The effects of prolonged ingestion of dieldrin on the livers of male rhesus monkeys

Abstract

This paper reports on the biochemical aspects of a wide-ranging study of the effects of long-term (ca. 6 years) exposure of male rhesus monkeys to technical grade dieldrin at dietary concentrations from 0.01 to 5 ppm. Apart from small changes associated with the hepatocellular endoplasmic reticulum, the overall study revealed no effects that could be attributed to dieldrin. Increases in the activity of the liver microsomal monooxygenase system, determined in vitro with a range of substrates, provided the most sensitive criteria for an effect. Significant increases, to a maximum of threefold, were observed in the 1.75- and 5-ppm treatment groups. These increases in monooxygenase activity were paralleled by increases in cytochrome P-450. There was no effect on glucose 6-phosphatase, a constitutive enzyme of the hepatocellular endoplasmic reticulum, or on the activities of hepatic alkaline phosphatase and succinic dehydrogenase. Although the increases in microsomal enzyme activity were associated with small increases in microsomal protein, there was no significant effect on liver weight nor on the DNA content of liver. The concentrations of dieldrin in the tissues of the 0.1-ppm treatment group of monkeys were very similar to those measured in humans receiving a similar daily intake of dieldrin per kilogram body weight. The concentrations of dieldrin in these monkey livers were, however, ca. 200 times higher than in male rats receiving a daily intake of dieldrin ca. 3 times higher than the monkeys and were very similar to the concentrations measured in the livers of male mice ingesting ca. 50 times more dieldrin per kilogram body weight per day than the monkeys. The dietary intake of dieldrin required for the induction of the rhesus monkey liver microsomal monooxygenase system was 25 to 30 μg/kg body w/day, approximately 300 times greater than that of the general human population in 1966–1967. The corresponding threshold concentration in the liver was 6 to 7 ppm. Such concentrations are associated with marked microsomal enzyme induction and overt liver enlargement in rats and mice. The results obtained with rhesus monkeys and the absence of any detectable changes in the livers of humans exposed to high endogenous concentrations of dieldrin point to a slow rate of metabolic clearance of dieldrin in these primate species and to a low sensitivity of their livers to this compound.