Pesticides metabolic effects

In both these cases where an Insect cytochrome P-A50 system has been shown to be responsible for the oxidation of a-plnene and pulegone, the enzyme had to be Induced to higher activity to effectively catalyse the reaction. This leads to the question of whether Insect P-A50-dependent oxidations are sufficiently active In natural situations to produce a significant amount of the metabolites. Due to the Importance of cytochrome P-A50 oxidations In pesticide metabolism, there are, fortunately, several studies which show that the Insect oxidase system Is easily and rapidly Induced In response to a large variety of non-nutrient chemicals In the food. 

Hodgson, E., and Philpot, R. M. Interaction of methylenedioxyphenyl (1,3-benzodioxole) compounds with enzymes and their effects on mammals. Drug Metab. Rev. 3, 231,1974. Hodgson, E. Induction and inhibition of pesticide-metabolizing enzymes Roles in synergism of pesticides and pesticide action. Toxicol. Ind. Health 15, 6,1999. 

Of course, species do differ in the metabolism of pesticides, these differences are sometimes quite dramatic, and they can be of great significance in interpreting comparative toxicological effects. Also, species differences in pesticide metabolism, once identified, quite often provide impetus to the development of more selective pest-control agents. 

Pesticide metabolism studies are, without question, very important components in the evaluation of the toxicological significance of pesticides to man. The rate, extent, mechanisms, and products of metabolism are inevitably linked to the expression of toxic action, and a clear definition of pesticide biotransformation is often a necessary prerequisite to understanding mechanisms of toxicity and to the formulation of approaches for assessment and management of potentially undesired toxic effects. 

What does the future hold Can pesticide metabolism studies and the data they generate be more effectively used in the safety evaluation process Can these studies be made more predictive and thus more toxicologic ally relevant to man It is, of course, difficult if not impossible to foresee the future accurately. We will, however, make a few observations on these and other matters. 

Chadwick, R.W., Copeland, M.R. and Chadwick, C.J. (1978). Enhanced pesticide metabolism - A previously unreported effect of dietary fibre in mammals. Food Cosmet. Toxicol. 16, 217-225. 

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. 

Compounds that affect activities of hepatic microsomal enzymes can antagonize the effects of methyl parathion, presumably by decreasing metabolism of methyl parathion to methyl paraoxon or enhancing degradation to relatively nontoxic metabolites. For example, pretreatment with phenobarbital protected rats from methyl parathion s cholinergic effects (Murphy 1980) and reduced inhibition of acetylcholinesterase activity in the rat brain (Tvede et al. 1989). Phenobarbital pretreatment prevented lethality from methyl parathion in mice compared to saline-pretreated controls (Sultatos 1987). Pretreatment of rats with two other pesticides, chlordecone or mirex, also reduced inhibition of brain acetylcholinesterase activity in rats dosed with methyl parathion (2.5 mg/kg intraperitoneally), while pretreatment with the herbicide linuron decreased acetylcholine brain levels below those found with methyl parathion treatment alone (Tvede et al. 1989). 

Lodovici M, Aiolli S, Monserrat C, et al. 1994. Effect of mixture of 15 commonly used pesticides on DNA levels of 8-hydroxy-2-deoxyguanosine and xenobiotic metabolizing enz5mies in rat liver. J Environ Pathol Toxicol and Oncol 13 163-168. 

The need to develop and use chiral chromatographic techniques to resolve racemates in pesticide residues will be driven by new hazard and risk assessments undertaken using data from differential metabolism studies. The molecular structures of many pesticides incorporate chiral centers and, in some cases, the activity differs between enantiomers. Consequently, in recent years manufacturers have introduced resolved enantiomers to provide pesticides of higher activity per unit mass applied. For example, the fungicide metalaxyl is a racemic mix of R- and 5-enantiomers, both having the same mode of action but differing considerably in effectiveness. The -enantiomer is the most effective and is marketed as a separate product metalaxyl-M. In future, it will not be satisfactory to rely on hazard/risk assessments based on data from metabolism studies of racemic mixes. The metabolism studies will need to be undertaken on one, or more, of the resolved enantiomers. 

Pesticides have a statistically reliable effect on children in zones where OCPs are intensively used (in the Salyansk region of Azerbaijan, the amount of OCPs introduced into humans exceeded public health standards by up to 7.7 times). Primary illness of the endocrine system increased 3.1 times in children up to age 15 (over a five year observation period) in disruptions in diet and metabolism, the nervous system, and the sensory and respiratory organs in increased frequency of illness (over five years) in children up to age 15 (an overall increase by 3.6 times, and by class of illness, from 2.2-7.6 times) in the prevalence of pathological disruptions according to data from medical examinations of children from 8-14 years (an overall increase by 2.3 times, and by class of illness by 2.0-8.4 times) in... 

Even though all OP insecticides have a common mechanism of action, differences occur among individual compounds. OP insecticides can be grouped into direct and indirect ACHE inhibitors. Direct inhibitors are effective without any metabolic modification, while indirect inhibitors require biotransformation to be effective. Moreover, some OP pesticides inhibit ACHE more than PCHE, while others do the opposite. For example, malathion, diazinon, and dichlorvos are earlier inhibitors of PCHE than of ACHE. In these cases, PCHE is a more sensitive indicator of exposure, even though it is not correlated with symptoms or signs of toxicity. 

Kay, K. (1970) Pesticides and associated health factors in agricultural environments effects on mixed-function oxiding enzyme metabolism, pulmonary surfactant and immunological reactions, in Pesticides Symposia, R. Dichmann (Ed.), Halos Co., Miami, FL. 

Lydon J and Duke S D (1989), Pesticides effects on secondary metabolism of higher plants , Pest Sci, 25, 361-374. 

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