Graduate Thesis Or Dissertation


Potentiation of acute carbon tetrachloride hepatotoxicity by dietary exposure to chlorophenothane (DDT) in rats Public Deposited

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  • There has been no toxicologic proof that the long-term, low-level exposure of man to chlorophenothane (DDT) is linked with an increased susceptibility to toxicity or disease. Acute pretreatment of rats with 75-100 mg/kg DDT has been demonstrated to potentiate CCI₄-induced hepatotoxicity in that species (McLean and McLean, 1966). Since the hepatotoxic response to CC1₄ is similar among mammalian species, it was believed man's response could also be altered by prior exposure to DDT. Chronic pretreatment of rats with DDT more closely duplicates man's exposure situation, which is mainly dietary. Therefore, this present investigation was undertaken to quantify the DDT-CCI₄ hepatotoxic interaction in rats from the standpoint of a chronic dietary exposure to DDT. Chronic and acute pretreatments with DDT were compared for their relative effects on acute CC1₄ hepatotoxicity. Subgroups of rats fed DDT at concentrations of 6-65 ppm for three weeks and 65 ppm for 24 weeks attained body burdens of DDT and its metabolites ranging from 6.1 to 30.6 ppm, compared to 0 ppm (no detectable) for controls. In the acute study, subgroups of rats were dosed with 35-150 mg/kg DDT by gavage 24 hours prior to CC1₄ exposure. Doses of CC1₄ ranging from 0.125 to 1.0 mi./kg were administered by gavage. All pretreatments with DDT, chronic or acute, resulted in a potentiated elevation of serum transaminase (SGPT and SGOT) activities following treatment with CC1₄. The degree of potentiation was dose-related to CCI₄ and to the total DDT body burden. In a temporal study, the onset of the potentiated response was noted six hours after CC1₄. All of the above-mentioned results were confirmed by histopathology. Plasma BSP disappearance, dose-response and temporal studies were conducted in control and DDT-fed rat groups, utilizing the BSP test as an index of hepatic functional impairment, CC1₄-induced BSP retention was greatly potentiated by prior dietary exposure to DDT. This potentiation effect was obscured at a dose of 2.0 ml/kg CC1₄, due to the severe hepatic damage produced by this dose of CCI₄ given alone. The onset and development of the potentiated hepatic dysfunction paralleled that of the parenchymal cell destruction. The potentiated CC1₄-induced increases in SGOT activity and centrilobularly-oriented coagulative necrosis in the DDT-fed animals were prevented by spinal cord transection at the level of the seventh cervical vertebra. Chronic DDT pretreatment did not enhance CC1₄ uptake into the blood or livers of intact rats, and this was ruled out as a possible mechanism for the potentiation effect. Cord-sectioning did enhance tissue CC1₄ uptake, yet these animals were protected against CC1₄-induced central necrosis. Neither cord-sectioning nor the resultant hypothermia reduced the microsomal cytochrome P-450 content in control or DDT-fed rats. Hypothermia depressed the in vitro N-demethylation of ethylmorphine, so that oxidative drug metabolism was probably also decreased in vivo in the cordotomized animals. Maximal blood and liver concentrations of CC1₄ were measured between 2-4 hours in the intact control and DDT-fed groups. These tissue CC1₄ concentrations decreased more rapidly between 4-12 hours in the DDT-fed rats, thus suggesting an increased rate of CC1₄ metabolism could have occurred at this time in vivo in these animals. Unlike the other indices of hepatic damage, the cytochrome P-450 response preceded rather than followed the hepatocellular destruction. About 75% of the induced cytochrome P-450 concentration in the DDTfed rats was destroyed within six hours after CC1₄, at which time the onset of potentiated hepatic damage was detected. In the controls, the cytochrome P-450 concentration regenerated from a low value at 18 hours to normal by 48 hours after CC1₄. Hepatic regeneration was impaired in the DDT-fed rats, since the cytochrome P-450 concentration continued to decline between 24-48 hours. The amount of cytochrome P-450 destruction appeared to correlate with the degree of hepatic damage observed. Lower absolute concentrations of cytochrome P-450 were measured in controls 24 hours after dosing with 0.125-2.0 ml/kg CC1₄. More cytochrome P-450 was destroyed in the DDT-fed group, however, as a result of the induced microsomal concentrations of this cytochrome present initially before CC1₄ was given. Thus, the CCI₄- cytochrome P-450 interaction could play an integral role in the potentiation phenomenon, as McLean and McLean (1969) have suggested. Liver weight increased in a dose-related manner to CC1₄ in both control and DDT-fed groups, but the response was greater in controls. In the control animals, the liver weight increased rapidly to a maximal value at 18 hours, but returned to normal by 48 hours after CC1₄. Although the onset of the response was slower in the DDT-fed rats, the liver weight continued to increase at 48 hours. Rectal temperatures declined between 6-24 hours only in the DDT-fed animals. The pharmacologic agents SKF 525-A (drug metabolism inhibitor) and lead (porphyrin biosynthesis inhibitor) were utilized to assess the role of cytochrome P-450 in potentiation. SKF 525-A provided protection against the potentiated CC1₄-induced centrilobular necrosis at 11 hours after CC1₄. This protection could not be positively ascribed to SKF 525-A binding with cytochrome P-450 or inhibiting CC1₄ metabolism, since SKF 525-A has been reported to alter the gastrointestinal absorption of CC1₄ (Marchand, McLean and Plaa, 1970). Lead significantly reduced the effect of prior DDT feeding in potentiating CC1₄ hepatotoxicity, but this protection did not result from a lowered microsomal cytochrome P-450 content. Thus, the role of cytochrome P-450 in the potentiation effect remains to be conclusively elucidated. Mecamylamine pretreatment was used to determine the importance of the sympathomimetic properties of DDT in potentiation. This ganglionic blocking agent produced an insignificant tendency to decrease the potentiated CC1₄- induced BSP retention. However, the histologic evidence of protection against CC1₄ -induced hepatic necrosis was not apparent in mecamylamine-pretreated animals. Thus, the central sympathetic nervous system stimulatory effects of DDT are probably not directly involved in potentiation. The basis for extrapolation of these results from rat to man could be the total DDT body burden, which was similar in these rats (6.1 -30.6 ppm) to that estimated for man, e.g., 10 ppm by Durham (1965). Since rats and man respond similarly to CC1₄, these results indicate that man's chronic exposure to DDT could render him highly susceptible to a secondary exposure to CC1₄.
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