Metabolism of DDT

Under anaerobic conditions, p,p -DDT is converted to p,p -DDD by reductive dechlorination, a biotransfonnation that occurs postmortem in vertebrate tissues such as liver and muscle and in certain anaerobic microorganisms (Walker and Jefferies 1978). Reductive dechlorination is carried out by reduced iron porphyrins. It is carried out by cytochrome P450 of vertebrate liver microsomes when supplied with NADPH in the absence of oxygen (Walker 1969 Walker and Jefferies 1978). Reductive dechlorination by hepatic microsomal cytochrome P450 can account for the relatively rapid conversion of p,p -DDT to p,p -DDD in avian liver immediately after death, and mirrors the reductive dechlorination of other organochlorine substrates (e.g., CCI4 and halothane) under anaerobic conditions. It is uncertain to what extent, if at all, the reductive dechlorination of DDT occurs in vivo in vertebrates (Walker 1974). 

One other biotransformation deserving mention is the oxidation of p,p -DDT to kelthane, a molecule that has been used as an acaricide. This biotransformation occurs in certain DDT-resistant arthropods, but does not appear to be important in vertebrates. 

Unchanged p,p -DDT tends to be lost only very slowly by land vertebrates. There can, however, be a certain amount of excretion by females into milk or across the placenta into the developing embryo (mammals) or into eggs (birds, reptiles, and insects). 

In discussing the enviromnental fate of technical DDT, the main issue is the persistence of p,p -DDT and its stable metabolites, although it should be bom in mind that certain other compounds— notably, o,p -DDT and p,p -DDD—also occur in the technical material and are released into the environment when it is used. The o,p isomer of DDT is neither very persistent nor very acutely toxic it does, however, have estrogenic properties (see Section 5.2.4). A factor favoring more rapid metabolism of the o,p isomer compared to the p,p isomer is the presence, on one of the benzene rings, of an unchlorinated para position, which is available for oxidative attack. p,p -DDD, the other major impurity of technical DDT, is the main component of technical DDD, which has been used as an insecticide in its own right (rhothane). p,p -DDD is also generated in the environment as a metabolite of p,p -DDT. In practice, the most abundant and widespread residues of DDT found in the environment have been p,p -DDE, p,p -DDT, and p,p -DDD. 

When DDT was widely used, it was released into the environment in a number of different ways. The spraying of crops, and the spraying of water surfaces and land to control insect vectors of diseases, were major sources of environmental contamination. Waterways were sometimes contaminated with effluents from factories where DDT was used. Sheep-dips containing DDT were discharged into water courses. Thus, it is not surprising that DDT residues became so widespread in the years after the war. It should also be remembered that, because of their stability, DDT residues can be circulated by air masses and ocean currents to reach remote parts of the globe. Very low levels have been detected even in Antarctic snow  

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Rice CP, HC Sikka (1973) Uptake and metabolism of DDT by six species of marine algae. JAgric Food Chem 21 148-152. 

The fundamental chemistry, especially of the newer economic poisons, is of primary importance. The mechanism of action of the various types of economic poisons and the relation of structure to toxicity of insects are of fundamental interest. Chemical versus biological methods of evaluation should be presented. Performance methods of evaluation of these chemicals have been given careful consideration by several workers. Emphasis was placed by several workers on the need for much additional information on various aspects of the problem regarding the use of DDT, 2,4-D, and other pesticides. There is direct importance in studies on the metabolism of DDT. 

DDT Metabolism.-- The metabolism of DDT has been studied in R and S fish, following similar protocols to chlorinated cyclodiene metabolism organic extraction (acetonitrile), thin layer chromatography of organic extracts, and liquid scintillation counting of the resultant spots (4). When S and R fish were exposed to 60 yg/l of 14C-labelled , -DDT for 4 hr, radioactivity was found in the spots which co-chromatographed with... 

Neudorf, S. and Khan, M.A.Q. Pick up and metabolism of DDT, dieldrin, and photodieldrin by a freshwater alga Ankistrodesmus amalloide and a microcrustacean (Daphnia pule, Bull. Environ. Contain. Toxicol, 13(4) 443-450,1975. 

Metabolism of DDT proceeds at a very slow rate. Liver microsomal P450 and other microsomal enzymes initially dechlorinate DDT to l,l-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) and reduce to 1,1 -dichloro-2,2-bis(p-chlorophenyl)ethane (DDD). The conversion of DDD to bis(p-chlorophenyl)acetic acid (DDA) involves the formation of an acyl chloride intermediate by hydroxylation followed by hydrolysis to yield the final product. 

Figure 15.16. Chiorohenzilate (52) can be regarded as a soft chemical obtained using an inactive metabolite-based approach based on the metabolism of DDT (45),...

A previous study for the evaluation of the organochlorine pesticides burden in the human body, of a non-occupational-exposed population (WHO Project European Cooperation on Environmental Health Aspects of the Control of Chemicals ) indicated that human milk levels in the range of 11-12 mg kg HCH and 2.8 mg kg DDT, were about 5 times higher than in other European countries. The adipose tissue and fat sampled from humans, indicated a mean content in DDT plus DDE in the range of 8-17 mg kg, the DDE p entages demonstrated over a long period involving the metabolization of DDT and a constant intake of DDE in food. 

When one considers the further metabolism of DDT, the picture becomes more confusing. Wedemeyer 16, 26) has proposed the pathway from DDD to DBP shown in Figure 5. This pathway is similar to that proposed originally for rats by Petersen and Robinson (27). It was developed by detecting the succeeding metabolites after incubating the various proposed intermediates with A. aerogenes. 

Because partitioning of organic compounds to living organisms is inevitably complicated by certain interfering processes, it is not unusual to anticipate that the correlation between BCF and A ow or S may depend highly on the stability of the compound and the type of organism, as well as the test procedure. Metcalf et al. (77) studied the distribution and metabolism of DDT, DDE, DDD, and methoxychlor in snail Physa), mosquito larvae Culex pipiens quinquefas-... 

Phillips DJH (1985) Organochlorines and trace metals in green-lipped mussels Perna viridis from Hong Kong waters a test of indicator ability. Mar Ecol Prog Ser 21 251-258 Phillips J, Wells M, Chandler C (1974) Metabolism of DDT by the freshwater planarian, Phagocata velata. Bull Environ Contam Toxicol 12 355-358... 

Neudorf, S. and M.A.Q. Khan. Pick Up and Metabolism of DDT, Dieldrin, and Photo-dieldrin by a Fresh Water Alga (Ankistrodesmus amalloides) and a Microcrustacean (Daphniapulex)( Bull. Environ. Contam. Toxicol, 13(4) 443 50 (1975). 

The metabolism of DDT 355), and presumably its analogues 356, 357, 393), involves a series of reductive dechlorinations and dehydrochlorina-tions/ Buselmaier et have reported that DDD is mutagenic with Ser-ratia marcescens but not with Salmonella strain G46 in the host-mediated assay DDT, DDE, and DDA [di(4-chlorophenyl)acetic acid] were not positive in similar testing. 

Figure 11. Metabolism of DDT (24) and chlorobenzilate (31. R = Et) as a soft chemical obtained using a formal inactive metabolite approach.

Examples of Synthesis Routes Inherently Safer Than Others As summarized by Bodor (1995), the ethyl ester of DDT is highly effective as a pesticide and is not as toxic. The ester is hydrolytically sensitive and metabolizes to nontoxic products. The deliberate introduction of a structure into the molecule which facilitates hydrolytic deactivation of the molecule to a safer form can be a key to creating a chemical product with the desired pesticide effects but without the undesired environmental effects. This technique is being used extensively in the pharmaceutical industry. It is applicable to other chemical industries as well. 

Hurst (19) discusses the similarity in action of the pyrethrins and of DDT as indicated by a dispersant action on the lipids of insect cuticle and internal tissue. He has developed an elaborate theory of contact insecticidal action but provides no experimental data. Hurst believes that the susceptibility to insecticides depends partially on the cuticular permeability, but more fundamentally on the effects on internal tissue receptors which control oxidative metabolism or oxidative enzyme systems. The access of pyrethrins to insects, for example, is facilitated by adsorption and storage in the lipophilic layers of the epicuticle. The epicuticle is to be regarded as a lipoprotein mosaic consisting of alternating patches of lipid and protein receptors which are sites of oxidase activity. Such a condition exists in both the hydrophilic type of cuticle found in larvae of Calliphora and Phormia and in the waxy cuticle of Tenebrio larvae. Hurst explains pyrethrinization as a preliminary narcosis or knockdown phase in which oxidase action is blocked by adsorption of the insecticide on the lipoprotein tissue components, followed by death when further dispersant action of the insecticide results in an irreversible increase in the phenoloxidase activity as a result of the displacement of protective lipids. This increase in phenoloxidase activity is accompanied by the accumulation of toxic quinoid metabolites in the blood and tissues—for example, O-quinones which would block substrate access to normal enzyme systems. The varying degrees of susceptibility shown by different insect species to an insecticide may be explainable not only in terms of differences in cuticle make-up but also as internal factors associated with the stability of oxidase systems. 

AP -DDT is rather stable biochemically as well as chemically. Thus, it is markedly persistent in many species on account of its slow biotransformation. Metabolism of p,p -DDT is complex, and there is still some controversy about its specifics. The most important metabolic pathways are shown in Figure 5.2. 

There has been renewed interest in DDT in spite of the fact that its use has been banned in many countries for several years. The degradation of DDT has been discussed in Chapter 7, Part 3, and attention has been directed to the apparently recalcitrant DDE (Quensen et al. 1998) and DDA (Heberer and Diinnbier 1999). Uptake and metabolism of p,p -DDT and the isomeric o,p -DDT have been examined in a range of plants, and the results illustrate a number of important issues. 

Kupfer D, Levin E and Burstein SH (1973). Studies on the effects of tetrahydrocannabinol and ddt on the hepatic microsomal metabolism of the and other compounds in the rat. Chemical-Biological Interactions, 6, 59-66. 

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