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Industrial Hygiene Development of new products includes responsibility for toxicological data for safe manufacture and use
MELLON IN8TITUTE
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and more the scientist is expected to assume responsibility for the effects of his contributions on society. One phase of this broad problem is concerned with the toxicity of new chemical products. Information on toxicity is necessary to protect the health of workmen, employees of common carriers, consumers, and the general public, as well as the resesrcher himself. The experience of a research chemist working with a few grams of material in a ventilated hood is no criterion of the possible hazards that may be associated with the same material in ton lots handled by unskilled workers. If one is to have a sound program of prevention rather than correction, early knowledge of the potential effects of new materials is essential, and the need for toxicological studies as an integral part of a research program is evident. ORE
Indrcstrial tox&?olmg&alpropram Asmming thia philosophy to be accepted, what are the practical aspects of the problem? Admittedly it adds to the cost of research and development. What contributions are made to justify these additional costs? Toxicological studies can serve two basic purposes: (1) to guide research in the development stages to eliminate compounds which obviously would be too toxic for intended application; and (2) to provide the necessary data on which to develop an adequate control program to prevent injury to persons handling or coming in contact with the material. This information is also helpful in regard to I.C.C. regulations and labeling. Obj@ctCves The first objective definitely has economic value in preventing unnecessary work and expense in the development of a compound which must be discarded for certain applications because of its toxicity. In those instances where a compound is being developed for a specific purpose, where a lorn order of toxicity is sought-for example, refrigerants-the close association of the toxicologist is obvious. The second objective, the development of basic toxicological data, cannot be evaluated as readily from the economic viewpoint, because the potential savings due to lack of injuries are more nebulous. Nevertheless, that there are savings due to health protection and also sales advantages resulting from good public relations cannot be denied. As the significance of these factors becomes better appreciated there will be less tendency to exploit new products without regard to industrial and public health and safety, even though there may appear to be advantages from the standpoint of competitive costs. If this responsibility is accepted by everyone, and its acceptance is increasing, the question of possible competitive cost advantages will no longer exist. An industrial 'toxicological program, to be effective, must be closely associated with the research, manufacturing, sales, and medical departments and there must be mutual understanding. The work to be economical should parallel the research and d.e\-elopment by utilizing tests which are conipa-
rable to the laboratory, pilot plant, and commercial development stages. For example, during laboratory research only the simplest toxicity tests which can be completed in a day or two need be conducted. These data together with available inforniation on similar compounds should be adequate a t this stage. When a compound reaches the pilot plant stage, more complete studies, possibly requiring several weeks or more, may be indicated. However, when a compound reaches commercial production, the work required may span several years, particularly if intended for use where the general public is concerned, as in foodstuffs.
Preliminary tests Some first questions to be answered regarding the toxicity of a compound are: (1) What is the general order of magnitude of toxicity-low, intermediate, or high? (2) What is the hazard through inhalation? (3) Is there skin absorption? (4)Is there primary irritation of the skin? ( 5 ) Is there eye irritation? Preliminary answers to these questions can bo obtained in a matter of 2 or 3 weeks, using established procedures. Acute oral toxicity may be determined by adniinistration of the compound by stomach tube to white rats. By using a range of doses, a dosage is found which kills few or none of the animals and another that kills all or nearly all of the animals, thus permitting an estimation of the LDSo. These data in comyarison with toxicity data on other compounds permit an estiniation of the order of magnitude of the oral toxicity. An indication of inhalation toxicity may be obtained by esposing albino rats to the satiirated vapor a t room temperature for varying exposure periods to obtain an exposure time which kills none of the animals and another that kills all. In addition to toxicity data, this procedure also indicates haznrd as the concentration used is dependent on the vapor pressure of the compound. For example, a compound having a high order of toxicity may not be hazardous by inhalation of vapor owing to a low vapor pressure. The possibility of skin absorption mid irritation may be determined by application of the substance to the clipped abdomen of rabbits. Observations are made for systemic as well as local action. Possible irritation of the eye may be studied by applying the substance to the center of the cornea of the eye and observing the eye for corneal necrosis as revealed by fluorescein staining. It is emphasized that these tests are conducted to obtain preliminary information during the developnient stage of :i compound. The number of animals used and time are kept to a minimum so that the cost of the tests will be rerzsonable, particularly when one considers that many compounds so tested will not be commercially produced. In other words. (Continued on page 82 d) this procedure is essentially a 81 A
Industrial Hygiene compromise between. the amount of toxicity data obtained and number of compounds that can be studied. When one considers the large number of compounds devcloped each year, some such tests are absolutely essential, if we are to have even meager data on it significant proportion of these compounds. Bade t o x h h g k a l s t d i e 8 The need and significance of preliininary toxicity data and the large number of compounds that can be studied by this method may tend to exaggerate its importance in relation to more comprehensive toxicological investigations. A proper perspective may be obtained by comparing the preliminary toxicity data to the boiling point or vapor pressure of a compound and the basic toxicological data to the fundamentaI chemistry. Incidentally, it is interesting to contemplate LL closer association of simple chemical, physical, snd toxicity data and acceptance that all three should be routinely determined to characterize a new chemical compound. Basic toxicological investigations have m their objective a detailed and reasonably precise evaluation of potential occupatiorial and public health problem that may be associated with the commercial application of chemical compounds. This requires information on rate of absorption, distribution, metabolism, and rate of elimination as well as effects on specific organs and tissues slid other factors indicative of physiological response. &vera1 species and large numbers of animals must be used and repeated exposures of various types over long periods of time must be conducted. Frequently, carefully controlled experiments using human subjects are included. Studies of this character provide information on most likely route of absorption and levels of expowre which may be considered reasonably safe. I n addition, tests may be developed such as blood and urine analyses; these indicate degree of absorption which can be evaluated in terms of potential injury. Other diagnostic signs as well as type of response may be made available to the industrial physician to aid him in his examination of exposed persons. This is particularly desirable in the initial use of new compounds as the interpretntion of toxicological data obtained on animals in terms of human response must be made with due recognition of the limitation involved. However, if the interpretation has been in error, but the physician has a t his disposal information that permits early recognition of adverse effects, corrective procedures can be instituted before serious damage results. It may seem at first thought that toxicological studies on chemical compounds are an unnecessary requirement and contribute little. However, when one considers the great espansion in the chemical industry and its impact on our everyday life, it is evident that a great responsibility has been incurred. T h i ~responsibility includes an obligation to provide information on the proper handling and use of chemicals so that the good which they do is not submerged in adverse effects which may label a worth-while development as a detriment rather than an outstanding contribution. It is apparent that information on the proper and safe handling and uue of chemicals is an important responsibility of the chemical industry.
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