Toxication

Abstract: The continued increase in use of the persistent pesticides over the last decade is well documented. Their widespread application in the control of disease-carrying and agriculturally important arthropods and other invertebrates has resulted in thousands of millions of kilograms of these materials being introduced into the environment. During 1962, in the United States alone, 177 800 000 kg of insecticides were used. Herbicides and fungicides were also applied in great quantity; according to Thimann (1964) the amounts of these totalled about half that for insecticides. Since the trend is for increased consumption, the total quantities released into the environment in 1965 will be substantially higher. Some of the effects of these pesticides are known and well documented. The relative sensitivity of a variety of living systems to lethal concentrations has been studied in some detail (Doudoroff, Katz & Tarzwell 1953; Sawyer 1959; Pickering, Henderson & Lemke 1962). Less attention has been paid to physiological effects, and little is yet known of the ecological consequences of pesticides in natural water supplies, despite some excellent studies of the problem (Harrington & Bidlingmayer 1958; Prevost 1960; Cope 1961). Even allowing for these recent gains, surprisingly little is yet known regarding the biological effects of pesticides. For example, in spite of the near-ubiquitous use of the organochlorine compounds for almost 20 years, their biochemical mode(s?) of action remains obscure. Recently O'Brien & Matsumura (1964) advanced a new hypothesis for the mode of action of DDT, attempting to reconcile the high level of toxicity of organochlorine compounds with their extreme resistance to biochemical degradation. Whether or not this new and interesting hypothesis proves correct, the significant fact remains that for years we have been introducing vast quantities of these compounds into the environment without knowing in detail the nature of their biological properties. We have tended to assume, when questions of potential danger to living systems are raised, that the toxic properties of pesticides are limited to those effects which are already well known through previous experimentation or trial-and-error activities. The many-faceted problems of pesticide-altered ecosystems are even more complex. A review of the recent and current research on both field and laboratory aspects of microchemical contaminants makes one point very evident: we are today still working largely in an unknown and complex realm, our efforts dominated by the search for suitable means of measuring the effects which these compounds have on living systems. This search is the necessary first step. It is now clear that only after we have devised thoroughly adequate methods of measurement, capable of detecting physiological, behavioural and ecological changes due to sublethal concentrations of pesticides and other biocides, shall we be able properly to evaluate their impact on ourselves and our environment.

Abstract: The relatively high oncostatic specificity of cyclophosphamide (CP) in vivo is shown to be due to the cytotoxic specificity of 4-hydroxycyclophosphamide (4-hydroxy-CP), the first product of metabolic activation of CP in the liver. This specificity can be evaluated not only in vivo by measuring the therapeutic index, but also in vitro by determining its cytotoxicity against Yoshida ascites tumor cells. Evidence is given that 4-hydroxy-CP is not an alkylating agent itself, but attains this property only by release of an alkylating N,N-(2-chloroethyl)phosphorodiamic acid moiety and acrolein. The energetic source for this rate-limiting toxication results from the resonance stabilization of the released acrolein. Reactions at the cryptoaldehyde group of 4-hydroxy-CP, which reduce or prevent the resonance stabilization of the 3-carbon unit to be released, lead to a deactivation of the primary metabolite of CP thus reducing or even preventing toxication, and hence influencing both the alkylating and cytotoxic activities of the molecule. Accordingly, it could be demonstrated by the reaction of 4-hydroxy-CP with thiols yielding 4-(S-R)-mercapto CP derivatives that the toxication of 4-hydroxy-CP can be controlled under physiologic conditions of pH and temperature. In the case of free protein sulfhydryl groups, this reaction also leads to fixation onto a macromolecule of the CP metabolite. On the basis of these peculiar reactivities of the oxazaphosphorine ring of 4-hydroxy-CP and of the partial reaction kinetics involved during toxication or deactivation, the significance of these findings to the problem of CP specificity is discussed.