Hepatic transcript levels for genes coding for enzymes associated with xenobiotic metabolism are altered with age.

Metabolism studies are crucial for data interpretation from rodent toxicity and carcinogenicity studies. Metabolism studies are usually conducted in 6 to 8 week old rodents. Long-term studies often continue beyond 100 weeks of age. The potential for age-related changes in transcript levels of genes encoding for enzymes associated with metabolism was evaluated in the liver of male F344/N rats at 32, 58, and 84 weeks of age. Differential expression was found between the young and old rats for genes whose products are involved in both phase I and phase II metabolic pathways. Thirteen cytochrome P450 genes from CYP families 1-3 showed alterations in expression in the older rats. A marked age-related decrease in expression was found for 4 members of the Cyp3a family that are critical for drug metabolism in the rat. Immunohistochemical results confirmed a significant decrease in Cyp3a2 and Cyp2c11 protein levels with age. This indicates that the metabolic capacity of male rats changes throughout a long-term study. Conducting multiple hepatic microarray analyses during the conduct of a long-term study can provide a global view of potential metabolic changes that might occur. Alterations that are considered crucial to the interpretation of long-term study results could then be confirmed by subsequent metabolic studies.

Respiratory tract lesions in noninhalation studies.

This paper reviews respiratory tract lesions observed in rodents administered various chemicals by noninhalation routes. Chemicals administered by inhalation caused lesions in the respiratory tract and were well described; however, when chemicals were administered by noninhalation routes the effort to evaluate tissues for lesions may have been less or not considered, especially in the upper respiratory tract, and some lesions may have gone undetected. Lesions described in this review mostly occurred in rodent chronic noninhalation studies conducted by the National Toxicology Program; however, some were noted in studies of shorter duration. The nasal cavity was vulnerable to damage when chemicals were administered by noninhalation routes. Changes included respiratory epithelial hyperplasia, degeneration and necrosis of olfactory epithelium, olfactory epithelial metaplasia, adenoma, adenocarcinoma, squamous cell carcinoma, and neuroblastoma. In the lung, compound-related lesions included alveolar histiocytosis, alveolar epithelial hyperplasia, bronchiolar metaplasia of the alveolar epithelium, squamous metaplasia, alveolar/bronchial adenoma and carcinoma, and squamous tumors. Pathogenesis of these lesions included regurgitation of volatiles, metabolites arriving from the blood stream, and additional metabolism by olfactory epithelium or Clara cells. The presence of respiratory tract lesions in noninhalation studies emphasizes the need for a thorough examination of the respiratory tract including nasal passages, regardless of the route of administration.

Olfactory epithelial metaplasia and hyperplasia in female Harlan Sprague-Dawley rats following chronic treatment with polychlorinated biphenyls.

The National Toxicology Program recently completed a series of studies to evaluate the relative potency for toxicity and carcinogenicity of several polyhalogenated aromatic hydrocarbons including dioxin-like compounds (DLCs) and polychlorinated biphenyls. Female Sprague-Dawley rats were administered by gavage for up to 2 years with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 3,3',4,4',5-pentachlorobiphenyl (PCB126); 2,3,4,7,8-pentachlorodibenzofuran (PeCDF); 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153); a tertiary mixture of TCDD, PCB126, and PeCDF; a binary mixture of PCB126 and 153; or a binary mixture of PCB126 and 2,3',4,4',5-pentachlorobiphenyl (PCB118); control animals received corn oil-acetone vehicle (99:1) alone. Nasal epithelial changes were observed only in animals exposed for 2 years to the higher doses of the binary mixtures of PCB126 + PCB153 (1000 ng/kg and 1000 microg/kg) and PCB126 + PCB118 (216 and 360 ng TCDD equivalents/kg). In both studies, the changes were of the same nonneoplastic nature, localized to nasal sections II and III located, respectively, at the level of the incisive papilla anterior to the first palatial ridge (section II) and through the middle of the second molar teeth (section III). The changes consisted of hyperplasia of the respiratory epithelium (level II) and metaplasia of olfactory epithelium to respiratory epithelium with further hyperplasia of the metaplastic respiratory epithelium (levels II and III). Variable amounts of acute inflammatory exudate appeared within the lumen of the nasal cavity, overlying the affected epithelium. Occasionally, the inflammation eroded through the skull and into the adjacent olfactory bulbs.

Toxicology and carcinogenesis studies of dipropylene glycol in rats and mice.

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.