems and the food chain. It is necessary to consider not only local effects at the site where the pesticide is being used, but also the potential of the pesticide to move and to be transported to other sensitive environmental compartments such as groundwater or lakes and rivers, or via atmospheric transport and deposition into remote environments.

Since it is not possible to study all potentially affected organisms and ecological systems, it is important to specify at the outset of a risk assessment the parts or levels of the environment intended to be protected. The PMRA includes in its consideration the maintenance of biological diversity, ecosystem health, achievement of sustainable development and the protection of particular species of animals or plants. The characterization of environmental risk identifies which, if any, organisms or ecosystems environmental compartments are at risk, and also identifies any uncertainties in estimating risk.

Based on this information, risk management strategies can be explored to see if any are available that might sufficiently mitigate the risk. It provides the basis for deciding if risk management strategies are necessary to ensure that there are no unacceptable environmental risks and provides a focus for protection of a particular environmental compartment. Environmental risk assessment is thus based on effects on indicator organisms and expected environmental exposures for defined environmental compartments.

A key component of the assessment is consideration of the persistence of a pesticide in the various environmental compartments and its potential for accumulation up the food chain.

Statistical Science

Laboratory and field studies, including acute and chronic toxicity tests in a range of standard test organisms from different taxonomic groups, are used to characterize the toxic response and to determine the dose-effect relationship of the pesticide and its major transformation degradation products. These are used as predictors for effects on ecosystems.

The adverse effects considered are lethal and sub-lethal effects, including mortality, organ toxicity and reduced growth. The median lethal dose or the median lethal concentration LD 50 or LC 50 and the median effective dose or the median effective concentration ED 50 or EC 50 are determined as well as the concentration at which there is no observed adverse effect, the No Observed Effect Concentration NOEC. Potential effects in non-target biota are assessed and characterized by using a series of internationally recognized indicator species.

Terrestrial species used represent the following major taxonomic groups: birds, mammals, terrestrial invertebrate species including insects and terrestrial plants. Potential effects in aquatic biota can be characterized in both freshwater and, when necessary, marine species that include fish and aquatic invertebrates, as well as algal species and aquatic vascular plants, both submergent and emergent.


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To estimate environmental exposure to pesticides, it is essential to know how, when and under what conditions a pesticide is being used and to predict from its behaviour and fate in the environment the extent of exposure concentrations in soil, surface and ground water at the use site and in other environmental compartments. For a pre-market assessment, the estimation of exposure is based to a significant degree on modelling of Expected Environmental Concentrations EECs. The modelling requires a detailed understanding of the physico-chemical properties and information on transformation rates.

These rates give an indication of the transformation potential in the various environmental compartments, sometimes under a range of different conditions. This is necessary to predict fate and transport of a pesticide in soil, water and air, as well as the potential for uptake by plants or animals and the transfer from organism to organism through the food web to higher trophic levels.


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The reliability of the models can be enhanced with results from field trials under conditions that reflect the Canadian environment. The larger the ratio, the larger the margin of safety, and the more limited the environmental impact is expected to be. This allows PMRA to decide when additional risk management options need to be implemented to ensure that environmental concentrations do not approach or exceed effect concentrations.

The PMRA is following closely recent advances in methods for environmental risk assessments on the basis of probabilistic exposure assessments and will consider incorporation of these new methods in future adjustments of its approach to environmental risk assessments. The determination of value is an important element of the pre-market evaluation of pest control products.

Value assessments, as conducted by the PMRA , consist of three components: an assessment of efficacy, of economic benefits and competitiveness, and of a pesticide's contribution to sustainability. The PMRA carries out a value assessment for all new pesticides corresponding to a new active ingredient or new formulation, or amendments to existing products proposing new uses, such as addition of new pests, new hosts or new application methods. The extent and focus of the value assessment is case specific.

It may include a review of all the components of efficacy, of economics and competitiveness and of sustainability, or a review of efficacy only for an amendment to add a new pest to a registered pesticide. The assessment of pesticide efficacy involves an evaluation of the pesticide's performance under field conditions. Pesticides that do not achieve an effective level of control or suppression of a pest are not candidates for registration, even if they do not pose risks to human health or the environment.

Where the efficacy of a pesticide is acceptable, the assessment serves to establish appropriate label claims or directions and the lowest application rate or rate range that is required to provide effective and consistent pest control, without unacceptable damage or injury to the host or crop and subsequent hosts or crops, under normal use conditions. In some cases, the objective is to attain the lowest overall amount of pesticide required to control the pest during a use season, rather than the lowest single application rate.

The efficacy of a pesticide is related to the concentration or amount of the pesticide that is used and the method and timing of use. These factors can also have a significant impact on the risks that are associated with the use. The required amount, method and timing of use for successfully dealing with a pest can lead to unacceptable risks, and thus preclude registration. There is also the possibility of modifying these factors while still maintaining an acceptable level of efficacy, thus providing a significant opportunity for developing risk management options.

Several aspects of product performance may be considered under the general category of efficacy assessment. These include the effectiveness of the pesticide in controlling the target pest, the tolerance of the host or crop to the pesticide applied and the tolerance of succeeding host s or crop s to the pesticide applied. Some or all of these components may be considered during the review of a submission, dependent upon the type of pesticide involved and the proposed use. Data for an efficacy assessment are derived from field or laboratory trials. Field trials are carried out at different geographical locations and can extend over more than one use season to allow determination of the pesticide performance over a variety of conditions.

In most cases, proof of efficacy establishes the nature of the expected benefits, so that the PMRA would not normally engage in an in-depth or extensive evaluation of benefits. Assessment of economic benefits and competitiveness may be undertaken in particular cases where aggressive risk management options must be developed.

A high economic value of the commodity to be protected usually allows consideration of a wider range of mitigation options than lower value commodities. In the case of high economic value, users may accept higher cost measures and thus more aggressive mitigation measures can be imposed. Otherwise, the product will not be registered. The PMRA assesses the compatibility of a pesticide with sustainable agricultural or industrial practices and production systems.

In particular, the assessment identifies existing alternative methods of control for the target pests, the fit of the pesticide with established integrated pest management IPM programs and the role of the pesticide in resistance management strategies. The PMRA also considers the potential impact on resistance development and the role a pesticide plays in the management of pesticide resistance. The introduction of a pesticide with an existing mode of action may accelerate the development of resistance, while a pesticide with a new, unique mode of action may provide the opportunity to delay the development of resistance, thus increasing its value.

The assessment of the value of a pesticide during re-evaluation has a particular purpose. During re-evaluation, value is examined under current conditions and in light of alternative pest control methods both chemical and nonchemical that may have been developed since the pesticide was first registered. The efficacy component of the value assessment is not repeated during re-evaluation because product performance has been established through its history of use.

With the development and implementation of IPM programs, however, the use of a pesticide may now be targeted to specific application times during the season, or the rate required for efficacy may be reduced owing to an IPM approach. In such cases, studies of pesticide efficacy from published sources may be incorporated in the reviews.

As discussed above, the outcome of the risk and value assessments can have various results which set the path for different regulatory decisions.

microbiological risk assessment in food safety: exposure assessment

When the risks to health and the environment are acceptable and the pesticide has value, i. In the context of a re-evaluation, the re-registration of an existing pesticide will be maintained. When a pesticide has value but the risks to health or the environment are unacceptable, PMRA will identify and develop risk management options to reduce the identified risk s in such a manner and to such an extent that the pesticide can be used without unacceptable risks to health and the environment. These mitigation options will reduce exposure and could include protective clothing for applicators, buffer zones to protect environment, reduction of application rates, and lengthening preharvest intervals.

The extent of these mitigation measures cannot reduce the efficacy beyond acceptable levels. If that is the case, the product is not registerable. When the risks to the environment or health, or the pesticide's value are unacceptable, and the risks cannot be mitigated through modifications of the conditions of use, then the registration of a new pesticide will be denied and, in the context of a re-evaluation, the registration of an existing pesticide will be discontinued or its uses will be phased out.

When the use of the pesticide is incompatible with federal policies and international agreements, such as the TSMP , the Montreal Protocol on ozone depleting substances and international agreements on POPs , or the use of a pesticide would contravene other federal acts, a new pesticide can be refused and the registration of an existing pesticide can be discontinued or its uses may be phased out. The outcomes of the assessments of risks to health and the environment, and the assessment of value, are the basis for the next step: identification and analysis of risk management options.

The goal is to identify a range of options that have the potential to reduce the extent of human and environmental exposures, and to analyse these options to determine if they can achieve acceptable risk standards for human health and the environment. The identification and analysis must be focussed and must be responsive to the nature and extent of risk, its source, the affected human population and the environmental populations and compartments that were identified in the risk assessment steps.

It is essential that the scientists who assessed the potential risks and risk managers participate in the identification and analysis of management options. As mentioned previously, the identification and analysis of risk management options is a dynamic process, requiring recalculation of risk under various risk mitigation scenarios. In many cases, the choice is not between individual risk management options, but the choice of a combination of options.

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Application of risk analysis to food standards issues

Thus, development of options must provide a clear basis to ensure that all risk elements are considered and are acceptable. The range of risk management options is constrained by legal and practical considerations. The risk management options must be consistent with the requirements of the Pest Control Products Act and must be legally enforceable. The development of risk management options, therefore, relies on mitigative measures that can be prescribed in the conditions of use, as prescribed on the legally binding label. The risk management options available under these legal constraints can include denial of registration or imposition of conditions and restrictions with respect to: classification of use domestic, commercial or restricted class , provincial permit requirement, professional qualification of applicator, specification of application technique and equipment, personal protective equipment, use conditions use quantities, application rates, timing and frequency of application, pre-harvest intervals, re-entry intervals , crops, use scenario, buffer zones and other mitigative measures to protect sensitive environments and particularly vulnerable plant and animal species, and safe storage and disposal.

Options can also consider changes to the pesticide product, such as changes to the formulation, or the physical and chemical make-up of the pesticide product. The practicality of risk management options is guided by a thorough understanding of the use situation, use practices, application technology, extent of use, and geographical location. This level of detailed understanding is necessary to focus the development of options on those that are appropriate and can realistically be achieved.

Quantitative Risk Assessment for Environmental and Occupational Health

The value assessment plays a significant role in defining some of the limits of management options because application rates, frequency, technology and practices influence the effective use of a pesticide. The efficacy assessment provides the basis for determining these practical limits. The value assessment also provides an estimate of the cost to the user of implementing a particular option. Since no management option is without cost, excessive or disproportionate costs can influence the benefit to the user.

It provides a measure for gauging the cost tolerance of the user and thus focuses the development of management options on realistic options. If the cost of reducing the risk to an acceptable level outweighs the benefit of the pesticide, it would not be registered. There is a growing recognition that, in addition to these regulatory approaches to risk mitigation, there are a number of ways to further strengthen the label statements to influence the pesticide users in their practices and choice of dealing with pests.

These additional management options have become increasingly important, particularly within the context of modern agriculture. They can significantly enhance regulatory measures and compliance. The PMRA is working with a variety of stakeholders, including user groups, to develop IPM programs to help reduce reliance on pesticides as a sole means of pest management.

The selection of a risk management strategy, including the selection of one or a combination of management options developed and elaborated in the previous step, involves a great deal of scientific expertise. Expertise has been built up in the PMRA over many years and on numerous practical examples. The selection of a strategy is to a significant degree based on data indicating that the anticipated risks to health and the environment are acceptable and that the pesticide is effective. It also includes experience in deciding if the selected strategy is practicable from both a use pattern and a compliance and enforcement perspective.

Part of the strategy selection process involves the recalculation of the margins of exposure or level of risk remaining under various possible management strategies. This recalculated level of risk provides a measure of how well a management option fulfills criteria of acceptable risk. Options that do not ensure that risks are within acceptable limits are not further pursued. The peer review is an in-depth assessment of the assumptions, calculations, extrapolations, alternate interpretations, methodology, acceptance criteria, and conclusions pertaining to specific work and of the documentation that supports them.

The following links exit the EPA website Exit. For example, the NAS places equal emphasis on fully characterizing the scope, uncertainties, limitations, and strengths of the assessment and on the social dimensions of interacting with decision makers and other users of the assessment in an iterative, analytic-deliberative process. The purpose of this process is to ensure that the assessments meet the intended objectives and are understandable.

EPA risk assessment practices have evolved over time along with this progression of thought, and in many cases helped drive the evolution of thinking on risk assessment. The Policy calls for all risk assessments performed at EPA to include a risk characterization to ensure that the risk assessment process is transparent; it also emphasizes that risk assessments be clear, reasonable, and consistent with other risk assessments of similar scope prepared by programs across the Agency.

Risk assessment

Effective risk characterization is achieved through transparency in the risk assessment process and clarity, consistency, and reasonableness of the risk assessment product-TCCR. Its mandate was to make a full investigation of the policy implications and appropriate uses of risk assessment and risk management in regulatory programs, under various federal laws, designed to prevent cancer and other chronic health effects that may result from exposure to hazardous substances. More specifically, its mandate was to provide guidance on how to deal with residual emissions from Section hazardous air pollutants HAPs after technology-based controls have been placed on stationary sources of air pollutants.

These discussed the importance of better understanding and quantification of risks, as well as the importance of evaluating strategies to reduce human and ecological risks. The Silver Book recommends that risk assessment should be viewed as a method for evaluating the relative merits of various options for managing risk, and not as an end in itself. This has a number of implications for the practice of risk assessment. It implies a greater need for upfront planning of the risk assessment, and the involvement of risk managers, risk assessors, and other stakeholders helps to determine the risk-management questions that risk assessment should address.

They also recommended the technical analyses within the risk assessment should be more closely aligned with the questions to be answered. For example, the level of detail of uncertainty and variability analyses should be determined by what is needed to inform risk management decisions. EPA used some of the recommendations from the Silver Book to support the development of the Human Health Risk Assessment Framework , and is currently working to incorporate other recommendations into its risk assessment policies and practices.

EPA is dedicated to helping you with whatever risk assessment issues you come across, but we recommend you try these first 2 steps before using the "contact us" option. The table below outlines several EPA offices or other federal agencies that are responsible for assessing and managing risks associated with particular stressors. Though the EPA Office contacts listed below go to the head of each office, you will need to request a "risk assessment specialist" so you are put in touch with the appropriate EPA staff. Contact Us to ask a question, provide feedback, or report a problem.

Jump to main content. An official website of the United States government. Contact Us. In general terms, risk depends on the following 3 factors: How much of a chemical is present in an environmental medium e. This was the first application of quantitative procedures developed by EPA to a large number of carcinogens, and the first EPA document describing quantitative procedures used in risk assessment. EPA has integrated the principles of risk assessment from this groundbreaking report into its practices to this day.

Although EPA efforts focused initially on human health risk assessment, the basic model was adapted to ecological risk assessment in the s to deal with risks to plants, animals and whole ecosystems. It is understood that risk assessment provides important information about the nature, magnitude, and likelihood of possible environmental risks to inform decisions — principles that evolved out of these many efforts.

Getting Help with Risk Assessment Issues EPA is dedicated to helping you with whatever risk assessment issues you come across, but we recommend you try these first 2 steps before using the "contact us" option. Contact the EPA hotline s. EPA has several topic specific hotlines, we recommend you try these if you know what type of issue you are requesting assistance with. Contact the Program Office or other Federal Agency. Some risk assessment related issues may actually be handled by other parts of the US Government.

EPA has in-house risk assessors on hand to assist our local offices and can direct you to the proper channels you need to report or receive assistance with a risk assessment issue. Visit our Where you Live page for contact information.

Scientific Issues in Quantitative Cancer Risk Assessment Scientific Issues in Quantitative Cancer Risk Assessment
Scientific Issues in Quantitative Cancer Risk Assessment Scientific Issues in Quantitative Cancer Risk Assessment
Scientific Issues in Quantitative Cancer Risk Assessment Scientific Issues in Quantitative Cancer Risk Assessment
Scientific Issues in Quantitative Cancer Risk Assessment Scientific Issues in Quantitative Cancer Risk Assessment
Scientific Issues in Quantitative Cancer Risk Assessment Scientific Issues in Quantitative Cancer Risk Assessment
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