Toxicological considerations exposure 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. 

Another uncertainty in the children s MOE analysis is that the biomonitoring data showed that perfluorooctanoates related to PFOA—per-fluorohexansulfonate and N-methyl perfluorooctanesulfonamidoacetate— were considerably higher in children than in adults. The reason is unknown, but the original authors suggest that it may reflect a different exposure pattern in children (Olsen et al. 2004). Toxicology and exposure data on these analytes are not sufficient to enable a separate risk assessment to evaluate the children s exposures. 

Selection of the appropriate metric for use in the risk assessment can have a significant impact on the outcome of an assessment. Regardless of the mathematical approach used, it is important that harmonized guidance exists for metric selection. Guidance should be based on a number of considerations, including data quality, data quantity, distribution type, duration of exposure and nature of the toxicology endpoint. Based on personal experience with numerous deterministic exposure assessments, it is clear that regulatory authorities differ with respect to input and output metric selections. 

In order to understand the use and intent of the various immunotoxicology regulatory guidelines and guidance documents, the difference between two concepts familiar to toxicologists should be emphasized. Hazard, identification refers to a method which is essentially qualitative that is, it is designed to detect the ability of a test article to produce a certain (in the context of toxicology) adverse effect, without reference to exposure issues. Risk assessment, on the other hand, takes into consideration method, dose, and duration of exposure, condition(s) of the exposed population, and concurrent... 

In this approach, the toxicological uncertainties are addressed as part of the hazard assessment and standard setting (Chapter 5), and are thus incorporated before considerations of exposure. 

The preclinical assessment for the safety of potentially new pharmaceuticals represents a special case in the general practice of toxicology. This phase has its own peculiarities and considerations and differs in several ways from the practice of toxicology. Pharmaceuticals, unlike industrial chemicals, agriculture chemicals, or environmental agents, are intended for human use and systemic exposure. Therefore, pharmaceuticals are specific in action and have biological effects on those treated for different diseases. 

Component-Based Methods. Component-based approaches (Figure 5.5) are generally used to evaluate human health risks from exposure to a limited number of chemicals as a mixture. Key issues for component-based assessments include similarity in dose-response curves and similar vs. independent toxic modes of action (MOAs) among mixture components. A distinction can be made between 1) assessments using relatively simple additivity methods without the consideration of potential interaction effects, and 2) assessments that include data on toxicological interactions. Both types of assessments are discussed in more detail below. 

Exposure estimates that are required for risk assessment may be obtained from chemical-specific field studies, or from extrapolations from other field studies. This requires high-quality exposure data that have been obtained under conditions relevant for the exposure and use scenarios under consideration (Krieger et al, 1992 Eenske and Teschke, 1995 Krieger, 1995 Turnbull et al, 1995). For risk assessment purposes, the exposure data obtained for relevant use scenarios can be compared with an appropriate accepted exposure level (e.g. Acceptable Operator Exposure Level (AOEL)) based on the toxicological profile of the compound. 

Tiered approaches to dermal exposure and risk assessment have been developed (OECD, 1997 de Heer et al, 1999 Harney, 2000 EC, 2002). Although the number of tiers differ depending on the specific approach, common to all approaches is the sequential refinement of the value used for dermal absorption in the risk assessment. For example, in a Tier 1 risk assessment, a conservative value of 100 % dermal absorption is often used. If required, a more refined default may be justifiable, based on a number of considerations such as the physico-chemical properties of the substance and the toxicological database. Use of dermal absorption data would be the third tier. Biological monitoring data would be a potential fourth tier, if required. 

---