PHARMACOLOGY OF CHEMICAL IRRITATION niques as screening measures prior to human patch testing. We have seen that redness is usually the earliest visible symptom and it is widely used as a criterion. It is the one symptom which may be casually observed during the study of other phases of drug action in the routine pharmacological investiga- tion. Important considerations in the evaluation of redness tests are the method of application, the con- centration of the chemical, the site of application, and the relative degree of effect produced by a given ex- posure time. Water-soluble chemi- cals are usually applied in aqueous solution to the eye by instilladon into the conjunctival sac, to the skin by wet dressings or intracu- taneous injection. Preliminary range-finding tests are made to establish a suitable concentration for more detailed study. This leaves perhaps the most difficult problem of all, the evaluation of the effect. Various approaches to this problem have been described, but no one method is found to be universally satisfactory. The qualitative esti- mation is relatively simple since it might be considered an all or none reaction, either there is or is not redness. Of the quantitative meth- ods the most widely used are meas- urement of the area of redness, application of an arbitrary scale for depth of redness such as pale pink, pink, etc., and a measurement of the duration of the reaction. Offhand it would appear that the measurement of area and of time would be the most satisfactory, but either or both 165 of these cannot give an accurate in- dex of the degree of action, for both are largely dependent upon the de- gree of vasodilation produced, which in turn is best measured by the color produced. The heat produced by local appli- cation of an irritant is of question- able value as a measurement of the degree of action. This can be easily understood when it is remembered that the reaction is limited to the irritated area and that the measure- ment must be made at that site it is not a systemic reaction which would be called a fever and could be measured by clinical methods. 'Al- though such techniques have been used, it is difficult to measure sig- nificant differences in the tempera- ture of a small area of skin or in the eye. Normal skin temperature varies widely and rapidly with en- vironmental temperature, muscular exertion, and excitement. Under ideally controlled conditions, which would be extremely difficult to achieve on a large scale in the lab- oratory, the maximum variation in temperature would be between the normal skin temperature and the body temperature as measured systemically. Aside from these practical obstacles there is the more fundamental objection that maxi- mum temperature increase might be reached considerably sooner than maximum dilation. Therefore, while temperature measurement may have some specific advantages, it has not come into widespread use in the evaluation of irritation. Swelling, or the production of

166 JOURNAL OF THE SOCIETY edema, is one of the most useful of the symptoms for quantitative esti- mation of irritation, and many dif- ferent methods have been developed for its measurement. Here again, measurement of the area is perhaps most common and rapid, but is in- complete because it neglects the third dimension which is elevation. If area and elevation are both measured the volume can be com- puted and the evaluation is much more complete. In recent years two entirely different metho:ts have been advocated for the measurement of the edema produced by irritation. In the first of these methods one eye of a rabbit is exposed to the irritant, which may be a vapor, liquid, or solid, for a definite period of time. Immediately after exposure. the animal is sacrificed and both the normal and irritated eyelids are re- moved and accurately weighed. After drying at elevated tempera- tures both lids are again weighed. A comparison .of the wet/dry weight of the two lids gives an estimate of the amount of edema produced. The second method makes use of a whealometer, which is essentially a diaphragm connected to a manome- ter. By recording the manometric readings from a plane surface of the body before and after irritation, the volume of the edema may be meas- ured. These two methods are per- haps the most quantitative yet de- veloped but their scope of usefulness is limited by the fact that the existing irritation must be suf•- ciently great to produce edema. They are of no value in estimating OF COSMETIC CHEMISTS mild irritation. Another method for which quantitative accuracy is claimed is probably a measure of edema although the exact mecha- nism has not beendelineated. In this method very small quantities of the irritant solution are injected sub- cutaneously into the ears of rabbits. After a period of time a solution of trypan blue is injected intravenously and in a relatively short time the dye tends to collect at the site of irritation. The depth of color, which within limited range is pro- portional to the degree of irritation, may be determined by appropriate scales. On the basis of available data this test seems to be somewhat more sensitive than most of the others for certain types of chemicals. The last of the cardinal symptoms is pain, which to the average in- dividual seems to be a very real entity. Unfortunately, however pain is an extremely elusive phe- nomenon. A review of the method- ology of pain measurement, with all its theoretical implications, would be beyond the scope of the present paper and would not be justified in view of the role played by pain in the study of irritation. While it is true that pain usually accompanies irritation, it cannot be taken as an accurate criterion, for, as has already been pointed out, the pain may be of only fleeting duration while the irritation may be extensive. From the practical standpoint too, the problems of accurate pain measure- ment even from standardized stimuli are extremely complex and much literature has been devoted to the