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human diseases. Pesticides are also indispensable in the management of a seemingly endless variety of pest organisms, including insects, fungi, bacteria, weeds, mammals, birds, and others that attack or compete with our food and fiber crops, livestock and poultry.

Because of their purpose, pesticides are intentionally toxic. Ideally, these chemicals should be poisonous only to targeted pest organisms; however, such an ideal is almost never fully attained due to the simple fact that, biochemically, all living things have much in common. Thus, we must accept and deal with the unavoidable circumstance that the introduction of pesticides into the environment almost always carries with it some risk of unforeseen toxic consequences to non-target species, including man.

There are numerous physical, chemical and biochemical forces that can act on and chemically transform pesticide residues in the environment. When one considers the multiplicity and complexity of these interactions, it is easily seen that the environmental fate of pesticides must be critically evaluated to provide an adequate basis for estimation of the toxicological significance of these chemicals to man and other organisms. In obtaining such data, the application of radioisotope techniques has, in my opinion, contributed more than any other single factor to the ability of the pesticide scientist to accurately assess the metabolic and environmental behavior of pesticides. By using radioisotope-labeled pesticidal chemicals as tracers, we are in an excellent position to conduct truly definitive fate studies in which, through the application of modern chromatographic, analytical and spectrometric techniques, we can solidly characterize most, if not all, of the metabolites generated in a given system. At the other extreme, radioisotope studies can provide valuable data in research applications where there is essentially no instrumentation backup, either chromatographic or spectrometric. Very useful data can be obtained from isotope studies in which the only instrumentation available to the researcher is that for detection and quantitation of radioactivity. Such applications might include distribution and residue studies in animals or plants where, with straightforward sample preparation and analysis procedures, highly relevant data with respect to pesticide safety can be obtained. Such studies can, for example, reveal the tendency of a pesticide in a given system to yield residues in meat, milk, or eggs of food animals, or in the edible portions of human food plants.

At a somewhat more sophisticated level, low-cost chromatographic techniques, particularly thin-layer chromatography (TLC), can be coupled to isotope studies to provide definitive data on metabolic pathways, or at least on the extent of metabolism of the parent pesticide. Extraction of tissues, excreta, etc. with appropriate solvents and subsequent resolution of radioactive IAEA-SM-263/32 85 components by TLC can usually give excellent resolution of the parent compound from any metabolites generated. The metabolites themselves can often be characterized by co-chromatographic studies with analogs of known structure. Metabolite characterizations based on chromatographic techniques certainly must be considered less definitive than those obtained through spectral studies, but such a limitation should in no way discourage the efforts of researchers who do not have access to such costly techniques as nuclear magnetic resonance or mass spectroscopy. Chromatographic-based metabolism studies, if conducted well, generate usually reliable data that are accepted by the scientific community, as evidenced by the fact that most such studies are fully appropriate for publication in major scientific journals.

From the above considerations, it is apparent that radioisotopes can, and often do, represent irreplaceable tools for the researcher whose goal is to define the environmental behavior and fate of pesticides and other agrochemicals.

Importantly, it is not necessary for the researcher to have a fully equipped analytical, chemical, or spectroscopic laboratory in order to effectively utilize radioisotope techniques in pesticide metabolism studies. Thus, researchers from a number of scientific backgrounds and laboratory situations are fully capable of conducting such studies to generate toxicologically relevant data on pesticides that have either broad scientific interest and impact or that relate to specific local or regional needs.

In this discussion, m y purpose is to convey some thoughts with respect to the rationale that might be appropriate as one considers the design and execution of radioisotope-aided pesticide metabolism studies. This will not be a review of literature on the topic--one would in fact be hard pressed to successfully accomplish a conventional review of such an elusive concept as scientific "rationale", for the literature documents the end product of the process rather than the process itself.

It similarly will not be "technique" oriented, for one can through the literature readily gain access to specific and detailed research techniques. Rather, m y approach will be more philosophical in nature and is based primarily on my own personal research experience and perspectives developed during the past 16 years as first a graduate student, then a bench scientist, and subsequently as a leader of a small research team. The value of my comments will no doubt be limited by my own bias and shortcomings, particularly in the capacity to view the rather complex discipline of pesticide metabolism chemistry from a very broad perspective.



The word metabolism, from the Greek word "metabole," which means "change", has a rather limited connotation. A pesticide metabolism study is, however, usually considered in a much broader sense to encompass not only the metabolic alterations of the pesticidal chemical in question but also the absorption, transport, storage and elimination of the parent pesticide and its metabolites by the exposed organism. For my purposes, radioisotope-aided "metabolism" studies will be considered to include approaches that, at one extreme, are aimed simply at tracing the labeled chemical in question through an organism or, at the other extreme, are targeted for complete and definitive characterization of all transformation products generated.


As with all scientific endeavors, there should be logical reasoning behind the conduct of any pesticide metabolism study.

One can quickly think of a number of specific purposes for which metabolism studies might be designed and conducted, and some of these are discussed below.

Studies in mammals as metabolic predictors for man. A primary purpose for evaluating the metabolic behavior of pesticides is to facilitate ultimate assessment of toxicological risk to man that may result from pesticide use. Because ethical and other considerations prevent direct studies of pesticide metabolism in man except in most unusual circumstances, extrapolations to man are usually made on the basis of metabolic data obtained with monogastric laboratory mammals.

Studies in animals and plants to evaluate the potential for residue occurrence in human foods. Dependent upon the proposed use patterns for specific pesticides, it may be crucial to determine the metabolic behavior of these chemicals in animals and plants used as human foods so that predictions can be made relative to the chemical nature and quantity of residues that may enter the human food chain.

Studies to elucidate activation and detoxication phenomena, and mode of action. The metabolic transformation of pesticidal chemicals may result in metabolites of either reduced or enhanced toxicological significance. In either case, it is important to define both the qualitative and quantitative aspects of metabolism that are involved. In addition, metabolic considerations may lead to a more thorough understanding of the mechanisms of pesticidal or toxicological action, be such actions the result of acute or chronic exposures.

IAEA-SM-263/42 87 Studies to evaluate effects on non-target organisms. In this age of greatly enhanced concern over the environmental impact of pesticides and other man-made chemicals, metabolism studies in non-target organisms provide valuable insight regarding the potential toxicological significance of pesticides to these species.

Studies to define metabolic bases for pesticide selectivity.

The development of pesticides that are toxic to target species but have little or no adverse effects on other life forms is a major goal in pesticide development. Selective toxicity can often be attributed primarily, if not totally, to metabolic differences between species, either in the rate of metabolism or the nature of products formed. Thus, metabolism studies in appropriate organisms can be of utmost importance in explaining and, in many cases, predicting selective toxicity. Two wellknown examples of pesticidal selectivity attributed to metabolic differences are the highly selective insecticide malathion, which is rapidly detoxified by ester hydrolysis in mammals but not in susceptible insects, and the herbicide linuron, which is detoxified through N^-demethylation and J^-demethoxylation by tolerant crops but not by certain weeds.

Studies to satisfy regulatory requirements. Many metabolism and other toxicology studies with pesticides are conducted primarily, if not solely, to satisfy regulatory requirements for pesticide registration and use. Although such mandated studies are generally based on solid scientific logic and are justifiable under one or more of the considerations discussed above, it is a simple fact that many such studies would not be conducted in the absence of regulatory needs. To the individual pesticide metabolism scientist, regulatory considerations can be, and often are, major factors to be considered in the design of his studies.

Studies to generate basic research data. This final category is included to cover those studies for which it might be difficult to ascribe a specific need or purpose. However, it can be argued that because of the potential environmental interactions and impact associated with essentially all pesticides, any metabolism study is potentially useful in environmental impact and/or toxicological significance evaluations, irrespective of the pesticidal chemical or the test organism involved.

Considering the seven categories just discussed, and more could probably be added, it is clear that there are a tremendous number of potential pesticide/organism interactions that may be of human health, animal health, or environmental significance.

The pesticide metabolism scientist thus finds himself playing a crucial role in the evaluation of the overall impact of pesticides on man and the environment.

88 IVIE Comments will now be directed toward factors that relate to the effective use of radioisotopes to generate pesticide metabolism data that are both scientifically sound and toxicologically relevant.

4. ISOTOPE SELECTION A number of factors may influence the researcher's selection of a specific radioisotope for use as a tracer in metabolism studies with a given pesticidal chemical. Perhaps the most obvious is the structure of the pesticide itself and the fact that elemental composition naturally limits what isotopes may or may not be considered. Synthesis c o n s i d e r a t i o n s — t h e ability to successfully and at acceptable cost incorporate the desired radiotracer into the pesticide molecule--are certainly significant and sometimes limiting considerations. Safety, facility, and instrumentation limitations, and personal preferences are also major factors in isotope selection.

A cursory examination of the literature shows clearly that the vast majority of pesticide metabolism studies conducted during recent years have utilized chemicals tagged either with carbon-14 or with tritium. Radiocarbon has been the isotope of choice for most studies, and the reasons are quite obvious: 1) a variety of. С precursors are available that can be incorporated into appropriate synthetic schemes for most organic pesticides; 2) radiocarbon is a soft beta emitter that poses no major health, contamination, or disposal problems; 3) this isotope is readily detected and quantitated by standard radiometric techniques; and 4) radiocarbon is a long-lived isotope and thus there are no radioactive decay.factors to consider. Tritium is a very acceptable radioisotope for use in metabolism studies for many of the same reasons mentioned above for carbon-14, although the extremely low beta energy of tritium may require somewhat more sophisticated detection and quantitation procedures. Other beta-emitting radioisotopes, particularly sulfur-35 and phosphorus-32, are appropriate for certain pesticidal chemicals but the frequency of their application to pesticide metabolism studies has certainly declined over the years. This is due perhaps to the relatively short half-lives of these isotopes, but probably more than anything else is due to the widespread availability and acceptability of radiocarbon and tritium as alternative isotopes that allow much more flexibility in labeling with respect to label positions. Gamma-emitting isotopes are seldom used in pesticide metabolism studies for a number of reasons, including safety, facility, and instrumentation considerations. Gamma- emitting elements are appropriate for a few inorganic and very few organic pesticides, but the availability of radiocarbon and tritium as more appropriate isotopes usually precludes the use of gamma emitters.

IAEA-SM-263/30 89


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