722 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISIS degradation and synthetic compounds are also attacked, although often less readily. In spite of this, relatively few accounts of the microbial degradation of pharmaceuticals or cosmetics have been published (1). This is partly due, no doubt, to the careful control measures exercised by responsible manu- facturers. It is also due to the difficulties of elucidating the mechanisms involved in a spoilage event. Each tends to be a unique encounter between a specific organism and substrate and often there is only time to record the happening and remedy the situation. In contrast, much has been written on the contamination of pharmaceuticals and cosmetics by micro-organisms (2). If the contaminants are potential pathogens then the products are obviously rendered unfit for use and are therefore spoiled. However, in this paper we are mainly concerned with degradation caused by contaminating micro-organisms. Their clinical significance is dealt with in detail elsewhere in the Symposium. MANIFESTATIONS AND MECHANISMS OF MICROBIAL SPOILAGE Before spoilage can occur organisms which are capable of altering the components of a product in situ must first be introduced via raw materials, the processing plant, packaging materials, operatives or elsewhere in the environment. Although spoilage does not necessarily depend upon the growth of these contaminants it is generally facilitated if the formulation and the ambient conditions of temperature and humidity encourage their multiplication. When these criteria are satisfied changes in the product will occur and may ultimately manifest themselves to the user in one or more of the following ways: Toxic effects Microbial toxins Several species of micro-organisms produce toxic molecules and may render a product dangerous if they grow in it under conditions supporting toxin production. Endotoxins, produced by Gram-negative bacteria such as Escherichia coli, are intimately bound to the cell, lipopolysaccharide in nature and are not necessarily inactivated by sterilization as they are heat stable. Toxins of this type are poorly absorbed by the oral route but are very important in connection with injectable products, particularly per- fusion fluids. Exotoxins are much more highly lethal and are bound less rigidly to the cell so that they are readily liberated into the growth medium. The outstanding example, of course, is that produced by Clostridium

MICROBIOLOGICAL SPOILAGE IN PHARMACEUTICALS AND COSMETICS 723 botulinum which is lethal to mice in doses of the order of 0.1 ng. Fortunately conditions for growth and toxin production are quite strict anaerobiosis, the presence of suitable pH and nutrients and of few competing bacteria is required. Such conditions are not often attained in pharmaceuticals and cosmetics and we know of no case of botulism arising from their use. Certain strains of Staphylococcus aureus produce a toxin, characterized as a specific polysaccharide, but the organism must grow to a density of several million cells per gram before its toxin becomes a problem. The evidence in connection with other bacteria, e.g. Clostridium perfringens, Bacillus cereus, Strepto- coccusfaecalis, Proteus and Pseudomonas species is less clear, but poisonous metabolites are certainly produced by a variety of fungi. Over the last decade there has been much interest shown in the aflatoxins produced by Aspergillus flayus (3). These heat-stable compounds exhibit potent toxic and carcinogenic properties in animals. A. flayus commonly infects peanuts, cotton seed and grain which are all components of animal foods. Under poor storage conditions mould growth occurs and toxic doses of aflatoxin accumulate in the food stuff. While it is difficult to visualize this occurring with cosmetics or pharmaceuticals, it is wise to ensure that ingredients such as talc, kaolin or starch are not stored for long periods under conditions supporting mould growth. Metabolic products In addition to microbial toxins, which are complex molecules and may be looked upon as biosynthetic products, simpler catabolic products such as organic acids and amines, which can be toxic to man, may be produced. Indeed, many microbial metabolites exhibit pharmacological activity (4). As these compounds are considerably less toxic than are the classic bacterial toxins, relatively high concentrations have to be attained before a spoiled product causes illness and the senses often detect that something is wrong before food spoiled to this extent is swallowed. This may not apply to medicines, as they are expected to be unpleasant and, indeed, frequently contain a flavouring agent in order to mask an unpleasant taste. However, well-documented examples incriminating specific metabolic products in pharmaceuticals are not easy to find. Irritancy Incidents of irritation following the application of cosmetics occasion- ally occur, and the offending preparation may subsequently be shown to contain a high level of microbial contamination. Direct evidence that irritation is caused by the presence of the micro-organisms is lacking but it