Groups of 50 male and 50 female B6C3F1 mice were exposed 6 hours per day, 5 days per week, for 60 to 61 weeks to air containing 0, 625, or 1250 parts per million 1,3-butadiene. These concentrations are somewhat below and slightly above the Occupational Safety and Health Administration standard of 1000 parts per million for butadiene. The study was designed for 104-week exposures but had to be ended early due to cancer-related mortality in both sexes at both exposure concentrations. There were early induction and significantly increased incidences of hemangiosarcomas of the heart, malignant lymphomas, alveolar-bronchiolar neoplasms, squamous cell neoplasms of the forestomach in males and females and acinar cell carcinomas of the mammary gland, granulosa cell neoplasms of the ovary, and hepatocellular neoplasms in females. Current workplace standards for exposure to butadiene should be reexamined in view of these findings.

Control data on F344/N rats and (C57BL/6N X C3H/HeN)F1 (B6C3F1) mammary tumor virus-free mice from the National Toxicology Program (NTP) were examined to determine if animals receiving corn oil by gavage showed tumor incidences that differed from those of untreated control animals. Analyses of these data were adjusted for interlaboratory variability, time-related trends, and supplier effects. Two biologically significant effects were found: Male F344/N control rats receiving corn oil by gavage showed a higher (P less than .05) incidence of pancreatic acinar cell adenoma and a lower (P less than .001) incidence of leukemia (primarily mononuclear cell leukemia) than did the corresponding untreated controls. The increased incidences of pancreatic acinar cell adenoma seen in male rats administered corn oil by gavage were associated with elevated body weights observed in these animals relative to untreated controls. Female F344 rats and male and female B6C3F1 mice showed little or no evidence of a difference in tumor incidence between corn oil gavage-treated and untreated controls. A review of nearly 300 carcinogenesis studies done by the National Cancer Institute (NCI) and the NTP revealed that there were no corn oil gavage studies in which increased incidences of pancreatic acinar cell tumors or leukemia in male F344/N rats were the sole evidence of the carcinogenicity of a test chemical. Thus use of corn oil appears to have little impact on the interpretation of NCI-NTP carcinogenicity studies.

Since the establishment of the National Toxicology Program (NTP), there have been gradual changes in strategies to evaluate the overall toxicity of chemicals as well as their carcinogenic potential. The spectrum of toxicologic information sought on selected chemicals has been broadened by the multidisciplinary approach to evaluating chemicals. This paper describes the scientific rationale and experimental processes used by NTP in designing studies. Also, an outline of current NTP protocols are given for prechronic and chronic toxicitv/carcinorenicitv studies. IntroductionThe National Toxicology Program (NTP) was established in November 1978 by the Secretary of the Department of Health and Human Services (DHHS). The primary rationale was to better integrate DHHS activities and resources concerned with determining the toxicologic potential of chemicals and to establish a more effective dialogue between the health research and regulatory agencies, enabling stronger links between the health research and regulatory needs. Four specific goals of NTP continue to broaden the spectrum oftoxicologic information obtained on chemicals selected; increase the number of chemicals evaluated within resource limits; develop and validate a series of assays and protocols appropriate for regulatory needs; and communicate the plans and results to governmental agencies, the medical and scientific communities, and the public (1).Since the establishment of the NTP, there have been gradual changes in strategies to evaluate the toxicity and carcinogenic potential of chemicals. The spectrum of toxicologic information sought on selected chemicals has been broadened by the multidisciplinary approach to The objectives of this paper are to present an overview of the scientific rationale involved in designing toxicology and carcinogenesis studies and to outline the experimental protocols used by the NTP in conducting these studies. The studies designed by the NTP are planned to provide maximal toxicology information on chemicals selected. Figure 1 levels, epidemiology studies indicative of the association of chemicals with increased incidence of cancer in human population, results of a prechronic toxicity study showing nonneoplastic lesions that could progress to neoplastic lesions during chronic exposure, chemicals that are structurally related to carcinogens, and a need for such studies by the nominating/regulatory agencies. Currently, nearly 50% of prechronic studies are followed by 2-year chronic toxicity/carcinogenicity studies. Toxicological Evaluation Process

Trichloroethylene (TCE) has been an industrial chemical of some importance for the past 50 years. First synthesized by Fischer in 1864, TCE has enjoyed considerable industrial usage as a degreaser and limited medical use as an inhalation anesthetic and analgesic. This TCE overview provides a narrative survey of the reference literature. Highlights include history, nomenclature, physical and chemical properties, manufacture, analysis, uses, metabolism, toxicology, carcinogenic potential, exposure routes, recommended standards, and conclusions. Chemically, TCE is a colorless, highly volatile liquid of molecular formula C2HCl3. Autoxidation of the unstable compound yields acidic products. Stabilizers are added to retard decomposition. TCE's multitude of industrial uses center around its highly effective fat-solvent properties. Metabolically, TCE is transformed in the liver to trichloroacetic acid, trichloroethanol, and trichloroethanol glucuronide; these breakdown products are excreted through the kidneys. Most toxic responses occur as a result of industrial exposures. TCE affects principally the central nervous system (CNS). Short exposures result in subjective symptoms such as headache, nausea, and incoordination. Longer exposures may result in CNS depression, hepatorenal failure, and increased cardiac output. Cases of sudden death following TCE exposure are generally attributed to ventricular fibrillation. Current interest in TCE has focused on recent experimental data that implicate TCE as a cause of hepatocellular carcinoma in mice. No epidemiological data are available that demonstrate a similar action in humans. The overall population may be exposed to TCE through household cleaning fluids, decaffeinated coffee, and some spice extracts. The NIOSH recommended standard for TCE is 100 ppm as a time-weighted average for an 8-hr day, with a maximum allowable peak concentration of 150 ppm for 10 min.

Sources of Variability in Rodent Carcinogenicity Studies. HASEMAN, J. E., HUFF, J. E., RAO, G. K, AND EUSTIS, S. L. (1989). Fundam. Appl Toxicol . 12 , 793–804. A number of factors may influence tumor rates in rodent carcinogenicity studies, including the animal room environment, genetic differences, food consumption/weight gain, survival/age of the animals, identification of gross lesions, pathology sampling procedures and preparation of the histology slides, and histopathologic diagnosis The relative importance of these factors is evaluated, making use of laboratory animal carcinogenicity data from the National Toxicology Program and from other sources. An investigator must be aware of these potentially confounding factors, so that appropriate measures can be taken to reduce or eliminate their impact on the interpretation of study results. Certain potential sources of within-study variability can be controlled by appropriate experimental design and by proper conduct according to standard operating procedures. The effect of certain factor influencing tumor prevalence may be magnified when variability from study to study is considered, and thus it may be difficult to formulate a biologically meaningful statistical analysis that uses historical control data in a formal testing framework.