trans-Cinnamaldehyde is a widely used natural ingredient that is added to foods and cosmetics as a flavoring and fragrance agent. Male and female F344/N rats and B6C3F(1) mice were exposed to microencapsulated trans-cinnamaldehyde in the feed for three months or two years. All studies included untreated and vehicle control groups. In the three-month studies, rats and mice were given diets containing 4100, 8200, 16,500, or 33,000 ppm trans-cinnamaldehyde. In rats, feed consumption was reduced in all exposed groups. In mice, feed consumption was reduced in the highest dose groups. Body weights of all treated males were less than controls. Body weights were reduced in female rats exposed to 16,500 or 33,000 ppm and female mice exposed to 8200 ppm or greater. All rats survived to the end of the study but some male mice in the highest dose groups died due to inanition from unpalatability of the dosed feed. The incidence of squamous epithelial hyperplasia of the forestomach was significantly increased in rats exposed to 8200 ppm or greater and female mice exposed to 33,000 ppm. In mice, the incidence of olfactory epithelial degeneration of the nasal cavity was significantly increased in males and females exposed to 16,500 ppm and females exposed to 33,000 ppm. In the two-year studies, rats and mice were exposed to 1000, 2100, or 4100 ppm trans-cinnamaldehyde. Body weights were reduced in mice exposed to 2100 ppm and in rats and mice exposed to 4100 ppm. In rats, hippuric acid excretion was dose proportional indicating that absorption, metabolism, and excretion were not saturated. No neoplasms were attributed to trans-cinnamaldehyde in rats or mice. Squamous cell papillomas and carcinomas of the forestomach were observed in male and female mice but the incidences were within the NTP historical control range and were not considered to be related to trans-cinnamaldehyde exposure.

Dipropylene glycol (DPG) is a component of many commercial products such as antifreeze, air fresheners, cosmetic products, solvents, and plastics. Male and female F344/N rats and B6C3F1 mice were exposed to DPG in the drinking water for 2 weeks, 3 months, or 2 years. In the 2-week and 3-month studies, rats and mice were exposed to 0, 5000, 10,000, 20,000, 40,000, or 80,000 ppm DPG. There was no mortality in the 2-week studies. In the 3-month rat study, all animals survived to the end of the study. Liver weights of rats exposed to 10,000 ppm or greater and kidney weights of rats exposed to 40,000 and 80,000 ppm were greater than those of the controls. The incidences of liver and kidney lesions were significantly increased in males exposed to 20,000 ppm or greater and females exposed to 80,000 ppm. Focal olfactory epithelial degeneration was present in all rats exposed to 80,000 ppm. In males, the incidences of testicular atrophy, epididymal hypospermia, and preputial gland atrophy were significantly increased in the 80,000 ppm group. In the 3-month mouse study, three males and one female exposed to 80,000 ppm died. Liver weights were increased, as was the incidence of centrilobular hypertrophy in males exposed to 40,000 ppm and males and females exposed to 80,000 ppm. In the 2-year studies, exposure groups were 0, 2500 (rats only), 10,000, 20,000 (mice only) or 40,000 ppm DPG. Survival of male rats exposed to 40,000 ppm and mean body weights of males and females exposed to 40,000 ppm were significantly less than controls. In male rats, exposure to DPG resulted in increased incidences and severities of nephropathy and secondary lesions in the parathyroid and forestomach. Increased incidences of focal histiocytic and focal granulomatous inflammation of the liver were also observed. In male and female rats, there were increased incidences of bile duct hyperplasia and changes in the olfactory epithelium of the nose. In mice, survival of males and females was similar to controls. Mean body weights and water consumption of males exposed to 40,000 ppm were less than that of the controls. Treatment-related nonneoplastic lesions did not occur in mice. Treatment-related neoplastic lesions did not occur in rats or mice.

Citral, a widely used natural ingredient, is added to foods and cosmetics as a flavoring and fragrance agent. Male and female F344/N rats and B6C3F1 mice were exposed to microencapsulated citral in the feed for 14 weeks or two years. All studies included untreated and vehicle control groups. In the 14-week studies, rats and mice were given diets containing 3900, 7800, 15,600, or 31,300 ppm citral. In rats, food consumption was reduced in the two highest dose groups. In mice an apparent increase in food consumption was observed, but was due to mice scattering the feed. Body weights of all treated animals were less than controls. All rats and four male mice were killed moribund in the high dose groups. In rats, forestomach and kidney lesions were observed. At the higher doses, lesions observed in the bone marrow, testes, and thymus in rats and in the ovary in mice were considered related to inanition and resultant moribundity. In the two-year studies, rats were exposed to 1000, 2000, or 4000 ppm citral. Body weights were reduced in the 4000 ppm rats. Mice were exposed to 500, 1000, or 2000 ppm citral. Body weights in the 1000 and 2000 ppm groups were reduced. No neoplasms were attributed to citral in rats or mice. Malignant lymphoma occurred with a positive trend and was significantly greater than controls in female mice in the 2000 ppm group. However, the incidences were within the NTP historical control range and could not be clearly related to citral administration.

p,p'-Dichlorodiphenyl sulfone (DDS) is used as a starting material in the production of polysulfones and polyethersufones, a family of thermoplastics. DDS was studied because of its high production volume and use. In toxicology studies, 10 Fischer 344 rats and 10 B6C3F1 mice/sex/group were fed diets containing 0, 30, 100, 300, 1,000 or 3,000 ppm DDS for 14 weeks. All animals survived until the end of the studies. Mean body weights of groups exposed to 300 ppm or greater were significantly decreased. Liver and kidney in rats and liver in mice were the major target organs of DDS toxicity. Dose-related increases in liver weights and incidences of centrilobular hepatocyte hypertrophy were observed in DDS-exposed groups. Nephropathy was seen in male and female rats only at and above 300 ppm. Neurotoxicity evaluations were negative in DDS-treated animals. Clinical chemistry and hematology parameters were minimally affected. In the 2-year toxicity and carcinogenicity studies, 50 rats and 50 mice/sex/group were fed diets containing 0, 10 (male rats), 30, 100, or 300 ppm DDS for 104 to 105 weeks. Survival of exposed groups was not affected. There were no clinical signs of toxicity related to DDS exposure. Final mean body weights were 2-17% lower in DDS-treated groups. Liver was the only target organ of DDS-induced toxicity. The incidence of centrilobular hepatocyte hypertrophy in mice and rats, and the incidence of bile duct hyperplasia and centrilobular degeneration in female rats was significantly greater than in controls. A no-observed-adverse-effect level (NOAEL) of 30 ppm DDS in the diet (1.5 mg/kg body weight) was established for rats. DDS was not carcinogenic in these studies.

A 44-day dosed feed study was performed to compare the bioavailability of lead from contaminated soil versus two lead salts and the effect of soil on gastrointestinal absorption of ingested lead. Male Fischer rats (approximately 4 weeks of age) received lead, 17, 42, or 127 ppm, in the form of lead acetate, lead sulfide, lead-contaminated soil, or combinations thereof in the diet for 7, 15, or 44 days. Control soil was added to the diets of some animals to determine how it might alter lead bioavailability. Blood Δ-aminolevulinic acid dehydratase (Δ-ALAD) and blood, bone, kidney, and liver lead were determined in groups of animals at each time-point. Blood Δ-ALAD was inhibited in a dose-dependent manner and to the greatest degree in the lead acetate and lead acetate/control soil groups, followed by the lead sulfide and lead-contaminated soil groups. Bone and tissue lead levels increased in a dose-dependent manner and were greatest in animals receiving lead acetate and significantly less in animals receiving lead sulfide and lead-contaminated soil. Blood lead levels were generally greatest by 7 days and stabilized at lower levels thereafter. Bone lead concentration–time patterns did not demonstrate the biphasic change seen with tissues and continued to increase in most treatment groups through the course of the study. The presence of soil in the diet clearly attenuated the absorption of lead acetate, but had little effect on the absorption of lead sulfide. Results of these studies confirm previous observations that lead absorption is highly dependent on the form of lead ingested and the matrix in which it is ingested. More important, these studies demonstrate that lead in soil may be significantly less available than estimated by current default assumptions and that the presence of soil may decrease the availability of lead from lead salts on which the default assumptions are based. Results presented here also demonstrate that the weanling rat may represent an appropriate model that could be used to obtain relatively rapid and economical estimates of the availability of lead in complex matrices such as soil.

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 B6C3F(1) mice received oxazepam in feed at concentrations of 0, 2500, or 5000 ppm. Additional groups of 60 male and female B6C3F(1) 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 B6C3F(1) 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 B6C3F(1) 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 B6C3F(1) mice has shown that many of the neoplastic and nonneoplastic responses of mice to oxazepam resemble those observed with phenobarbital. (C) 1994 Society of Toxicology.

The primary purpose of this study was to generate data that could be used to determine the absolute bioavailability of lead using data from a previous study in soil containing lead from mining waste was mixed with feed. Young male and female Sprague-Dawley rats (7–8 weeks of age, five/sex/group) were given either soluble lead acetate mixed in a purified diet (AIN-76TM) at three different dose levels (1, 25, and 250 ppm Pb for 30 consecutive days) or intravenously at doses of 0.02, 0.20, and 2.0 mg Pb/kg BW for 29 days. A control group (purified diet only) was also included. The intravenous groups were used to provide maximal absorption (lead presumed to be 100% bioavailable) and accumulation data for lead in blood, bone, and liver. The lead acetate groups were used to evaluate the comparability of the present study with a previous study that compared bioavailable lead from ingested soil and lead acetate. Group mean whole blood, bone and liver lead concentration values increased with increasing dose levels for all treatment groups. A linear relationship was observed between blood lead concentration and dose following intravenous administration of lead and this provided empirical support for using blood lead concentrations at supposed steady state (∼30 days) to compute the bioavailability of lead administered by different routes and from different sources. The absolute bioavailability values of mining waste lead in soil were low based on the results for all tissue types. Absolute bioavailability values for lead acetate in dosed feed for blood, bone, and liver were approximately 6-, 19-, 20-fold greater, respectively, than mining waste lead. Based on the current design and test system used, the absolute bioavailability of mining waste lead in soil administered in feed was approximately 3% based on blood data and less than 1% base on bone and liver data. These data are consistent with the low solubility of the constituent lead mineral phases in Butte soils.

This study determined the extent of arsenic (As) absorption from soil from Anaconda, Montana. Prepubescent male and female SPF New Zealand White rabbits (5/sex/group) were given a single oral (capsule) administration of soil (3900 ppm As) at three different dose levels (0.2, 0.5, and 1.0 g of soil/kg, corresponding to 0.78, 1.95, and 3.9 mg As/kg, respectively). Standard groups included untreated controls, an intravenous sodium arsenate group (1.95 mg As/kg), and a gavage sodium arsenate group (1.95 mg As/kg). Urine, cage rinse, and feces were collected at 24-hr intervals for 5 days and were analyzed for total As concentration. Clinical signs, body weights, and food consumption for treated animals were similar to controls. Maximum As concentrations were obtained over the initial 24-hr collection interval. A dose-dependent delay in urinary As excretion, the major elimination pathway, was observed in the oral soil group compared to that in the gavage group. For the animals in the soil groups, approximately 80% of the administered As dose was eliminated in the feces compared to approximately 10 and 50% for the intravenous and oral gavage groups, respectively. The relative oral bioavailabilities (+/- SD) of As in the gavage and test soil groups based on comparison with excreta data from the intravenous group were approximately 50 +/- 5.7 and 24 +/- 3.2%, respectively (after normalization of intravenous group's As recovery data to 100%). These results indicated that As in the soil was probably in a less soluble and therefore a less absorbable form than sodium arsenate.

The purposes of this study were to determine the extent of absorption of lead (Pb) in mining waste soil from Butte, Montana, and to investigate the effect of mining waste soil dose (g soil/day) on tissue lead concentrations. Young, 7- to 8-week-old male and female Sprague-Dawley rats (5/sex/group) were given mining waste soil that contained 810 or 3908 ppm lead mixed in a purified diet (AIN-76) at four different dose levels (0.2, 0.5, 2, and 5% dietary soil) for 30 consecutive days. Standard groups included untreated controls and dosed feed soluble lead acetate groups (1, 10, 25, 100, and 250 μg Pb/g feed). The test soil dose levels bracketed a pica child's soil exposure level and the lead acetate concentrations bracketed the test soil dose levels of lead. Liver, blood, and femur were analyzed for total lead concentration using graphite furnace atomic absorption spectroscopy. Clinical signs, body weight, food consumption, and liver weights for test soil and standard groups were similar to control. Tissue lead concentrations from test soil animals were significantly lower than the tissue concentrations for the lead acetate group. Relative percentage bioavailability values, based on lead acetate as the standard, were independent of the two different test soils, dose levels, and sex and were only slightly dependent on the tissue (blood > bone, liver). Mean relative percentage bioavailability values of lead in the Butte mining waste soil were 20% based on the blood data, 9% based on the bone data, and 8% based on the liver data. The results of this study will provide the information needed to determine the significance of lead exposure from Butte soils in assessing human health risks as part of the Superfund Remedial Investigation/Feasibility Study process.