In the area of general toxicology assessments, the scope and types of studies performed are dictated to a large degree by the data needs for the specific test articles nominated for study. The NTP performs appropriate toxicity studies in part to provide dose-setting information for chronic studies and also to address specific deficiencies in the toxicology database for the chemical. Toxicology/Carcinogenicity studies generally fall into two categories: Prechronic Toxicity Studies and 2-Year Toxicology and Carcinogenesis Rodent Studies. Each of these study types are performed according to the Specifications for the Conduct of Studies to Evaluate the Toxic and Carcinogenic Potential of Chemical, Biological, and Physical Agents in Laboratory Animals for the National Toxicology Program (NTP) October 2006.
General toxicology screens are typically carried out as contracted studies at several commercial laboratories in the U.S. Although designs are flexible, these studies usually involve exposures of rats and mice of both sexes to test articles for periods of 14 days or 13 weeks. Assessments almost always performed include tissue histopathology, clinical pathology, and sperm motility or measurements of estrous cycle length. A determination of the frequency of micronucleated erythrocytes is done as an in vivo measure of genotoxic potential, and, in some cases, a Functional Observational Battery is included as a neurotoxicology screen. The study protocol may include more detailed or focused studies when findings published in the existing scientific literature or identified in initial NTP studies suggest a target organ or system. Also, the study protocol may include separate studies of reproductive, genetic, or immunological toxicity based on the outcome of the toxicity screens.
Two-year studies in laboratory rodents remain the primary method by which test articles are identified as having the potential to be hazardous to humans. Studies in rodents along with studies in human populations (epidemiology studies) are the best means currently available for identifying potential human hazards. Chemicals recognized by the International Agency for Research on Cancer (IARC) as human carcinogens essentially all cause cancer when adequately tested in at least one species of laboratory animals. Data from NTP rodent studies strengthen the science base in toxicology and contribute to the information used by regulatory agencies for the promulgation of regulations that protect human health. These data are used in the hazard identification step of the risk assessment process.
The NTP long-term toxicology and carcinogenesis studies (bioassays) in rodents generally employ both sexes of rats (Harlan Sprague Dawley) and mice (B6C3F1/N hybrid) with three exposure concentrations plus untreated controls in groups of 50 animals for two years.
For some test articles, rats are exposed during the perinatal phase prior to a 13-week or 2-year study. The perinatal phase includes gestation (in utero via the placenta) and lactation (via mother's milk). Perinatal exposures are selected after considering patterns of human exposure. Perinatal exposure occurs during critical periods of development and can result in differences in toxicity/carcinogenicity as compared to exposure starting only from adulthood.