Experimental conditions, risk assessment

In section 2.3 of this chapter the present approach to characterisation of dose-response relationships was described. In most cases it is necessary to extrapolate from animal species that are used in testing to humans. It may also be necessary to extrapolate from experimental conditions to real human exposures. At the present time default assumptions (which are assumed to be conservative) are applied to convert experimental data into predictive human risk assessments. However, the rates at which a particular substance is adsorbed, distributed, metabolised and excreted can vary considerably between animal species and this can introduce considerable uncertainties into the risk assessment process. The aim of PB-PK models is to quantify these differences as far as possible and so to be able to make more reliable extrapolations. 

The first type concerns the hazards of these chemicals their flammability, their explosivity, their radioactivity, and their toxicity. In the present context we are interested in the toxic properties of these chemicals. So, it would be necessary, under what is called the hazard evaluation step of risk assessment, to assemble all the available epidemiology and experimental toxicity data (the latter to include animal toxicity studies, ADME data, and studies of mechanisms of toxic action). The assembled data would then be critically evaluated to answer the question what forms of toxicity can be caused by the chemical of interest, and how certain can we be that human beings will be vulnerable to these toxic effects (under some conditions) ... 

A similar conclusion was derived from analysis of how data are used in making pesticide risk assessments, where the authors concluded that the inability to match a specific exposure scenario to available data (c.g., species and duration of dosing) led to overestimation of absorption and thus risk Ross et al., 2000). The take home lesson from this chapter is that the experimental conditions under which pesticide absorption studies are conducted often overshadow differences between individual compounds, as can easily be appreciated in the classic studies comparing absorption of pesticides in mice (Shah el ai, 1981) versus humans (Fcidmann and Maibach, 1974). 

Great efforts have been made to develop methods for quantitative assessments of dermal absorption. For risk assessment of chemical mixtures, many challenges are encoimtered (1) lack of quantitative data for chemical mixtures because most of the data are measured with individual chemicals (2) even for individual chemicals, only limited data acquired under comparable experimental conditions, and many data acquired imder incomparable conditions are not useful for the uigent need for risk assessment of dermal absorption (3) lack of fundamental methodology to handle thousands of chemicals and nulhons of their combinations. It is impossible to mechanistically study all of the chemicals and their combinations. This problem is likely to worsen with the increasing number of chemicals required to be evaluated. 

The updated guidance document (EPA, 2001) includes refinements to the above equation to accoimt for the potential bioavailability of contaminants in the stratum comeum when exposure has ended and variable exposure times. Furthermore, the newer document discusses, in depth, the use of mathematical predictions of the permeability coeffident in dermal risk assessment. It is important to appreciate that the permeability coefficient should be determined experimentally using, ideally, a donor phase that mimics as closely as possible the existing environmental conditions. The use of permeability coeffidents predicted from theoretically derived equations adds a further imcertainty to the overall risk calculation. Although it has been suggested that the dermal permeability estimates are the most uncertain of the parameters in the dermal dose computation (EPA, 1992), it could be argued, given the refinement of in vitro techniques and the correlation between in vitro and in vivo measurements of human skin (Franz, 1978 Wester et al., 1992 van de Sandt et al., 2000 Cnubben et al., 2002 Zobrist et al., 2003 Colombo et al., 2003), that these measurements are the least assumptive and the most accurate of all the parameters used. 

The foregoing discussion indicates that choice of an appropriate experimental model (one based on anticipated enviromnental exposure conditions or exposure during accidental or deliberate product use) is probably the most important aspect of the design of in vitro skin pmetration studies for risk assessment and will have a direct impact on the applicabihty of resultant data for use in environmental contaminants and cosmetic risk assessment Careful consideration of individual protocol elemmts will greatly enhance the quality of results, their usefulness in the prediction of skin pmetration in vivo, and the assessment of risk following actual human exposure. 

Adiabatic temperature rise values were obtained in this study as a index of thermal hazard prediction of MEKPO. Feasible reactions at every MEKPO decomposition steps were identified from the possible reaction clusters by obtaining Gibbs free energy of reaction. And for each feasible reaction, enthalpy of reaction, heat capacity values and adiabatic temperature rise were assessed. Thermal inertia and MEKPO mixture composition ratio were considered. Adiabatic temperature rise values for each reaction condition were easily obtained, and by this, it is shown that this approach in this study can be a good methodology to get both qualitative and quantitative risk assessment result for hazardous undesirable reaction. The results were compared with the experimental and simulation data from the reference, and the errors were less than reasonable range. 

Although the whole-body plethysmography for unrestrained animals is the most widely used method to assess the respiratory risk of new drugs in safety pharmacology, non-appropriate experimental conditions may mask deleterious side effects... 

The final estimation of the value of ay may appear tedious and several assumptions are made in its derivation, but experimental evidence suggests that it may be used with reasonable accuracy to assess the levels of potentially damaging cavitation erosion. In small valves with nominal bores up to 65 mm cavitation inception occurs in intermittent bursts when the value oy is approximately unity. The cavitation becomes continuous and audible as Oy is reduced to about 0.6, but the risk of damage does not become significant until the value falls below 0.4. As a design criterion the condition of light, steady noise has been described by Tullis as the critical level and is sug-... 

---