Safety evaluation of benzophenone.

Benzophenone (FEMA No. 2134; CAS No. 119-61-9) was administered in the diet to rats at target dose levels of 20 mg/kg body weight/day for 90 days and 100 or 500 mg/kg/day for 28 days. Body weights and food consumption were measured weekly; haematology, clinical chemistry and urinalysis values were obtained at 4 wk and at the end of the study. Gross and microscopic pathological examinations were conducted and organ weights were recorded. Treatment-related changes occurred in erythrocyte count, haemoglobin, haematocrit, bilirubin, total protein and albumin at the mid- and high-dose levels, although all changes did not occur in both groups in both sexes. There were indications of increased absolute and relative liver and kidney weights in the mid- and high-dose groups, but this was not statistically consistent for absolute kidney weights. Histopathology of the liver in the mid- and high-dose groups showed hepatocellular enlargement with an associated clumping of cytoplasmic basophilic material around the central vein. A no-effect level was demonstrated at 20 mg/kg/day for 90 days of administration. This would be equivalent to an intake of 1200 mg/day for a 60-kg human. On the basis of the calculated Possible Average Daily Intake of 0.33 mg/day, a safety factor of greater than 3600 is demonstrated. The safety factor based on the more realistic per capita consumption of 0.32 microgram/day would be approximately 3.7 million.

Differential effects of cadmium on the hepatic microsomal cytochrome P-450 system in male and female rats.

Cadmium (Cd) produced a marked sex-related difference with respect to inhibition of the hepatic microsomal monooxygenase enzyme system in the rat. Following in vivo cadmium (2 mg/kg i.p.) treatment, significant decreases in the levels of cytochrome P-450, significant reductions in the magnitudes of spectral binding (aniline or ethylmorphine), and significant inhibitions of microsomal metabolism (aniline and ethylmorphine) were observed with microsomes isolated from male but not female rats. Of these parameters only aniline metabolism was significantly altered in females. Following the in vitro addition of Cd (10(-6) M to 10(-3) M) to hepatic microsomes isolated from untreated male or female rats, sex-related changes were also observed in these parameters. Significant, concentration-dependent reductions were observed in cytochrome P-450 levels of both sexes but the males showed greater sensitivity to the cadmium effect. With respect to binding spectra, cadmium addition produced a concentration dependent inhibition of aniline only in the male rat. Ethylmorphine binding was inhibited only at the higher cadmium concentrations in both sexes. With respect to drug metabolism, cadmium addition inhibited both aniline and ethylmorphine metabolism in male rats and only aniline metabolism in female rats. These results showed that there are sex-related differences in the interaction of the hepatic microsomal monooxygenase enzyme system with cadmium both after in vitro addition as well as in vivo treatment with the metal.

Sex-related differences in the effect of cadmium on the induction of hepatic microsomal monooxygenases by phenobarbital in male and female rats.

3 days following an intraperitoneal injection of cadmium [Cd] (2.0 mg Cd/kg) an inhibition in hepatic microsomal drug metabolism for ethylmorphine and aniline was observed in male rats. Such treatment in female rats only inhibited metabolism of aniline. Following treatment with phenobarbital (50 mg/kg, i.p., for 4 days), the metabolism of both substrates was induced in rats of both sexes. In male rats, but not in female rats, Cd blocked the inducing action of phenobarbital.

Cadmium-induced inhibition of zoxazolamine metabolism in male and female rats.

Pretreatment of rats with cadmium potentiates the duration of hexobarbital hypnosis and inhibits the rate of hepatic hexobarbital metabolism in male and female rats. In contrast, treatment with cadmium pe and female rats. Thus, sex-related differences in cadmium inhibition of hepatic drug metabolism is apparently substrate dependent.

Studies on cadmium-induced inhibition of hepatic microsomal drug biotransformation in the rat.

Cadmium is a potent inhibitor of hepatic microsomal drug biotransformation in the rat. Male rats receiving a single intraperitoneal dose of cadmium exhibit significant decreases in hepatic microsomal metabolism of a variety of substrates. The threshold cadmium dose is 0.84 mg Cd/kg, and the effect lasts at least 28 days. Mechanistically, the inhibitory effect results from decreased cytochrome P-450 content since cadmium does not alter NADPH cytochrome c reductase activity. This effect is also observed following acute oral administration of cadmium in doses greater than 80 mg Cd/kg but is not observed following chronic administration of the metal via drinking water in concentrations of 5-200 ppm for periods ranging from 2 to 50 weeks. A tolerance to the inhibitory cadmium effect is observed if male rats are pretreated with subthreshold doses of the metal prior to the challenge cadmium dose. The degree of tolerance can be overcome by increasing the challenge dose of cadmium. Characterization of the tolerance phenomenon in terms of onset, duration, and intensity reveals a good correlation with the kinetics of metallothionein production, suggesting that the underlying basis for the tolerance phenomenon is likely the induction of metallothionein. A sex-related difference in the inhibitory effect of cadmium was observed. Cadmium did not inhibit the metabolism of hexobarbital or ethylmorphine in female rats but did inhibit that of aniline or zoxazolamine. Cadmium did not lower cytochrome P-450 content in female rats.

Sex-related differences in biotransformation of aniline hydroxylase in Sprague-Dawley rats.

A significant difference was found in the rate of aromatic hydroxylation of the type II substrate, aniline, between male and female rats of the Sprague-Dawley strain. In addition, microsomal cytochrome P-450 levels were significantly lower in female rats and aniline-induced spectral binding was significantly greater in microsomes isolated from male rats. Castration caused a significant reduction in aniline metabolism in male rats and testosterone treatment elevated this metabolism toward control level. Treatment of male rats with 17beta-estradiol significantly reduced aniline hydroxylase activity and female rats receiving testosterone for 1 month exhibited significantly increased rates of aniline metabolism over control females. Enzyme activities measured in immature male and in mature and immature female rats were all significantly lower than in mature male rats. These results suggest that the metabolism of aniline in Sprague-Dawley derived rats is controlled by androgen and, thus, is sex-dependent.

Effect of acute and chronic cadmium treatment on hepatic drug metabolism in male rats.

The effect of acute and chronic cadmium administration on hepatic drug metabolism was investigated in the male rat. 3 days after the acute administration of cadmium by either the intraperitoneal (0.84 mg Cd/kg) or the oral (greater than 80 mg Cd/kg) route, there was a significant potentiation in duration of hexobarbital hypnosis and inhibition of hepatic microsomal metabolism of hexobarbital and aniline. Administration of cadmium in the drinking water at levels of 100 or 200 ppm Cd for periods of 2--12 weeks or at levels of 5 or 20 ppm Cd for 50 weeks did not produce alterations in either drug response or hepatitic drug metabolism. Significant levels of metallothionein, a cadmium binding protein, found in the liver of the rats receiving cadmium chronically may offer an explanation for the observed differences in drug metabolism between the acute and chronic administration of cadmium. In additional studies, pretreatment of the rats with subthreshold doses of cadmium (0.21 or 0.42 mg Cd/kg) intraperitoneally produced a tolerance to the alterations in drug metabolism induced by the previous cadmium dose (0.84 mg Cd/kg, i.p.). However, chronic cadmium treatment (5 or 20 ppm Cd for 50 weeks) did not impart any such tolerance to subsequently administered Cd (0.84 mg/kg) by the intraperitoneal route. The hepatic levels of metallothionein induced by the chronic cadmium treatment were only 30--60% of those induced by the subthreshold cadmium and thus may not have bound enough of the large challenge cadmium dose to produce the tolerance phenomenon.

Sex-related differences in cadmium-induced alteration of drug action in the rat.

3 days after pretreatment of rats of both sexes with cadmium (2 mg/kg, 1.p.) the duration of hypnosis induced by hexobarbital (75 mg/kg, 1.p.) was potentiated in males but not females. Likewise similar treatment with cadmium leads to significant inhibition of the metabolism of hexobarbital by hepatic microsomal enzymes obtained from male but not female animals. These data suggest that there is a sex-related difference in the ability of cadmium to alter drug action in rats.