Risk characterization

Risk characterization is the calculation of risk for all potential receptors that may be exposed to hazardous wastes. It includes calculating risk for different exposure routes to both noncarcinogenic and carcinogenic hazardous chemicals. Often this requires the use of toxicological data derived from animal studies. Furst (1994) discussed issues in the interpretation of this data, and suggested that animal toxicity data should only be used for risk calculation when experiments employ routes that mimic human exposure (i.e., oral, inhalation, or dermal). 

Risk characterization estimates tlie healtli risk associated with tlie process under investigation. The result of tliis cliaracterization is a number tliat represents tlie probability of adverse healtli effects from tliat process or from a substance released in tliat process. For instance, a risk cliaracterization for all effects from an incineration process might be expressed as one additional cancer case per 1 million people. 

Once a risk characterization is made, tlie meaning of tliat risk must be evaluated. Public hetiltli agencies generally only consider risk greater tlian 10 in 1 million (10 or lOxlO ) to be significant risks warranting action. 

Several major t qies of risk are detailed below. 

Individual Risk - This provides a measure of tlie risk to a person in tlie vicinity of a liazard/accideiit, including tlie nature of the injury or otlier undesired outcomes, and tlie likelihood of occurrence. Individual risk is generally expressed in terms of a likelihood or probability of a specified undesired outcome per unit of time. For example (as indicated above), tlie 

Moximum Individual Risk (MIR) - Tliis is tlie maximum risk to an individiuil person. This individual is considered to have a 70-year lifetime of exposure to a process or a chemical. For discliarge from a stack, for instance, tlie individual is considered to live downwind of the stack, never leaving tliis spot for every hour and every day of a 70-year life. 

Risk characterization a measurement or estimation of both current and future adverse effects (USEPA, 1989c). 

Ecological risk may be expressed as a true probabilistic estimate of risk or may be deterministic or even qualitative in nature. The likelihood of adverse effects is expressed through a semi-quantitative or qualitative comparison of effects and exposure. 

The approach to ecological risk assessment emphasizes three areas (Norton et al., 1995)  

Ecological risk assessment can consider effects beyond those on individuals and the populations of a single species and may examine multiple populations, communities and ecosystems. 

There is no single set of ecological values to be protected (e.g. health effects such as cancer or birth defects) that can be applied generally. Values are selected from a number of possibilities based on both scientific and policy considerations. 

Risk characterization combines the results of the hazard assessment and exposure assessment to project the potential risk to human health or the environment. The way in which it is done in the European Union under REACH illustrates the process [76]. 

A risk characterization comprises a series of evaluations, each pertaining to a specific population, route of exposure, and frequency and duration of exposure. (ECHA refers to this combination of factors as the exposure pattern ) Assessors characterize the risk to human health by comparing the estimated exposure level for a given exposure pattern with the lowest DNEL/DMEL value for that exposure pattern. If the exposure could exceed the DNEL/DMEL, resulting in a risk characterization ratio (RCR) above 1, then the risk could be significant. 

Similarly, an environmental risk characterization is carried out by comparing the predicted exposure concentrations (PECs) with the corresponding PNECs. If a PEC exceeds the corresponding PNEC, then the risk may be significant. A series of comparisons may be performed to assess the risks at different trophic levels, in different media, or at different scales (e.g., regional versus local). 

The process is often iterative. If an assessment made using worst-case assumptions shows that the risk would be acceptable, then no refinement is necessary if the worst-case calculations show that the risk would be significant, however, then the assessor often gathers additional information to refine the assumptions. 

Even the most sophisticated risk assessment has limitations. It involves numerous assumptions about both exposure and hazard. Exposure assessments typically reflect modeled concentrations or extrapolations from measured data. The degree of exposure by different individuals may vary, and their response can depend on factors such as general health, genetic predisposition, or other factors. Dose-response factors are typically extrapolated from animal studies and thus inherently introduce the imcertainty of relating the response of laboratory animals to that of humans or one of the many species in an ecosystem. The endpoints characterized may not include all of the potential effects for example, the potential for endocrine disruption has not been considered in many risk assessments and in fact standardized testing methods were not published until approximately 2007 or later [90]. And risk assessment tools only model relatively simple scenarios. They rarely account for exposure to multiple chemicals, or fully accoimt for the effects on a complex web of organisms in an ecosystem. 

Integration of the results of the first three steps in a risk assessment typically results in a quantitative estimate of risk. Estimated 

ENGINEERED BARRIER BREACH (DEGRADATION AND FAILURE OF ENGINEERED BARRIERS) 

GEOSPHERE TRANSPORT (HAZARDOUS SUBSTANCE TRANSPORT THROUGH THE GEOSPHERE) 

PERFORMANCE MEASURES (HAZARDOUS SUBSTANCE INVENTORY AND HEALTH EFFECTS) 

The final step of the risk-assessment process, risk characterization, is a narrative that incorporates all the information assembled in the previous three steps. It also marshals qualitative evidence of risk that is not included in the formal risk-assessment calculations. The narrative weighs all the evidence and uses professional judgment to draw conclusions regarding risk. 

Using the PECs from section 6 and the above PNECs (Table 28), both based on the organotin chlorides, risk ratios (PEC/PNEC) can be derived for each of the identified uses of organotins these are summarized in Table 29. Regional PEC/PNEC ratios are given in Table 30. 

Lack of exposure data for most organotins together with limited toxicity information for marine organisms preclude the calculation of risk factors for the marine environment. For dibutyltin, measured concentrations in seawater reflect the use of tributyltin as a marine anti-foulant rather than the use of dibutyltin in plastics. It is therefore not possible to conduct a reliable risk assessment for the current uses of the compormd. 

It is important that both the qualitative and quantitative characterization be clearly communicated to the risk manager. The qualitative characterization includes the quality of the database, along with strengths and weaknesses, for both health and exposure evaluations the relevance of the database to humans the assumptions and judgements that were made in the evaluation and the level of confidence in the overall characterization. The quantitative characterization also includes information on the range of effective exposure levels, dose-response estimates (including the uncertainty factors applied), and the population exposure estimates. Kimmel et al. (2006) reviewed many of the components of the risk characterization for reproductive and developmental effects and provided a comprehensive list of issues to be considered for each of the components of the risk assessment. 

In general, integration of the health and exposure assessments should include statements regarding the relevance of the route, timing, and duration of exposure modelled from the experimental 

The uncertainties and variability of the database, along with the judgements and assumptions that were made during the assessment, should be clear. The description should include the major strengths and weaknesses of the database and the limits of understanding of particular mechanisms of toxicity that may be involved in the effect(s). Whenever alternative views can be supported by the database, these should be addressed in the risk characterization. If the assessment favours one view over others, the rationale for choosing that view should be stated. 

The use of Monte Carlo and other stochastic analytical methods to characterize the distribution of exposure and dose-response relationships is increasing (IPCS, 2001a). The Monte Carlo method uses random numbers and probability in a computer simulation to predict the outcome of exposure. These methods can be important tools in risk characterization to assess the relative contribution of uncertainty and variability to a risk estimate. 

Three types of descriptors of human risk are especially useful and important in risk characterization (Kimmel et al., 2006). The first of these is related to interindividual variability — i.e. the range of variability in population response to an agent and the potential for highly susceptible subpopulations. The second is related to highly exposed individuals — i.e. individuals who are more highly exposed because of occupation, residential location, behaviour, or other factors. The third descriptor that is sometimes used to characterize risk is the margin of exposure (MOE) — i.e. the ratio of the NOAEL (or BMDL/BMCL) from the most appropriate or sensitive species to 

These basic differences between the toxicity values describing cancer and noncancer effects are important because they impact the way in which the next step, risk characterization, is conducted. In addition, these differences make interpreting the results of the risk characterization more complicated. 

This is the component of a risk assessment where risks are estimated by combining exposure and toxicity information for the chemicals at a site. There is an important distinction between cancer and non-cancer chemicals in this step. These two types of effects are separately discussed below. 

Typically, sites in the United States are managed by U.S. EPA and most states so that the extra cancer risk from chemical exposure is no greater than one chance in one million, or 1x10 . This means that, if one million people were exposed to the same concentrations as found at a site and all received identical doses over the same time period, one person would develop cancer due solely to the chemicals present at the site. In reality, the affected populations are typically much smaller 

For the non-cancer effects of chemicals, risks or probabilities of effects are not estimated. This is because, unlike the assumption of no threshold used for cancer chemicals, there are doses below which no adverse effects are expected from chemical exposure for non-cancer effects of chemicals. Instead of generating a risk, the estimated dose is divided by the reference dose, which is considered a safe level below which toxicity is not expected to occur. The result of this division is a ratio that will either be above or below one. This ratio is referred to either as a hazard quotient, if only one chemical is considered, or a hazard index, if multiple chemicals are included. If the ratio is below one, this means that the estimated dose is below the threshold dose, and no toxicity is expected. If the ratio is above one, the estimated dose is above the threshold dose, and toxicity may result. Ratios above one do not mean that toxicity will resnlt, but that there is a chance of this occurring. The higher the ratio is above one, the greater the chance that toxicity can result from exposure. 

Therefore, calculation of excess risk is only relevant for cancer effects of chemicals. For all other effects, there is either no risk (if the ratio is below one), or some degree of likelihood that adverse effects can occur (if the ratio is above one). This degree of likelihood for non-cancer effects of chemicals is typically referred to cis hazard. Regulatory agencies typically manage the non-cancer effects of chemicals so that concentrations at a site resnlt in ratios no greater than one. Therefore, non-cancer effects would not be expected from chemical exposure at properly managed sites. 

European Community Regulations 470/2009 and 37/2010 have introduced a new system of classification, whereby all pharmacologically active substances are now listed in a single annex in alphabetical order in two tables, the first to include all compounds listed in Annexes I, II, and III and a second table listing prohibited substances from Annex IV. In the United States procedures are broadly similar [see Code of Federal Regulations (CFR) Title 21, Part 556, on the FDA website ]. In the United States a tolerance is not required if there is no reasonable expectation that residues may be present, or when the drug is metabolized or assimilated into tissues in such form 

There is no consistency in procedures used to establish MRLs either between national authorities and JECFA or, indeed, between different national authorities. This is regrettable from a sponsor s perspective, as it may involve, at worst, several similar studies (with major implications for animal welfare and added expense) and variance in achieving (or not) a MA between jurisdictions. The rational procedures proposed by JECFA for MRL determination are based on three premises (1) they can be enforced by regulatory programs that use available analytical methods, 

Practically, the MRL is that point on the tolerance limit as defined above at or beyond which the predicted EDI using the median concentration guarantees that EDI ADI. 

In contrast, the EU approach consists of computing a TMDI using MRL, not median residue concentrations CVMP criticized the JECFA approach for its intrinsic limitation to a chronic risk scenario and also for several technical reasons, including difficulties of using linear regression to estimate the tolerance limit of residue concentrations with its confidence interval and to the rather loose concept of good veterinary practice. (For further details, see Ref. 106. For further details on and a discussion of the USFDA approach, see Refs. 105 and 108.) 

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Risk characterization is defined as the integration of the data and analysis of the above three components to determine the likelihood that humans wiU. experience any of the various forms of toxicity associated with a substance. When the exposure data are not available, hypothetical risk is characterized by the integration of hazard identification and dose—response evaluation data. 

Hazard characterization and delineation of dose-effect or dose-response relationships. 3. Assessment of exposure 4. Risk characterization... 

Risk characterization should preferentially include qualitative and, if possible, also quantitative risk assessment based on steps 1-3. 

In risk characterization, step four, the human exposure situation is compared to the toxicity data from animal studies, and often a safety -margin approach is utilized. The safety margin is based on a knowledge of uncertainties and individual variation in sensitivity of animals and humans to the effects of chemical compounds. Usually one assumes that humans are more sensitive than experimental animals to the effects of chemicals. For this reason, a safety margin is often used. This margin contains two factors, differences in biotransformation within a species (human), usually 10, and differences in the sensitivity between species (e.g., rat vs. human), usually also 10. The safety factor which takes into consideration interindividual differences within the human population predominately indicates differences in biotransformation, but sensitivity to effects of chemicals is also taken into consideration (e.g., safety faaor of 4 for biotransformation and 2.5 for sensitivity 4 x 2.5 = 10). For example, if the lowest dose that does not cause any toxicity to rodents, rats, or mice, i.e., the no-ob-servable-adverse-effect level (NOAEL) is 100 mg/kg, this dose is divided by the safety factor of 100. The safe dose level for humans would be then 1 mg/kg. Occasionally, a NOAEL is not found, and one has to use the lowest-observable-adverse-effect level (LOAEL) in safety assessment. In this situation, often an additional un-... 

The risk characterization, where the likelihood of an exposure sufficient for an impact is estimated. 

Most human or environmental healtli hazards can be evaluated by dissecting tlie analysis into four parts liazard identification, dose-response assessment or hazard assessment, exposure assessment, and risk characterization. For some perceived healtli liazards, tlie risk assessment might stop with tlie first step, liazard identification, if no adverse effect is identified or if an agency elects to take regulatory action witliout furtlier analysis. Regarding liazard identification, a hazard is defined as a toxic agent or a set of conditions that luis the potential to cause adverse effects to hmnan health or tlie environment. Healtli hazard identification involves an evaluation of various forms of information in order to identify the different liaz.ards. Dose-response or toxicity assessment is required in an overall assessment responses/cffects can vary widely since all chemicals and contaminants vary in their capacity to cause adverse effects. This step frequently requires that assumptions be made to relate... 

In risk characterization, the toxicology and exposure data are combined to obtain a quantitative or qualitative expression of risk. 

Dose-Response Evaluation The process of quantitatively evaluating toxicity information and characterizing the relationship between the dose a contaminant administered or received, and the incidence of adverse health effects in the exposed population. From a quantitative dose-respoiise relationship, toxicity values can be derived that are used in the risk characterization step to estimate the likelihood of adverse effects occurring in humans at different exposure levels. 

Risk characterization is lire process of estimating llie incidence of a health effect under the various conditions of human or animal exposure described in lire exposure assessment. It is performed by combining the exposure (see Cliapter 12) and dose response (see Cluipter 11) assessments. The summary effects of the uncertainties in lire preceding steps should also be described in lliis step. 

A risk estimate indicates the likelihood of occurrence of the different types of health or enviromiiental effects in exposed populations. Risk assessment should include both human healtli and environmental evaluations (i.e., impacts on ecosystems). Ecological impacts include actual and potential effects on plants and animal (otlier than domesticated species). The numbers produced from the risk characterization, representing tlie probability of adverse health effects being caused, must be evaluated. 

In tlie risk characterization, conclusions about hazard and dose response are integrated witli those from the exposure assessment. In addition, confidence about tliese conclusions, including information about tlie micertainties associated with each aspect of the assessment in the final risk sununary. should be higlilighted. In tlie previous assessment steps and in tlie risk characterization, tlie risk assessor should also distinguish between variability and uncertainty. 

Risk characterization is tlie process of estimating tlie incidence of a healtli effect under tlie various conditions of human or animal exposure as described in the exposure assessment. It evolves from both dose exposure assessment and toxicity response assessment. The data are then combined to obtain qualitative and quantitative expression of risk. 

The risk assessment steps and the risk characterization are influenced by uncertainty and variability. Variability arise from heterogeneity such as dose-response differences within a population, or differences in contaminant levels in tlie environment. Uncertainty on tlie other lumd, represents lack of knowledge about factors such as adverse effects or contaminant levels. 

Risks to human health and the environment will vary considerably depending upon the type and extent of exposure. Responsible authorities are strongly encouraged to characterize risk on the basis of locally measured or predicted exposure scenarios. To assist the reader, examples of exposure estimation and risk characterization are provided in CICADs, whenever possible. These examples cannot be considered as representing all... 

Based upon the review of the toxicological data, reliable lifetime TDI values for the organotin species in question cannot be derived, since long-term studies at the appropriate doses and in the appropriate species are not available. Medium-term exposure results have therefore been used to derive TDIs for preliminary risk characterization. For dimethyltin, there is a reliable NOAEL as a basis for setting a TDI against a neurotoxicity endpoint. For the remaining compounds, best estimates of amedium-term exposure TDI for preliminary risk characterization have been derived from the available studies (Table 25). 

Based upon the various sources of adult consumer exposure to organotin compounds (section 6) and the TDI values derived above, it is possible to estimate the relative exposure from the various organotin compounds expressed as a percentage of the TDI values. The exposure calculations in section 6 were based on a realistic worst-case exposure assessment. Table 26 presents the results of this risk characterization. 

Table 26 Worst-case adult consumer risk characterization as percentage of TDI.

Exposure of both consumers and organisms in the environment is highly dependent on accurate values for production and use results presented here are based on refined information provided by industry following an earlier draft risk characterization, ft is beheved to be as accurate as possible. 

Risk characterization is the last step in the risk assessment procedure. It is the quantitative or semi-quantitative estimation, including uncertainties, of frequency and severity of known or potential adverse health effects in a given population based on the previous steps. Risk characterization is the step that integrates information on hazard and exposure to estimate the magnitude of a risk. Comparison of the numerical output of hazard characterization with the estimated intake will give an indication of whether the estimated intake is a health concern. ... 

The degree of confidence in the final estimation of risk depends on variability, uncertainty, and assumptions identified in all previous steps. The nature of the information available for risk characterization and the associated uncertainties can vary widely, and no single approach is suitable for all hazard and exposure scenarios. In cases in which risk characterization is concluded before human exposure occurs, for example, with food additives that require prior approval, both hazard identification and hazard characterization are largely dependent on animal experiments. And exposure is a theoretical estimate based on predicted uses or residue levels. In contrast, in cases of prior human exposure, hazard identification and hazard characterization may be based on studies in humans and exposure assessment can be based on real-life, actual intake measurements. The influence of estimates and assumptions can be evaluated by using sensitivity and uncertainty analyses. - Risk assessment procedures differ in a range of possible options from relatively unso-... 

Renwick, A.G., Risk characterization of chemicals in food, Toxicol. Lett., 149, 163, 2004. 

There is a growing need to better characterize the health risk related to occupational and environmental exposure to pesticides. Risk characterization is a basic step in the assessment and management of the health risks related to chemicals (Tordoir and Maroni, 1994). Evaluation of exposure, which may be performed through environmental and biological monitoring, is a fundamental component of risk assessment. Biomarkers are useful tools that may be used in risk assessment to confirm exposure or to quantify it by estimating the internal dose. Besides their use in risk assessment, biomarkers also represent a fundamental tool to improve the effectiveness of medical and epidemiological surveillance. 

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