Risk characterization ratio

The risk characterization procedure will result in a quantitative comparison per substance of the outcome of the exposure assessment and of the effects assessment. This comparison is made through the ratio PEC/PNEC. The generic name for PEC/ PNEC in EUSES is risk characterization ratio (RCR). Other ratios are used in EUSES for the risk characterization such as the margin of safety (MOS) or the ratio of the estimated no-effect or effect level parameter to the estimated exposure level for human subpopulations and the acceptable operator exposure level (AOEL). 

Finally, if the registrant can prove that all risks are under control and the substance can be safely manufactured and used, the corresponding initial exposure scenario is defined as the final exposure scenario. In the end, the final exposure scenario is communicated within the framework of extended safety data sheets in order to ensure the safe use of the substance down the supply chain (Caveat The legal text of REACH usually refers to the term exposure scenario while in reality speaking of the final exposure scenario.) By contrast, if the registrant fails to lower the risk characterization ratio below 1, despite the aforementioned refinements and modifications, he must prevent the use of the substance under circumstances where the risks are not controlled. 

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. 

The CSR indicates that the risk characterization ratio is not far below 1 (for human and/or environmental exposure)... 

Risk characterization based on comparing either predicted or measured environmental concentrations with effects data for the most sensitive organisms (PEC/ PNEC or MEC/PNEC, respectively). An environmental risk is considered unacceptable if the ratio equals or exceeds 1. In general, this phase considers the worst-case scenario. 

The POD is used as the starting point for subsequent extrapolations and analyses. For linear extrapolation, the POD is used to calculate a slope factor, and for nonlinear extrapolation the POD is used in the calculation of a Reference Dose (RfD) or Reference Concentration (RfC). In a risk characterization, the POD is part of the determination of an MOE, defined as the ratio of the POD over an exposure estimate (MOE = POD/Exposure). 

In this approach, the toxicological uncertainties, which are essentially similar to those involved in standard setting for threshold effects (Chapter 5), are addressed as part of the risk characterization step, i.e., considering whether the ratio is sufficiently large to give the degree of confidence that the exposure situation will not result in adverse human health consequences. 

The risk characterization is carried out by quantitatively comparing the outcome of the hazard (effects assessment) to the outcome of the exposure assessment, i.e., a comparison of the NOAEL, or LOAEL, and the exposure estimate. The ratio resulting from this comparison is called the Margin of Safety (MOS) (MOS = N(L)OAEL/Exposure). This is done separately for each potentially exposed population, i.e., workers, consumers, and man exposed via the environment, and for each toxicological endpoint, i.e., acute toxicity, irritation and corrosion, sensitization, repeated dose toxicity, mutagenicity, carcinogenicity, and toxicity to reproduction. 

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... 

The human health risk characterization is typically carried out by comparing the No-Observed-Adverse-Effect-Level (NOAEL) to the human exposure level. The ratio is called Margin of Safety. If human exposure is estimated to exceed the NOAEL, the substance is considered to be of concern . If the exposure estimate is less than the NOAEL, the appropriate margin of safety is assessed case-by-case (European Commission 2003a). 

The environmental risk characterization is typically carried out by comparing the predicted no effect concentration (PNEC) to the predicted environmental concentration (PEC). A PEC/PNEC ratio above 1 indicates that the substance poses a potential risk to the environment (European Commission 2003a). 

A second use for NOAELs (or LOAELs) is in the calculation of a proposed margin of exposure (MOE) for developmental toxicity to be used in risk characterization. The MOE is defined as the ratio of the NOAEL from the most sensitive or appropriate species to the estimated human exposure level from all potential sources. If the MOE is very high relative to the estimated human exposure level, then risk to the human population would be considered low. 

As stated at the outset of the section on threshold agents, risk is characterized (Step 4) by deriving what is sometimes called a hazard index, the ratio of known or expected doses incurred by the human population (Du) to the RfD, TDI, ADI, or MRL. A hazard index exceeding 1.0 suggests a risk that is, it can be taken to mean that some members of the population are exposed at levels exceeding the estimated population threshold. It is an unquantified risk, in two senses. First, although the RfD (or other estimates of safe dose) is considered... 

The comparison of the T25 method with the LMS method showed a good correlation between the two methods (correlation coefficient of 0.85 in a log-log plot) for 33 substances identified in the US-EPA IRIS database. The ratios between the lifetime cancer risks calculated by the T25 method and the LMS method were in the range 0.5-2.0 for 30 out of the 33 substances (calculated for the 10 lifetime cancer risk). The distribution of the ratios was plotted and the parameters characterizing this distribution were estimated. The mean and the median were both 1.21, the 5 th and 95 th percentiles were 0.50 and 1.87, respectively, and the minimum and maximum values were 0.45 and 2.31, respectively. For 24 substances, the T25 method gave a higher result than the LMS method, and for the remaining 9 substances a lower result. 

The third descriptor that is sometimes used to characterize risk is the margin of exposure ( ). The is the ratio of the NOAEL (or BMD) from the most appropriate or sensitive species to the estimated level of human exposure from all potential sources. 

However, the exceptional size-specific behavior of nanomaterials in combination with their relatively large surface-to-volume ratio might result in potential risk for human health and the environment [26-28]. For example, fullerene (C60) particles suspended in water are characterized by antibacterial activity against Escherichia coli and Bacillus subtilis [29] and by cytotoxicity to human cell lines [30]. Single- and multiwalled carbon nanotubes (CWCNTs and MWCNTs) are toxic to human cells as well [31, 32]. Nano-sized silicon oxide (Si02), anatase (Ti02), and zinc oxide (ZnO) can induce pulmonary inflammation in rodents and humans [33-35],... 

Problems that have been solved in the risk assessment of single substances have not been solved equally well in mixture assessments. Even the most generic question in prospective risk analyses— What is a safe level —poses problems. Often the mixture composition is unknown, and the mixture problem is then that the safe level would only be applicable to that particular mixture. Even if the mixture composition is well characterized, the safe exposure or concentration level would apply only to mixtures with the same or similar concentration ratios between the mixture compounds, as in cigarette smoke, diesel exhaust, or some polychlorinated biphenyl (PCB) mixtures. One option in such cases is to set a safe level for the mixture by using one of the mixture components as an indicator compound for the whole mixture. If the concentration ratios between the mixture compounds vary, there is no unique safe mixture concentration, but an infinite number of possible safe concentration combinations. 

The first step of the framework is a clear description of the mixture problem at hand, including the assessment goals and strategy (Section 5.4.1). The next step is the choice of one or more suitable methods for assessing mixture effects. This choice depends on the mixture problem at hand, for example, whether the mixture composition is known, its frequency of occurrence, the variation in concentration ratios, and the availability of toxicity data (Section 5.4.2). A distinction is made between assessment methods that estimate the toxicity of the mixture as a whole and component-based methods. Different methods for whole mixture assessment are discussed, varying from inaccurate to accurate and from poorly characterized to well characterized (Section 5.4.3). The component-based methods are discussed within the framework of a tiered approach, varying from rough methods that likely produce a conservative estimate of mixture risk to sophisticated methods that likely produce more accurate estimates (Section 5.4.4). 

A risk assessor has different options to evaluate the potential effects of a mixture. This raises the question of which option should be preferred in a particular situation. The answer depends not only on the level of determinacy of the mixture, but also on other factors, for example, the capacity to further chemically characterize the mixture, whether it is a common or rare mixture, whether the concentration ratios between the components are more or less stable, and whether data on a sufficiently similar mixture are available. For example, it does not seem sensible to put much effort into full characterization of the mixture components if dealing with a rare mixture of unique composition. In this situation, it is more efficient to test a mixture sample directly in the laboratory or the held. 

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