Date of Award:

1969

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Animal, Dairy, and Veterinary Sciences

Department name when degree awarded

Toxicology

Advisor/Chair:

Joseph C. Street

Abstract

Induction of hepatic microsomal hydroxylative enzymes is an important aspect of detoxication of fat-soluble toxicants. The magnitude of induction depends on numerous factors, such as the nature and dose of toxicant as well as dietary factors. Research was conducted on (1) endrin tolerance in rats, (2) preliminary comparisons of inductive effects of various organochlorine pesticides in rats to select compounds for further study in guinea pigs, (3) general effects of various dietary factors on induction, and (4) effects of ascorbic acid deficiency on induction of hepatic microsomal hydroxylative enzymes by organochlorine pesticides in guinea pigs. Measurements were made of body weight gain, feed consumption, liver weight, in vivo and in vitroenzyme activities, and body levels of pesticides and vitamins.

Tolerance developed in rats fed 25 ppm endrin in the diet. There was severe intoxication during the first week but complete recovery of rate of body weight gain and feed consumption occurred during the second week, in spite of continued ingestion of the endrin-containing diet. Induction of endrin-degrading microsomal enzymes was proposed as the mechanism for tolerance. Pretreatment with the potent inducer, dieldrin, diminished the severity of endrin intoxication. However, pretreatment with another inducer, phenobarbital, afforded less protection in proportion to the extent of microsomal enzyme induction.

Organochlorine pesticides, tested for their inductive capacity in rats, in decreasing order of effectiveness then fed as 25 ppm of the diet for 15 days, were heptachlor epoxide, dieldrin, endrin, 1,1-Bis-(p-chlorophenyl)-2,2,2-Trichloroethane (DDT), Ovex, gamma-chlordane, and lindane. Of these, DDT and dieldrin were compared over the range of 1 to 50 ppm of the diet. Dieldrin was a more potent inducer at all dietary levels. At low doses both compounds produced greater induction when measured by hexobarbital sleep time than by the in vitro enzyme procedures. At high doses, the in vitro 0-ethyl 0-p-nitrophenyl phenyl-phosphonothioate (EPN) detoxication was a more responsive measure.

Dieldrin, DDT, and lindane were fed to guinea pigs at 25 ppm of the diet for 15 days, but only dieldrin stimulated a significant level of induction. DDT antagonism of dieldrin storage seen in rats by Street (Sci. 146:1580, 1964) did not occur in guinea pigs, but rather dieldrin antagonized DDT storage.

Some general dietary factors affecting induction in rats were observed. A semipurified diet lowered the baseline microsomal enzyme activity but supported induction as effectively as a conventional diet. Vitamin A at very high dietary levels induced enzyme activity; this induction was apparently additive to that produced by 1 ppm dieldrin. Other fat-soluble Vitamins produced inconsistent responses.

Ascorbic acid deficiency in guinea pigs impaired induction by dieldrin. Impairment was seen by the second day on the deficient diet. However, dieldrin was able to produce a small amount of induction at all stages of deficiency. In frank scurvy, induction by DDT and lindane was completely blocked, but there was a moderate level of induction by dieldrin. Maintenance of maximum induction was related to dietary rather than liver levels of ascorbic acid; 50 ppm ascorbic acid in the diet was grossly inadequate while 200 ppm supported about 80% of the induction produced by feeding 2000 ppm.

It was concluded that (1) microsomal enzyme induction is important in resistance to organochlorine intoxication, (2) factors found in the normal diet can induce microsomal enzyme activity, (3) high dietary levels of ascorbic acid are necessary to support maximum induction, and (4) dieldrin is an inducer of such high potency that it can stimulate a limited amount of induction in spite of ascorbic acid deficiency.

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