Percutaneous absorption and dermal toxicity

Percutaneous absorption and dermal toxicity

Symposium 4. Cellular and Molecular Mechanism of Cutaneous Toxicity Therefore, extrapolation techniques and use of application factors are introduced ...

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Symposium 4. Cellular and Molecular Mechanism of Cutaneous Toxicity Therefore, extrapolation techniques and use of application factors are introduced in order to predict 'environmentally safe levels' for hazardous chemicals - individually and from experimental data only. In this process no specific factors are introduced to account for scientifically formulated uncertainties, and externally expressed precautionary principles are not accepted. On this background, the proposal is given that classification of chemicals as being dangerous to the environment and selection of priority chemicals should be done in clusters in stead of individually and in such a way that more chemicals and chemicals in mixtures could be handled under a precautionary principle. Application of higher extrapolation/uncertainty factors are also suggested in order to be more protective on behalf of multiple species and natural ecosystems.

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not translate into risk, although that is the way it is generally used. The solution would be to impose sound toxicological science rather than default options in regulatory policy. This involves development of quantitative models in the interpretation of toxicodynamic and toxicokinetic data, in order to minimize the difference between alleged and actual risk. Examples are provided in the assessment of carcinogenicity in rodents, for instance of potential human risk involving peroxisomal proliferators and other mitogenic animal carcinogens. Further recent issues relate to the potential of certain environmental chemicals to affect the endocrine system or to disturb normal immune functions. In all these areas, replacing misgivings and fear with good scientific data will reduce present uncertainties in assessing human risks.

Ko'words: risk assessment; default options; quantitative models; carcinogenicity; endocrine system; immunotoxicity

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IS SUSTAINABLE DEVELOPMENT A PRACTICAL POSSIBILITY GIVEN THE CONTINUED USE OF PLANT PROTECTION PRODUCTS? THE SCIENTIFIC VIEW

Monika Herrchen *, Werner Klein. Fraunhofer Institute for

Environmental Chemistry and Ecotoxicology, Schmallenberg, Germany Considering the fact that plant protection products generally are active ingredients with biocidal properties they have to have effects at least in the target environment. Sustainability in agriculture requires that agricultural areas keep their facility and that effects outside the target areas are at least reversible. This requires for a continued use of plant protection products that application technologies have to be optimised for minimum release into ecotons and to exhibit properties not resulting in long-term impacts (degradability, no bioaccumulation etc.). Furthermore when considering sustainability the different agricultural technologies should be weighted against each other as compared to their effects on soil fertility and ecological consequences. This means that plant protection products should be compared with tillaging, crop rotation, fertilisation-intensity of agriculture, alternative plant protection methods, ratio of use versus refugial areas in a region, use of genetically modified resistant crops, comparison of commercial costs, ecological costs and benefit. Some of this criteria will be substantiated by examples.

Keywords: long-term impacts; alternative agricultural technologies; comparative assessment

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IS SUSTAINABLE DEVELOPMENT A PRACTICAL POSSIBILITY GIVEN THE CONTINUED USE OF PLANT PROTECTION PRODUCTS? THE INOUSTRY VIEW

Abstract not available at time of publication.

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UNDERSTANDING RISK ASSESSMENT IN TOXICOLOGY

Robert Hess. University of Basel, Switzerland Reliable prediction of health risks for people exposed to potentially toxic chemicals requires knowledge of exposure levels and understanding of the mechanisms that associate exposure in air, water or food with the toxic response. In the absence of solid scientific evidence, however, regulators will use incomplete information to promote inadequate or disproportionate recommendations, often directed by undue conservatism. This is especially the case for low-level exposures for which low levels of risk cannot be validated by human experience. In the present regulatory framework, chemicals are frequently classified by a presumed "intrinsic" hazard. However, such hazard identification can be misleading, since it does

S4. Cellular and Molecular Mechanism of Cutaneous Toxicity

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PERCUTANEOUS ABSORPTION AND DERMAL TOXICITY

Hans Schaefer, Roland Roguet *. L'OreaL Clichy-sur-Seine, France The skin is a thin but large organ. It consists of multiple structural and cellular structures. The thinnest and - in respect to the defence against external insults - most important layer is the stratum corneum which, due to its barrier function, prevents the loss of essential metabolites as well as the entrance of xenobiotics. The underlying epidermis consists of slow reacting cell types like keratinocytes as well as rapidly reacting structures like nerve endings. Similarly the layer below the epidermis, that is the dermis consists among others of slowly proliferating and reacting fibroblasts and on the other hand of blood vessels which respond rapidly to external challenges. This is why the first responses to many noxious substances are those of the nervous system (stinging, itch, burning sensation, pain) and of the microvasculature (in essence reddening i.e. vasodilatation). There are now straight forward bioassays and protocols to quantify such responses. The situations are different with compounds which, though being toxic via the topical route, do not provoke immediate cutaneous reactions. This is typically the case for phototoxins, allergens and photoallergens. In some though not all cases the cutaneous concentrations for these classes can be established by analysing layer by layer their penetration into the skin under close to real life conditions. A typical example is the penetration of 8-Methoxypsoralen, a photosensitizing antipsoriatic. Recently we could demonstrate the importance of a particular structure, the hair follicle, for percutaneous absorption. In vitro systems like the response of cultured skin equivalents by liberation of cytokines to xenobiotics are very promising in that they not only replace animal models but mimic also more closely human skin reactions.

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EPIDERMAL CYTOKINES AND THE INDUCTION OF ALLERGIC AND NON-ALLERGIC CONTACT DERMATITIS

Ian Kimber. Zeneca Central Toxicology Laboratory, Macclesfield,

Cheshire SKIO 4TJ, UK The skin is an immunologically active tissue and epidermal cells, both keratinocytes and Langerhans cells (LC), are known to be important sources of cytokines. These molecules serve to induce and regulate cutaneous immune and inflammatory responses secondary