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Female Swiss-Vancouver (SWV) mice, 13 weeks old, were exposed to dietary dieldrin for up to 10 weeks. Liver mass, hepatic microsomal protein and cytochrome P-450, and the in vitro metabolism of imipramine were determined at intervals. Dieldrin (5, 10, 15, and 20 ppm) caused hepatomegaly and increases in P-450; both effects were dose-related. All doses increased microsomal protein by about 30% (control value was 15.3 mg of protein per gram of liver). Maximal responses were attained by 2 weeks of exposure and maintained thereafter. Plateau liver masses at these respective doses were 111, 119, 133, and 162% of the control value (57.9 mg of liver per gram of body weight). Cytochrome P-450 was, respectively, 124, 142, 185, and 173% of the control value (0.93 nmol per milligram of microsomal protein). These changes decreased pentobarbital sleeping times by an average of 540% in animals fed 5, 15, or 25 ppm for 4 weeks. Similarly, the latency to the onset of anesthesia was increased by 26% at all doses. The N-oxidation and aryl-hydroxylation of imipramine increased with age, while demethylation decreased. The hydroxylation and demethylation of imipramine was increased after 2 and 4 weeks, respectively, of exposure to 20 ppm; N-oxidation was decreased. Longer exposure to lower doses caused similar changes. The changes in liver parameters and imipramine metabolism induced by 4 weeks exposure to 20 ppm were absent 6 weeks after exposure ceased.

Hepatic carbohydrate metabolism was studied in adult and suckling rats given age-specific LD50 doses of dieldrin po. These doses in 5-, 10-, and 60-day-old Wistar rats were 38, 28, and 63 mg/kg, respectively. Plasma glucose and free fatty acids (FFA), and hepatic glycogen, phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-diphosphatase (FDP), and glucose-6-phosphatase (G6P) were measured 1 and 3 h after administration of the insecticide. Plasma glucose concentrations were elevated (17%) in some 5-day-old rats after 1 h and in all adults after 1 and 3 h (45 and 30%, respectively). Plasma FFA concentrations were decreased (9%) in the 5-day-old rat 1 h after dieldrin. Hepatic glycogen content was reduced in both 5- and 10-day-old pups at 1 hour (22 and 17%, respectively). Hepatic FDP activity was elevated in the 5-day-old rat at 1 h (17%) and was decreased (10%) in the 10-day-old rat at 3 h. Hepatic PEPCK activity was increased in adult animals by 30% 1 h after dieldrin. Furthermore, PEPCK activity was increased at 3 h in rats of all ages (76%, 5-day-old pup; 115%, 10-day-old pup; 56%, 60-day-old adult). Hepatic G6P activity was unaltered by dieldrin. Thus only the activity of hepatic PEPCK is consistently elevated by dieldrin exposure. However, this enhanced PEPCK activity is associated with dieldrin-induced hyperglycemia only in the adult rat.

Carbohydrate metabolism and central nervous sytem (CNS) intoxication were investigated as causes of dieldrin-induced congenital inviability. The 24-h LD50 was calculated using 5-day-old normal mice (CD-1 strain), fasted for 24 h, and gavaged with dieldrin. The LD50, 27 mg/kg, was 5% of the cumulative dose received by the dieldrin-treated, pregnant females. Acutely poisoned pups convulsed and tremored, inviable pups do not. Inviable pups were caesarian delivered on day 18 from dieldrin-treated females (p.o., 2 mg/kg per day, from day 6 to day 18), and aspects of carbohydrate metabolism were measured 0, 19, and 24 h postdelivery. Inviable and control pups weighed the same at all times but the liver weight of inviable pups was reduced by 0, 8, and 21%, at 0, 19, and 24 h, respectively (control: 61, 48, and 41 mg/g body weight). The inviable pups were hypoglycemic at delivery (0.69 vs. 0.95 mg/mL plasma in the controls), at 19 h (0.53 vs. control values of 0.94 mg/mL), and were aglycemic at 24 h (normal pups: 0.32 mg/mL). Liver glycogen, normal in inviable pups at birth (control: 71 mg/g liver), was reduced by 38% at 19 h (control: 19 mg/g) and by 77% at 24 h (control: 4.5 mg/g). Cardiac glycogen was reduced in treated pups only at 24 h (5.5 mg/g vs. control levels of 11.0 mg/g). Muscle glycogen was also reduced only at 24 h (2.2 mg/g vs. control levels of 5.4 mg/g). Prenatal dieldrin did not affect blood lactate, pyruvate, or urea, nor did it alter hepatic lactate dehydrogenase (LDH) or fructose diphosphatase (FDPase) activities. It is concluded that the inviability is not caused by CNS stimulation; it is associated with congenital hypoglycemia, enhanced glycogenolysis, and apparently normal gluconeogenesis.