THE METABOLIC BASIS FOR THE ACUTE AND CHRONIC TOXICITY OF FORMAMIDINE PESTICIDES

GUIRGUIS ZAKI GHALI, Purdue University

Abstract

The formamidine pesticide chlordimeform (N'-(4-chloro-o-tolyl)-N,N-dimethylformamidine) shows moderate acute toxicity to mammals. The N-demethylation of chlordimeform (CDM) yields metabolites of increasing acute toxicity, but of lower chemical and biological stability. Symptoms exhibited by mice poisoned with lethal doses of CDM or one of these formamidine metabolities are similarly excitatory in nature. Surviving animals subsequently show the prolonged depressed behavior typical of the non-formamidine metabolites of CDM. Pretreatment of mice with hepatic mixed function oxidase (MFO) inducers such as phenobarbital or inhibitors such as SKF 525-A or piperonyl butoxide, although having predictable effects on the rate of N-demethylation of CDM in vitro, did not affect its lethality to mice. Other MFO inducers such as Aroclor 1254 and 3-methylcholanthrene significantly decreased the lethality of CDM, although they increased the rate of N-demethylation. The same trends were observed with N-demethylchlordimeform (DCDM) and N,N-didemethylchlordimeform (DDCDM). Studies of the tissue levels of CDM and its metabolites in mice after pretreatments affecting MFO activity (phenobarbital, 3-methyl-cholanthrene, and piperonyl butoxide) indicated that the best correlation to account for the resulting variations in the toxicity of CDM is with the level of total formamidines (CDM, DCDM, and DDCDM) in the brain. It is therefore concluded that although the successive N-demethylations of CDM are potential activation steps, they are not obligatory for the overall toxicity of CDM. However, the N-demethylated metabolites probably do contribute importantly to the overall toxicity. The protective action of Aroclor 1254 and 3-methylcholanthrene was mainly due to an induced increase in the rate of formamidine cleavage to N-formyl-4-chloro-o-toluidine (NFT), a metabolite of low acute toxicity produced from all three formamidines. In order to examine the metabolic basis for the carcinogenic activity of the formamidine pesticides, chlordimeform and amitraz (1,5-di-(2,4-dimethylphenyl)-3-methyl-1,3,5-triazapenta-1,4-diene), the behavior of these formamidines and some of their common metabolites was investigated in Ames Salmonella mutagenecity assay. The only positive responses were shown by the bacterial tester strains TA 98 and TA 100 with 4-chloro-o-toluidine and 2,4-dimethylaniline, the aniline metabolites of chlordimeform and amitraz respectively. Metabolic activation by liver homogenates was essential for this response. Although both rat and mouse liver homogenates were capable of activating the promutagenic anilines, rat liver had greater activity. When other selected mono- and disubstituted anilines were tested on strain TA 100, it was found that ortho-para disbustitution with a methyl group in the ortho position favored mutagenic activity. Unfortunately, it is precisely this substitution pattern which favors pesticidal activity. Thus it may be difficult to develop pesticidal formamidines which are not potential mutagens and carcinogens through metabolic release of their parent anilines.

Degree

Ph.D.

Subject Area

Entomology

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