An overview of prechronic and chronic toxicity/carcinogenicity experimental study designs and criteria used by the National Toxicology Program.

Abstract

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

2-Butoxyethanol Female-Rat Model of Hemolysis and Disseminated Thrombosis: X-Ray Characterization of Osteonecrosis and Growth-Plate Suppression

“…Soft tissues were evaluated only in those animals sacrified immediately following the last dose, in order to confirm the presence of antemortem disseminated thrombosis. Tissues were embedded in paraffin, sectioned at 5-6 µm, and stained with hematoxylin and eosin (H&E) for microscopic examination (Chhabra et al, 1990). All bony tissues were decalcified prior to histological processing using Decalcifier II from Surgipath (Surgipath Medical Industries Inc., Richmond, IL).…”

“…The following sections were taken for histology: proximal coccygeal vertebrae (1 cm from tail base), distal coccygeal vertebrae (10 cm from tail base), right and left ilium, right and left proximal femur, right and left distal femur and proximal tibia, right and left tarsus, and the sixth lumbar vertebra. Tissues were embedded in paraffin, sectioned at 5-6 µm, and stained with H&E for microscopic examination (Chhabra et al, 1990).…”

Environmental Lead Is a Problem in Lima, Peru

“…Further, another study could be done using drinking water as the medium for administering arsenic; as suggested by Chappell et al (1), exposure levels could be geared toward actual and multiples of drinking water levels in the environment. Of course the highest exposure levels must be those typically chosen for long-term carcinogenicity studies (6,7). In addition, these studies should be conducted for longer periods of time than the standard 104 weeks to allow the opportunity for any late-stage carcinogenic effects to be manifested; perhaps 30 months or longer would be more adequate.…”

The Carcinogenesis Bioassay in Perspective: Application in Identifying Human Cancer Hazards

“…Long-term bioassays are designed to expose rodents to chemicals or environmental mixtures that cause only minimal toxic effects. The highest dose selected for these studies has been termed the "maximum tolerated dose" (MTD), when, in fact, it actually represents a minimally toxic exposure dose (6)(7)(8). Since nearly half the chemicals tested by the National Cancer Institute (NCI) (9) and the National Toxicology Program (NTP) (10) elicited a positive response in the rodent bioassays, some researchers have postulated that carcinogenesis in these studies results from cell killing and increased cell division (mitogenesis) (5).…”