PHARMACOLOGY OF CHEMICAL IRRITATION 163 tion, nociperception. Indulgence is asked for use of the common de- scriptive terms. Elucidation of the pharmacology underlying these symptoms involves two phases, first the immediate bi- ological phenomenon responsible for the symptoms, and next the phar- macodynamics by which the chemi- cal initiates this phenomenon. In the case of redness the color is due to distension or dilation of the cu- taneous vessels. This is the physi- ological response of the body seeking to remove the irritation by supply- ing additional blood to the area. In some instances this dilation is ac- complished _t •hrough the operation of the axon reflex, without participa- tion of the central nervous system, although the latter also responds and is responsible for the reactions known as referred pain, counter- irritation, and central stimulation. In other cases the dilation is due to a direct injurious action on the vascu- lar system. It should be pointed out here that the action is local and that when redness is the only symptom the blood is still entirely contained within the vessels, in contrast to the redness following bruises and the swelling accompanying more severe irritation. The heat produced by local irrita- tion is entirely relative to the normal skin temperature. Skin heat loss is regulated by the central nervous system on a systemic basis, there- fore the increase in vascularity is not accompanied by a similar in- crease in heat loss and there is a re- sultant local increase in temperature. As the vascular dilation becomes more severe the capillaries tend to become semipermeable permitting the extravasation of the blood serum into the extracellular spaces. If these exudates remain discrete no permanent tissue damage is done al- though swelling is apparent. If the exudates coalesce into large blisters there is tissue separation and repair is necessary. In view of the local character of the reaction there are seldom any systemic symptoms such as accompany the comparable but more generalized extravasation of shock. The pain of irritation is con- sidered to be a combination of two factors, first a pulling or stretching of sensory nerves plus a direct pres- sure or pinching due to the swelling. Perhaps the more important mech- anism is the direct irritation of the sensory nerves, for the pain is often replaced by local anesthesia due to damage of the nerve. If the degree of irritation is not excessive it is possible to produce all the above symptoms without per- manent injury to the tissue. If the irritation is excessive the cell is killed and a condition of irreversible injury exists. This is usually re- ferred to as necrosis and forms a basis for evaluating the severity of irritation, although it is not neces- sarily one of the symptoms. When we go one step back of the symptoms and attempt to explain irritation 'at the level of the cell we encounter a few apparently well- established facts, and a great num- ber of uncertainties. We know, for example, that heavy metals in solu-

164 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS tion will precipitate the protein of the cell and thus destroy the cell, yet in weak solutions such a reaction may be regulated to produce an astringency, as when zinc sulfate is used in the eye. The irritation of caustic acids and alkalies may be ex- plained in a similar manner. In the case of concentrated acids the with- drawal of water from the cell is also an important factor and we may generalize that the osmotic balance of the cell is quite sensitive. In clinical practice it is customary to adjust the tonicity of parenteral or injected solutions to that of the blood to avoid irritation. In general the body can withstand a reasonable range of pH and it has been recently claimed that even the eye may tolerate a solution with pH as low as 5 if the osmotic pressure is controlled. It is generally accepted that solutions with pH outside the range of about 5 to 9 will be irritat- ing to mucous membrane if not to intact skin. This admittedly brief summary of the more obvious mechanisms of irritant action includes those which are most easily controlled chemically by adjustment of concentration, masking of ionization as in the case of the silver proteinates, buffering, or adjustment of osmotic pressure. So far as these factors are concerned it would be relatively easy to predict the irritant potential of a drug or formulation. There are,' however, many chemicals, particularly the organics, whose mechanism of irri- tant action is not understood and cannot be predicted in advance, ex- cept in a general way. To further complicate the picture it is possible to increase the potency of a known irritant by the addition of another substance such as a wetting agent. To a large extent it is this latter group of chemicals which has made necessary the development of testing techniques to evaluate the irritant properties of chemicals by biological means. In developing satisfactory testing technique the pharmacologist strives for as much simplicity as is con-' sistent with the greatest possible re- liability and quantitation. Even so, the tests developed require multiple subjects and a rather wide variety to meet the particular requirements of each problem. Those methods to be discussed are the experimental tech- niques used on laboratory animals prior to the clinical tests on human subjects. Since the mechanism of irritant action is not clearly understood, the logical starting point in the develop- ment of methodology is the symp- toms of irritation which have been discussed. In general it may be said that each of the several symptoms has been used as an end point in various methods with varying de- grees of success. The rabbit and the guinea pig have come to be the most widely used animals, experience having shown that for primary irri- tation and sensitization there is a general agreement between the re- suits in these animals and man. There is an occasional exception to this correlaiion but not enough to invalidate the experimental tech-