Ronald L. Persing

Toxicology and Carcinogenesis Studies of Two Grades of Pentachlorophenol in B6C3F1 Mice

Toxicology and carcinogenesis studies of pentachlorophenol (penta), a biocide used primarily as a wood preservative, were conducted by feeding diets containing a technical-grade composite or Dowicide EC-7 (a commercial grade with lower levels of contaminants) to groups of B6C3F1 mice. Based primarily on liver lesions (hepatocellular necrosis, degeneration, and cytomegaly) observed in 6-month studies, diets containing 100 or 200 ppm technical-grade pentachlorophenol or 100, 200, or 600 ppm EC-7 were fed to groups of 50 male and 50 female mice for 2 years. Control groups consisted of 35 animals. For the most part, mean body weights of mice exposed to technical-grade penta were comparable to those of controls. During the second year, the 600-ppm EC-7 female mice averaged 85% of the control body weights. Feed consumption by exposed mice was similar to that by controls. The average daily doses of penta were approximately 0, 17-18, 35, or 114-118 (EC-7) mg/kg. Survival of mice did not appear to be significantly affected by exposure to either technical penta or EC-7 at the doses used in these studies; survival of the control male mice (technical-grade) was comparatively low. Compound-related neoplasms were observed in three organs/systems: liver, adrenal gland medulla, and vascular endothelium. Dose-related increases of hepatocellular adenomas and of carcinomas were observed in male and female mice exposed to both technical penta and EC-7, although the increase was less marked in females exposed to technical penta. Pheochromocytomas of the adrenal gland in exposed male mice were significantly greater than those in controls for both technical penta and EC-7. These neoplasms were also increased in female mice exposed to EC-7 but not to technical penta. Hemangiosarcomas in the spleen and/or liver were increased in female mice that received technical penta and EC-7. The results of these studies show that both technical penta and Dowicide EC-7 are carcinogenic for mice, causing neoplasms in multiple organs/systems. In addition, the results suggest that the carcinogenic responses were due almost exclusively to penta itself, with possibly a minimal potentiating influence by the contaminants in the induction of liver neoplasms in male mice.

Carcinogenicity Studies of Oxazepam in Mice

Oxazepam is a benzodiazepine widely used as a sedative-hypnotic and antianxiety drug. In chronic studies, groups of 60 male and 60 female Swiss-Webster (SW) or B6C3F1 mice received oxazepam in feed at concentrations of 0,2500, or 5000 ppm. Additional groups of 60 male and female B6C3F1 mice received 125 ppm in feed to allow for study of mice with serum concentrations of oxazepam similar to those achieved in humans taking a therapeutic dose. At 57 weeks, treatment-related mortality of exposed SW mice caused the study to be terminated. Enhanced systemic amyloidosis contributing to heart failure was considered the principal cause of death. Hepatocellular adenomas and carcinomas were increased in exposed SW mice. Survival of B6C3F1 mice receiving 2500 and 5000 ppm oxazepam was also lower than that of controls. Early deaths were due to increased incidences of hepatoblastoma and hepatocellular carcinoma, and nearly all mice receiving 2500 or 5000 ppm developed hepatocellular neoplasia. An increase in follicular cell hyperplasia of the thyroid gland occurred in all exposed groups of B6C3F1 mice, and thyroid gland follicular cell adenoma was increased in exposed females. Further studies of the capacity of oxazepam to induce liver cell mitogenesis and an evaluation of the frequency of activated H- and K-ras oncogenes in the liver tumors of B6C3F1 mice has shown that many of the neoplastic and nonneoplastic responses of mice to oxazepam resemble those observed with phenobarbital.

Chronic inhalation oncogenicity study of isoprene in B6C3F1 mice

The oncogenic potential of isoprene as affected by concentration, length of daily exposure, and weeks of exposure over the life-span of the animal, as independent variables, was evaluated. Ten groups were exposed for 8 h/day, 5 days/week as follows (ppm-weeks): 0-80, 10-80, 70-40, 70-80, 140-40, 280-20, 280-80, 700-80, 2200-40, 2200-80. Two groups were exposed for 4 h/day: 2200-20, 2200-80. Groups were held until 96 or 105 weeks on study. The concentration x time (duration of exposure) values provided a series of theoretically equivalent exposure hazards. There was an exposure-related increased incidence of liver, lung, Harderian gland and forestomach tumors, and hemangiosarcomas and histiocytic sarcomas. The LOEL appeared to be 70 ppm. These results are similar to the profile of tumors seen in 1,3-butadiene (BD)-exposed mice without the early onset of T-cell lymphoma as seen with BD. Isoprene appears to be about one order of magnitude less potent than BD in mice. Statistical analyses indicated that the product of isoprene concentration, and length/duration of exposure was not a sufficient basis for predicting tumor risk at any site. Extrapolation of tumor probability between the high and low doses based on cumulative exposure was not appropriate and could not be justified by statistical models. A threshold effect level and strong nonlinearities with respect to concentration appeared to exist for tumor development in this study.

Toxicity and Carcinogenicity of Rotenone Given in the Feed to F344/N Rats and B6C3F1 Mice for up to Two Years

Toxicity and carcinogenicity studies of rotenone were conducted in F344/N rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were given rotenone in their diet for up to 103 weeks. The doses were 0, 38, and 75 ppm for rats and 0, 600, and 1,200 ppm for mice. Reduction in body weight gain occurred in male and female mice given rotenone. No effects on survival were observed for rats of either sex or female mice. Survival of male mice at 1,200 ppm was significantly greater than that of controls (47/50 vs. 29/50). There were no observed nonneoplastic effects due to rotenone, and for male and female mice no neoplasms were induced by rotenone. Parathyroid adenomas occurred at a higher incidence (4/44) in male rats at 75 ppm than in the controls (1/41). Because these tumors are rare (historical rate in NTP studies is 0.3%), the increase in the incidence of these benign tumors may have been related to rotenone administration. Hepatocellular neoplasms were reduced (p less than 0.01) in males receiving 1,200 ppm 1/50 relative to controls 12/47. Because this low rate of liver tumors is unusual in male B6C3F1 mice, this decrease was considered to be related to rotenone administration.

Toxic responses to acute, subchronic, and chronic oral administrations of monochlorobenzene to rodents

Acute (single exposure), 14-d repeated exposure, 91-d subchronic, and 103-wk chronic toxicity studies of orally administered (gavage, in corn oil) monochlorobenzene were conducted in male and female Fischer-344 rats and B6C3F1 hybrid mice. A single exposure to 4000 mg/kg was lethal to male and female rats, while a single exposure to a dose as low as 1000 mg/kg was lethal to mice. Fourteen daily exposures to 1000 mg/kg caused death in rats of both sexes, but neither survival nor clinical health were compromised at 500 mg/kg in rats or mice. In the 91-d studies, wherein monochlorobenzene was administered once daily, 5 d/wk, survival was reduced by doses of 500 mg/kg and higher in rats, and by doses of 250 mg/kg and higher in mice. Dose-dependent necrosis of the liver (hepatocytes), degeneration or focal necrosis of the renal proximal tubules, and lymphoid or myeloid depletion of the spleen, bone marrow, and thymus (mild to severe) were produced by doses of 250 mg/kg or greater of monochlorobenzene in both sexes of rats and mice, although the incidences of these lesions varied considerably by sex and species. Consistent changes in the circulating blood components were not observed, but a mild porphyrinuria was detected at the higher doses. No toxic effects were observed at doses of 125 mg/kg or less. In the 2-yr studies, wherein monochlorobenzene was administered once daily, 5 d/wk, doses of 30 or 60 mg/kg in male mice and 60 or 120 mg/kg in female mice and male and female rats did not produce any evidence of toxicity. Doses of 60 or 120 mg/kg caused slight (statistically significant at 120 mg/kg; p less than 0.05) increases in the frequencies of male rats with neoplastic nodules of the liver. Increased tumor frequencies were not observed in female rats or in male or female mice receiving monochlorobenzene.

Subacute toxicity of ethylenebisisothiocyanate sulfide in the laboratory rat

Ethylenebisisothiocyanate sulfide (EBIS) was administered in the diet to groups of rats at 0, 1, 10, 100, and 1,000 ppm for up to 90 days. The rats receiving EBIS at 1,000 ppm demonstrated a toxic response within 8–14 days, reflected as a reversible paralysis of the hind legs. If left on the 1,000 ppm diet, the animals soon died. When removed from the diet, the animals recovered, only to become atoxic on further dietary exposure at the high level. No histologic lesion could be identified in either H&E‐ or luxol fast blue‐stained sections of brain, spinal cord, or peripheral nerves from the paralyzed animals. The ability to reverse the paralysis by removing the animals from the test diet coupled with the lack of histologically observable lesions suggests a biochemical (reversible) rather than somatic lesion. Ingestion of 1,000 ppm EBIS for 7 days resulted in measurable changes in thyroid function. Total serum thyroxine levels were markedly decreased, as was iodide uptake by the thyroid. Ingestion of EBIS a...