Toxicity Exposure Ratio Approach

In the toxicity exposure ratio approach, the output of the hazard (effects) assessment is compared with the output of the exposure assessment. 

The direct comparison of a POD (DNEL) with the estimated exposure (E) leads to the establishment of a ratio (DNEL/E), often denoted as the margin of safety (MOS) or margin of exposure (MOE). 

According to the OECD/IPCS dehnitions listed in Annex 1 (OECD 2003)  

Margin of Exposure is Ratio of the no-observed-adverse-effect level (NOAEL) for the critical effect to the theoretical, predicted or estimated exposure dose or concentration.  

A related term is the margin of safety, which, according to the OECD/IPCS definitions listed in Annex 1 (OECD 2003), for some experts, has the same meaning as the margin of Exposure, while for others, the margin of Safety means the margin between the reference dose and the actual exposure dose or concentration. 

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The toxicity exposure ratio approach, rather than a more rigid standard setting approach (Section 8.2.2), allows greater room for expert judgment because the size of an overall assessment factor is not fixed. Furthermore, this approach can be readily applied to substances for which limited data are available. The risk assessor can decide how wide the MOS should be in the light of the data available. 

An alternative approach to the toxicity exposure ratio approach described in the previous section is the standard setting approach. 

The same uncertainties exist in moving from hazard assessment to the development of a regulatory standard (e.g., ADI/TDI) as in the standard setting approach, or in applying the hazard information to assessing the significance of a derived ratio (e.g., MOS/MOE) as in the toxicity exposure ratio approach, i.e., the uncertainties inherent in the hazard assessment. 

In the case of the toxicity exposure ratio approach, it is part of the consideration of the magnitude of the ratio (i.e., MOS/MOE) between the hazard assessment output and the exposure assessment output, i.e., by considering whether the ratio is large enough to accommodate the numerical factors that are used to allow for uncertainty. In should be recognized that, in this approach, the toxicological uncertainties are essentially similar to those involved in the standard setting approach. 

In accordance with the requirements of Annex VI of 91/414/EEC [7], where the basic principles for decision-making are laid down, Toxicity/Exposure Ratios (TER) are to be calculated. Uncertainty factors of 10 (chronic risk) and 100 (acute risk) must be applied for aquatic organisms. For terrestrial organisms, imcertainty factors of 5 and 10 are to be used, respectively. Different approaches exist for the in-crop area and non-target arthropods and bees in general. Uncertainty arises mainly from the fact that only for a few representative species toxicity data are available. If these trigger values are not breached, a listing of an active substance on Annex I or an authorization of a formulated product respectively are possible. 

The measure used to describe the potential for noncarcinogenic toxicity to occur in an individual is not expressed as tlie probability of an individual suffering an adverse effect. The EPA does not at tlie present time use a probabilistic approach to estimate tlie potential for noncarcinogenic healtli effects. Instead, tlie potential for non carcinogenic effects is evaluated by comparing an exposure level over a specified time period (e.g., lifetime) witli a reference dose derived for a similar exposure period. Tliis ratio of exposure to toxicity is called a liazard quotient and is described below. (The reader is referred to Chapter 11 for additional details on tlie material tliat follows). The noncancer liazard quotient assumes tliat tliere is a level of exposure (i.e., RfD) below which it is unlikely for even sensitive populations to experience adverse healtli effects. 

If the exposure level (E) exceeds tliis tlireshold (i.e., E/RfD exceeds unity), tliere may be concern for potential noncancer effects. As a rule, tlie greater tlie value of E/RfD above unity, tlie greater tlie level of concern. However, one should not interpret ratios of E/RfD as statistical probabilities a ratio of 0.001 does not mean tliat tliere is a one in one tliousand cliance of the effect occurring. Furtlier, it is important to empliasize tliat tlie level of concern does not increase linearly as tlie RfD is approached or exceeded because RfDs do not have equal accuracy or precision and are not based on tlie same severity of toxic effects. Thus, tlie slopes of the dose-response curv e in excess of the RfD can range widely depending on tlie substance. 

The measure used to describe the potential for noncarcinogenic toxicity to occur is not expressed as the probability. Probabilistic approach is used in cancer RA. For noncancer RA, the potential for noncarcinogenic effects is evaluated by comparing an exposure level (E) over a specified time period with a reference dose (RfD). This ratio is called a hazard quotient ... 

EPA recommends three approaches (1) if the toxicity data on mixture of concern are available, the quantitative risk assessment is done directly form these preferred data (2) when toxicity data are not available for the mixture of concern, data of a sufficiently similar mixture can be used to derive quantitative risk assessment for mixture of concern and (3) if the data are not available for both mixture of concern and the similar mixture, mixture effects can be evaluated from the toxicity data of components. According to EPA, the dose-additive models reasonably predict the systemic toxicity of mixtures composed of similar (dose addition) and dissimilar (response addition) compounds. Therefore, the potential health risk of a mixture can be estimated using a hazard index (HI) derived by summation of the ratios of the actual human exposure level to estimated maximum acceptable level of each toxicant. A HI near to unity is suggestive of concern for public health. This approach will hold true for the mixtures that do not deviate from additivity and do not consider the mode of action of chemicals. Modifications of the standard HI approach are being developed to take account of the data on interactions. 

Two other approaches are used to estimate noncancer risks from toxic chemicals margin of exposure and therapeutic index. Both are less formal and more approximate than the hazard index. The margin of exposure (MOE) is the ratio of the NOAEL in an animal toxicity study to the CDI projected for a human population. Uncertainty factors are omitted from the calculation. Eor example, if the NOAEL for reproductive toxicity were, say, 1.5 mg/kg/day, and the CDI were 0.003 mg/kg/day, then the MOE would be 500. The MOE is interpreted by comparing it to a margin of safety (MOS) established by a government agency. In general, an MOE of less than 100 is considered to be cause for concern. 

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