The Alkylating Properties of Organophosphates

Abstract

1. A brief introduction to the concept of alkylation is given, which discusses reaction mechanisms and reactivity, and includes an assessment of the susceptibility to alkylation of biologically-important molecules. 2.A semi-quantitative colour test for alkylating agents, with 4-(pnitrobenzyl) pyridine (NBP), has been modified to give a quantitative method for the determination of second-order rate constants, k,, for reaction at 37.5". These constants have been determined for dichlorvos, several other organophosphorus insecticides, and, for comparison, some known biological alkylating agents. 3.These results are discussed in relation to the extensive literature data pertaining to the chemical and biological reactivity of these compounds, and an assessment of the biological importance of the alkylating properties of dichlorvos and related organophosphorus insecticides has been made.4. Since dichlorvos is rapidly metabolized in mammals by esterases present at high activity in the liver and moderate activity in lung, spleen, kidney and blood plasma, the chances of its manifesting spontaneous deleterious biological alkylating activity are very low, and may even be zero. Structure/activity correlations suggest that this will also apply to other organophosphate insecticides, but not necessarily to simple alkyl phosphates such as trimethyl phosphate. Recently Lofroth, Kim & Hussain (1969) have made a preliminary in nitro evaluation of the alkylating properties of dichlorvos (2,2-dichlorovinyl dimethyl phosphate, DDVP), which has prompted them to draw comparisons between dichlorvos and the powerful alkylating agents and known mutagenic agents, methyl and ethyl methanesulphonates.Recently, too, the alkylating properties of some other organophosphorus insecticides have been demonstrated by subjecting them to the NBP (4-(p-nitrobenzy1)pyridine) colour test for alkylating agents (Preussmann, Schneider & Epple, 1969). Strong positive ( + + + ) responses, it was claimed, were given by methylparathion, Chlorthion, Metasystox, thiometon, malathion, Dipterex and Gusathion, and weak positive ( + + ) responses by parathion, ethion, sulfotepp and Systox. Preussmann, et al. (1969) also measured the alkylating properties of about 200 other compounds, including aliphatic and aromatic halogen compounds, lactones and sulphones, epoxides, ethylenimines, diazo and azo compounds, nitrosamines, nitrosamides, and esters of other strong acids. Noteworthy in the latter group were dimethyl sulphate and methyl methanesulphonate, which were given the same (semi-quantitative) top rating of + + + as that given to seven of the organophosphorus insecticides. I n view of this, a critical study of the NBP colour reaction has been made. XB . T Xenobiotica Downloaded from informahealthcare.com by Nyu Medical Center on 07/30/15 For personal use only.T h e first section of this review provides a brief introduction to the concept of alkylation. This is followed by an appraisal of the relevance of the results of the NBP colour test as an index of biological al...

Cytological effects of herbicides and insecticides on Allium cepa root meristems.

“…Induction of 'subchromatid' connections is the result of true exchanges between homologous or non-homologous chromosomes whereas the presence of hetermorphic chromosomes can be attributable to terminal deletion of one of the chromatids (Rosenkranz and Rosenkranz 1972, Tomkins and Grant 1972, Grant 1978. Agents that act directly on DNA were shown to exert such exchange figures (Bedford andRobinson 1972, Wooder andWright 1981).…”

Cytological effects of organophosphorus insecticides on Allium cepa root meristems.

“…This induction of heteromorphic diplochromosomes and 'subchromatid' connections, which are the result of true exchanges, indicate that these chemicals are similar in their action to alkylating agents. Several other pesticides have been also shown to exert such action (Tomkins and Grant 1972, Bedford and Robinson 1972, Wild 1975). …”

Mutagenic studies on the insecticide Metasystox-R with Allium cepa.

“…Mitodepression has been seen to be related to the phosphorylating and alkylat ing properties of a chemical (Lofroth et al 1969, Bedford and Robinson 1972, Rosenkranz and Rosenkranz 1972, Dedek et al 1976. Metasystox-R is having both phosphate as well as alkyl groups.…”