Humane approches to toxicological evaluations of industrial chemicals — страница 2

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of toxicology. A primary objective for achieving general acceptance of any in vitro alternative to an animal model for the assessment of potential risk to humans and the environment is to have it accepted by regulatory authorities as a recognized assessment of a toxic property; nowadays there are very few circumstances in chemical manufacture, marketing, transportation, and use that do not come under the auspices of a government department somewhere in the world. In short, in vitro alternatives need to satisfy scientific criteria for their acceptability and need to satisfy the international regulatory community that their use will not compromise assessment of risk or pose serious problems to international trade in chemicals. 1. OCULAR TOXICITY The eye is one of the most valuable

and vulnerable of sense organs (Albino rabbits are used in the test). Dusturbance of vision, injury to the eye, or even loss of sight due to chemical or phisical damange must be recognized as a most traumatic experience. It is the abhorrence of such events that necessitates the testing of chemicals in order to reduce, and hopefully prevent, their occurrence in humans. This method is the basic for most eye irritation testing today. New chemicals and mixtures of chemicals pose a potential eye hazards to humans. The nature of the hazards needs to be assessed because warnings about the potential harm that a chemical can do to the eye only have credence if they are based on valid information. Labeling all chemicals as hazardous would substantially lessen the benefit of the warning

label. Convincing workes and customers that a hazards exicts and that there is a need for special care, including the use of protective eyeglasses or goggles, has to be related to good extrapolation from suitable model systems. The rabbit eye test has its liminations, but in our view it is still the best practical way of assessing ocular damage and can be conducted using a humane approach. 2. SYSTEMIC TOXICITY In testing for acute systemic toxicity, it is our opinion that in vitro test systems are unlikely to replace in vivo studies. The principle of the test method and procedures generally recommended have been reviewed by many, recently by Organisation for Economic Co-operation and Development. The rat and mouse are the species of choice because they are able to display a full

range of clinical signs of toxicity. The test substance is administered by the most appropriate route (either oral, dermal, or inhalation) to small groups of animals at a range of draduated doses. The formulations of substance and volume administered are standardized as far as possible to avoid the confounding effects of minor protocol variation. Acute systemic toxicity studies assess the relationship between the dose of a substance and adverse effects, its toxicity relative to other substances of know toxicity, the specific clinical sings of toxicity, the physiological systems affected, and often an indication of the mode and potential mechanism of toxic action. Such information may help the clinical to diagnose and treat adverse effects when they occur in humans using specific

antidotes. The humane approach employed in most industrial laboratories is he use of the minimum number of experimental animals and the use of euthanasia when toxic effects are detected. In our own laboratory, with experience of a number of different types of industrial chemicals, many substances are defined adequately by a limit dose or rangefinding study. Indeed, following acute exposure, a relatively small number of substances produce observable adverse systemic effects (Table 2). TABLE 2 Toxic Categories Following Acute Oral and Dermal Dosing Studies in the Rat Oral Category Dermal 65% Low toxicity 66% (>2000 mg/kg) (>2000 mg/kg) 29% Harmful 24% (200-2000 mg/kg) (400-2000 mg/kg) 5% Toxic 9% (25-200 mg/kg) (50-400 mg/kg) 0.8 % Very toxic 0.9 % (<25 mg/kg) (,50 mg/kg)

The use of fewer laboratory animals, coupled with a less rigid adherence to the need for statistical precision, is a rational approach that will allow assessment of toxicity hazard and heme prevent human suffering. 3. CUTANEOUS TOXICITY Skin contact is probably the most common form of exposure to industrial chemicals.The most common in vivo approach to determine such potential is based on the method of Draize et al. In the Draize skin test the animal of choice is the albino rabbit. The skin, like many other organs, is complex is born structure and function. Substances that interact with this tissue can produce different toxic effects. The skin represents tissue that will allow more readly the development of a variety of in vitro and ex vivo systems to assessirritancy and