Toxicity exposure ratio

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

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. 

Safety or uncertainty factors are often applied at the end of an assessment, for example, as a level of concern to which a risk quotient or toxicity-exposure ratio is compared. 

Guidance to date supports the risk assessment principles for general chemical substances already published by the Commission (1996). Consequently, the risk characterisation simply involves a quantitative comparison of the outcome of the hazard/effects assessment with the exposure assessment. For human risk this involves the calculation of the TER (Toxicity Exposure Ratio) and comparing it with the MOS (Margin Of Safety). For environmental risk the PEC/PNEC ratio (Predicted Environmental Concentration versus the Predicted No-Effect Concentration) for the various environmental compartments. 

Society of Environmental Toxicology and Chemistry Toxicity exposure ratio... 

The outcome of the risk assessment is expressed in real-world effects instead of a toxicity exposure ratio (TER) number, for which it is unclear how protective it is in terms of effects in the field. 

As shown in the risk assessment figure, the decision making takes place at the risk characterisation step, where the results of the environmental distribution, the calculated concentration, and the ecotoxicological data, the effect concentration, come together. The most common way is to divide the predicted environmental concentration by the effect concentration in the acute or chronic situation, called the PEC-PNEC-ratio. In the European Union the toxicological concentration is divided by the predicted environmental concentration revealing the TER the toxicity-exposure-ratio. 

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. 

Birds and mammals may be exposed to toxic effects of active substances following the field use of plant protection products. In current ecotoxicological risk assessments for pesticide registration endpoints, of toxicity tests are compared with estimations of the expected exposure of wildlife species in the field. From the data on toxicity and exposure, a risk quotient (e.g., TER Toxicity Exposure Ratio) is calculated and compared to safety factors (e.g., 10 for acute risk). If the quotient is larger than the safety factor, the risk is considered to be acceptable. On the other hand, if the quotient is below the safety factor, a possible risk is indicated and further refinement of the input parameters is necessary to show that no risk for wildlife species will exist when the substance is applied under practical field conditions. 

From a purely pragmatic perspective, it is clear that reactive metabolites are linked with toxicity and that a circumstantial link can be made to idiosyncratic toxicides. Consequently, even though the mechanism of this toxicity is not fully understood, since assays are available to measure the potential for bioactivation in an ideal world one would not carry this liability forward. Conversely, it is not an ideal world, all drug molecules have challenges and the definition of therapeutic index (i.e., the ratio between the toxic exposure and the therapeutic exposure) is critical. Covalent binding of reactive metabolites to macromolecules is a crude measure and not a full predictor of toxicity and it is well known that toxicity can be ameliorated by a lower dose. Furthermore, the so-called definitive assays require radiolabeled drug material which is expensive and generally slow to produce. 

The sex ratio has been used to monitor developmental toxicity. Declining sex ratios (fewer males) have been recorded over the last 50 years for a number of regions, including Denmark, the Netherlands, Canada and the USA (Allan et al., 1997 Safe, 2000). Several reports have implicated pesticide exposure, but the change in rate of male births in Finland in the last 250 years antedated any increase in exposure to environmental chemicals (Vartianen et al., 1999). The problem is difficult to study, because a very large population is required to determine if any changes observed are random variations or reflections of toxicant exposure. 

AAPCC-TESS American Association of Poison Control Centers-Toxic Exposure Surveillance System ALT Alanine aminotransferase ARDS Adult respiratory distress syndrome AST Aspartate aminotransferase BUN Blood urea nitrogen ECG Electrocardiogram INR International normalization ratio NAPQI A-acetyl-/>-benzoquinone-imine PPPA Poison Prevention Packaging Act (of 1970)... 

Exposure multiple or exposure ratio is a common term used in the pharmaceutical industry to describe the fold of exposure of Cmax or AUC observed at doses used in toxicity studies, compared to the Cmax or AUC at the highest marketed dose in humans or projected therapeutic dose based on preclinical data. This number provides an estimate for the safety margin of a compound and is helpful for guiding the dose selection of drug safety studies. 

Chemical Toxicity. Radiopharmaceuticals are subject to the same requirements for safety as are other pharmaceuticals, and are tested for chemical toxicity in much the same manner. It is generally understood, however, that patients are likely to receive relatively few doses of any given radiopharmaceutical so that the effects of long-term chronic exposure to the compound rarely need be assessed. Safety margins, that is, the ratio of the adininistered dose to the lowest dose that produces an observable effect, are usually on the order of 100 or more. 

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