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«: AGROCHEMICALS: FATE IN FOOD AND THE ENVIRONMENT PROCEEDINGS OF A SYMPOSIUM, ROME, 7 - 1 1 JUNE 1982 JOINTLY ORGANIZED BY IAEA AND FAO l^J I N T E R ...»

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The position of incorporation of the radiolabel into the pesticide molecule is of utmost importance to assure the validity of the metabolism data subsequently obtained. In his efforts, the metabolism scientist is seeking to accurately trace the pesticide and its metabolites in the test system, and to define the chemical changes that are inflicted upon the pesticide molecule by the enzymatic systems involved. Although metabolic changes can be grouped into four basic types (oxidation, reduction, hydrolysis, and conjugation), there are many specific metabolic alterations that can occur. Such alterations are dependent upon the chemical nature of individual pesticidal chemicals and upon the enzymatic reactions at work. The importance of label position becomes apparent when one considers that metabolic transformations quite often result in cleavage of chemical bonds; thus, such reactions may split off portions of the tagged chemicals. While the radiolabel is not literally "lost" as a result of such transformations it can, dependent upon its position within the molecule, be separated from the major portion of the pesticide, with the resultant effect that the radiolabel no longer serves its tracer function. In tritium labeled compounds, an additional consideration must be the potential lability or exchangeability of the hydrogen that is under consideration as a label site. Tritium exchange under normal physiological conditions or during metabolic reactions is a relatively common problem that can lead to considerable uncertainties in data interpretation.

Radiotracers incorporated into metabolically labile positions of pesticides can, as a result of metabolic conversions to rather simple labeled derivatives, be assimilated into natural constituents of the test organism. Obviously, such an occurrence can have serious implications with respect to the predictive value of the data obtained. A personal experience illustrates this problem. Early in my career, I was involved in a study in which a lactating cow was fed the carbamate insecticide, carbofuran, labeled with radiocarbon at the carbonyl position of the carbamic acid moiety. Soon after dosing we observed a rather substantial amount of radioactivity in milk, which was unexpected, because residues and metabolites of most carbamate insecticides show little tendency toward secretion into milk. We ultimately showed that the radiocarbon residues in the milk were not associated with carbofuran at all rather, they arose as a result of ester hydrolysis of the i 4 C-carbofuran and subsequent degradation of N-methyl carbamic acid- С to 1 4 C 0 o. The radiolabeled carbon dioxide, which was generated in considerable quantities, had been incorporated by normal biosynthetic pathways into natural milk constituents.

90 IVIE How does one rationally decide on an appropriate label position, particularly when dealing with a specific pesticide or pesticide type for which there are little or no background metabolism data available? The process is usually not that difficult, if the researcher has some understanding of the nature of metabolic reactions and is reasonably familiar with the metabolism literature. Many, if not most,.organic pesticides contain aromatic moieties, and because of the relatively high degree of stability of aromatic systems, aromatic rings are generally good label sites for radiocarbon, although less so for tritium because of potential substitution reactions (particularly hydroxylations) that may occur during metabolism. Certain label sites are obviously less than desirable for carbon-14 or tritium labeling; and N- substituted moieties are examples of usually poor label positions. Many pesticides are esters (e.g. organic phosphate and carbamate insecticides) that tend to be readily hydrolyzed in living systems. With such chemicals, it is preferable to label that portion of the molecule that is likely to be of the greatest toxicological significance. In the case of the OP and carbamate compounds, the best label position would usually not be the phosphoric acid or carbamic acid moieties.

Some pesticides are of such chemical complexity that a single position of labeling is simply not sufficient to permit accurate tracing of potential metabolic products. Synthetic pyrethroid insecticides, which are esters in which both the acid and alcohol moieties are usually rather complex, are a good example. With the pyrethroids, labeling on both the acid and alcohol moieties is required to permit conduct of definitive fate studies. Most metabolism scientists agree that with chemicals such as the synthetic pyrethroids, more useful and definitive data can be obtained from comparative studies with various preparations labeled at different sites rather than from studies with a single preparation labeled at two or more sites.

Additional factors that must be considered with respect to the position of label incorporation (as well as to the specific isotope to be used) are those of synthetic feasibility and cost.

It may be that the most appropriate label position is one that is very difficult or impossible to achieve synthetically or that is attainable only at high cost. In such circumstances, the researcher must consider the obstacles present and the alternatives available, then use his own judgment as to the best approach.

6. RADIOSYNTHESIS AND PURITY CONSIDERATIONS

The pesticide metabolism scientist can obtain radiolabeled pesticides by purchase from radiochemical supply firms, from appropriate pesticide development firms, or by radiosynthesis in IAEA-SM-263/30 his own or a colleague's laboratory. It is my opinion that in most circumstances, radiosyntheses are not appropriate for individual researchers--such procedures are best left to professionals who are specifically equipped for and trained in radiosynthesis techniques. If the pesticide to be studied is under active development or is one that is in current use, contact with the appropriate pesticide development firm may result in a radiolabeled preparation being provided to the researcher, often at no cost. If a custom synthesis by a commercial firm is required, one can usually anticipate considerable expense. However, putting the cost of the radiochemical in perspective to that of the entire study will more than likely show that the expense of a custom radiosynthesis is not excessive.





Once the radiochemical is in the researcher's hands, one criterion is of utmost i m p o r t a n c e — t h e radiochemical purity of the sample. It is quite obvious that the presence of an appreciable percentage of labeled impurities, which may be totally unrelated chemically to the labeled pesticide, could seriously compromise the validity of any studies subsequently conducted with that preparation. On the basis of my own experience with radiochemical supply firms, I do not hesitate to say that one cannot assume adequate radiochemical purity, even if a high percentage of purity is claimed by the manufacturer.

Appropriate techniques, usually chromatography, should be used to verify the radiochemical purity of any labeled pesticide, and it is probably safe to say that a radiochemical purity of 98% or greater is acceptable for most studies. Unacceptable preparations should either be returned to the manufacturer or purified by the researcher using appropriate techniques.

The chemical purity of a labeled sample is not as crucial as its radiochemical purity, simply because any non-labeled contaminants present are unlikely to interfere in any appreciable way in most studies. If spectrometric methods of structure confirmation are available (mass spectroscopy, NMR, etc.) one or more of these techniques should be used to verify the chemical identity of the sample. As a minimum, co-chromatographic studies of the radiochemical with a known unlabeled sample of the pesticide should be done to avoid the highly unlikely but always possible tragedy of conducting a study with the wrong compound.

7. SPECIFIC ACTIVITY AND DOSAGE CONSIDERATIONS

The specific activity of a radiolabeled pesticide is an important consideration in many studies, particularly when the researcher wants to quantitate residues at low levels. The use of labeled preparations of very low specific activity can carry with it the inability to detect and quantitate trace residues.

92 IV IE However, labeled preparations having very high specific activity are often similarly inappropriate. The use of high specific activity samples can be wasteful of radiochemical and can result in a level of sensitivity far above that which is reasonably required. The researcher should carefully consider the objectives of the planned study, being fully aware of levels of sensitivity that are required or are appropriate, and not be hesitant to lower the specific activity of his preparation by addition of unlabeled pesticide if this is deemed appropriate.

One must consider dosage levels from two standpoints: 1) the total amount of radioactivity, usually expressed in yCi or mCi, that is applied to the living system; and 2) the total amount of pesticidal chemical itself applied, which may be expressed in a number of ways dependent upon the system under study (e.g. mg/kg for animal dosing studies, ug/cm2 for plant surface applications, parts per million for aquatic or soil studies, etc.). The total isotope/chemical relationship obviously determines specific activity; thus, in dosage considerations, the researcher cannot consider either independent of the other. The determination of appropriate isotope and chemical dosage levels for a particular study can be a complex and sometimes frustrating exercise. Often, there are constraints on the total amount of radioisotope available to the researcher.

Certain studies may require low total dosage and relatively high specific activity preparations to approximate "real-world" exposure conditions and allow detection and quantitation of trace residues. In other studies, the researcher may choose a relatively high chemical dose of low specific activity if his primary goal is to conduct a study in which metabolites are generated in sufficient quantity to permit definitive spectral analysis and structure elucidation. In determining appropriate dosage levels, the researcher should look first at the most critical data needs or the major study objectives, realizing that in a single study it is seldom possible to obtain all the data one might desire. He can then develop specific activity and dosage parameters that are most appropriate for his study, given the limitations and constraints present.

8. RADIOISOTOPE, ANALYTICAL AND SPECTROMETRIC TECHNIQUES

While it is outside the scope of this discussion to deal with detection and analytical techniques in any detail, these will be touched on briefly here, primarily to emphasize the broad range of techniques that are available to the metabolism scientist who uses radioisotopes in his studies.

1 Ci = 3.70 X 10 ю Bq.

IAEA-SM-263/30

Although ionization detectors are available, liquid scintillation counting is without question the technique of choice for detection and quantitation in most radioisotope applications, particularly those utilizing soft beta emitters such as carbon-14 and tritium. Liquid scintillation counters are not overly expensive, they are highly reliable, and with appropriate sample preparation procedures can be utilized to quantitate radioactivity at high sensitivity in essentially all biological fluids and tissues. In recent years, radioisotope detectors for use with various chromatographic techniques (e.g.

TLC plate scanners, HPLC detectors) have become widely available and are finding appropriate applications in a number of research laboratories. However, the simple autoradiographic technique of using X-ray film over TLC plates to detect resolved metabolites that are subsequently quantitated by liquid scintillation counting remains a widely practised, fully acceptable çind, in many cases, the preferred technique.

Two chromatographic techniques, TLC and high performance liquid chromatography (HPLC), are widely used by pesticide metabolism scientists to resolve radiolabeled metabolites generated by living systems. TLC offers the advantages of low cost and applicability to a wide range of chemical structures that are likely to be encountered by the metabolism scientist, and TLC is readily adaptable to standard radioisotope detection and quantitation techniques (i.e. autoradiography and liquid scintillation counting). HPLC requires more expensive instrumentation, but can potentially offer much higher resolution power over a complete range of chemical structures and polarity.

This is particularly true with more polar pesticide metabolites for which most TLC methods may be only marginally applicable.

Gas-liquid chromatography (GLC) is generally not an effective primary chromatographic technique in pesticide metabolism studies because metabolites tend to be rather polar and are often not compatible with the temperature and volatility constraints presented by GLC. However, as a secondary technique or for studies of derivatized metabolites, GLC can be a very powerful tool, particularly when coupled with mass spectrometry for structure elucidation studies. Other chromatographic techniques, such as paper chromatography and conventional column chromatography, have been important in earlier years to the pesticide metabolism scientist, but their usefulness has dramatically diminished as more powerful techniques have become available.

As discussed earlier, the pesticide metabolism scientist need not have access to sophisticated spectroscopic instrumentation in order to conduct toxicological ly relevant studies. Various chromatographic techniques, often coupled with relatively simple chemical derivatization or degradation procedures, can result in metabolite characterizations with a 94 IVIE fully acceptable level of confidence. However, the researcher who is fortunate enough to have access to spectral techniques such as mass spectrometry and nuclear magnetic resonance spectrometry can undertake highly definitive pesticide metabolism studies. It is not uncommon today to see reports in the literature in which most, if not all, of the detected metabolites of a pesticide in a given system are fully and unequivocally characterized by spectral means.

One of the major advantages of radioisotope use in metabolism studies is that isotopes provide for a potentially total accountability of dose, irrespective of the metabolic transformations that the parent pesticide may be subjected to.



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