Evaluation of research activities and research needs to increase the impact and applicability of alternative testing strategies in risk assessment practice.

The present paper aims at identifying strategies to increase the impact and applicability of alternative testing strategies in risk assessment. To this end, a quantitative and qualitative literature evaluation was performed on (a) current research efforts in the development of in vitro methods aiming for alternatives to animal testing, (b) the possibilities and limitations of in vitro methods for regulatory purposes and (c) the potential of physiologically-based kinetic (PBK) modeling to improve the impact and applicability of in vitro methods in risk assessment practice. Overall, the evaluation showed that the focus of state-of-the-art research activities does not seem to be optimally directed at developing in vitro alternatives for those endpoints that are most animal-demanding, such as reproductive and developmental toxicity, and carcinogenicity. A key limitation in the application of in vitro alternatives to such systemic endpoints is that in vitro methods do not provide so-called points of departure, necessary for regulators to set safe exposure limits. PBK-modeling could contribute to overcoming this limitation by providing a method that allows extrapolation of in vitro concentration-response curves to in vivo dose-response curves. However, more proofs of principle are required.

New in vitro dermal absorption database and the prediction of dermal absorption under finite conditions for risk assessment purposes.

Most QSARs for dermal absorption predict the permeability coefficient, K(p), of a molecule, which is valid for infinite dose conditions. In practice, dermal exposure mostly occurs under finite dose conditions. Therefore, a simple model to predict finite dose dermal absorption from infinite dose data (K(p) and lag time) and the stratum corneum/water partition coefficient (K(SC,W)) was developed. To test the model, a series of in vitro dermal absorption experiments was performed under both infinite and finite dose conditions using acetic acid, benzoic acid, bis(2-ethylhexyl)phthalate, butoxyethanol, cortisone, decanol, diazinone, 2,4-dichlorophenol, ethacrynic acid, linolenic acid, octylparaben, oleic acid, propylparaben, salicylic acid and testosterone. For six substances, the predicted relative dermal absorption was not statistically different from the measured value. For all other substances, measured absorption was overpredicted by the model, but most of the overpredictions were still below the European default absorption value. In conclusion, our finite dose prediction model provides a useful and cost-effective estimate of dermal absorption, to be used in risk assessment for non-volatile substances dissolved in water at non-irritating concentrations.

Relative absorption and dermal loading of chemical substances: Consequences for risk assessment.

Quantification of skin absorption is an essential step in reducing the uncertainty of dermal risk assessment. Data from literature indicate that the relative dermal absorption of substances is dependent on dermal loading. Therefore, an internal exposure calculated with absorption data determined at a dermal loading not comparable to the actual loading may lead to a wrong assessment of the actual health risk. To investigate the relationship between dermal loading and relative absorption in a quantitative manner, 138 dermal publicly available absorption experiments with 98 substances were evaluated (87 in vitro, 51 in vivo; molecular weight between 40 and 950, logP between -5 and 13), with dermal loading ranging mostly between 0.001 and 10mg/cm(2). In 87 experiments (63%) an inverse relationship was observed between relative dermal absorption and dermal loading, with an average decrease of factor 33+/-69. Known skin irritating and volatile substances less frequently showed an inverse relationship between dermal loading and relative absorption.