Methods for NCI studies in Nonhuman Primates

The NCI Laboratory of Chemical Pathology conducted a 36-year project (1961-1997) on lifetime carcinogenesis studies in cynomolgus and rhesus monkeys. The CPDB includes lifetable analyses on 25 chemicals.

Some of the inclusion rules of the CPDB have been relaxed in order to include these monkey experiments. The following methodology has been adopted:

• An experiment with fewer than 5 animals is considered inadequate and is not included in the CPDB. To obtain at least 5 animals per group in these studies, results have been combined for both sexes of cynomolgus and separately for both sexes of rhesus monkeys.
• Although experiments with surgical intervention are generally excluded from the CPDB, in these monkey tests, laparoscopic examination of the liver was performed every 3-6 months, followed by wedge or needle biopsies of observed liver lesions.
• A few positive experiments are included that are shorter than one-half the standard 20-year life span, even though such tests are generally excluded from the CPDB.
• Experiments on sodium arsenate and sterigmatocystin are included even though monkeys were put on test as adults, at 4 years of age.
• Control monkeys are from the colony at NCI, which included breeders, offspring, and a small number of feral monkeys. The age of control animals ranged from neonate to greater than 25 years at a given time. Control monkeys were included only if they lived to be older than 8 months, the age of the first tumor in any group. Concurrent, vehicle controls were used only for IQ.
• The dose rate for a group is calculated as the mean of the dose-rate of individual monkeys. To obtain the daily dose rate for each monkey, the cumulative dose in mg/kg reported by NCI, was divided by the number of days of its life. Dosing schedules ranged across chemicals from once every 4 weeks to 5 times per week; for most experiments the chemicals were administered in a vitamin sandwich 5 times per week.
• TD₅₀ values are estimated using lifetable data and are reported for every site at which a tumor occurred, benign or malignant, in dosed animals.
• In experiments with multiple target sites, a composite TD₅₀ value is reported for all animals with tumors at any of the target sites (“MXB,MXB” in “All Experiments and Citations in CPDB,” as with NCI/NTP bioassays in rodents).

References

1. Adamson, R. H., and Sieber, S. M. Chemical carcinogenesis studies in nonhuman primates. In: Organ and Species Specificity in Chemical Carcinogenesis. (R. Langenbach S. Nesnow, and J. M. Rice, Eds.), Plenum Press, New York and London, 1982, pp. 129-156.
2. Adamson, R. H., Takayama, S., Sugimura, T., and Thorgeirsson, U. P. Induction of hepatocellular carcinoma in nonhuman primates by food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline. Environ. Health Perspect. 102: 190-193(1994).
3. Dalgard, D. W. Induction, Biological Markers and Therapy of Tumors in Primates. National Cancer Institute Final Report of Contract No. N01-CP-40510, Vienna, VA, Corning Hazelton Laboratory Study No. 421-166, Reporting period: July 1, 1994-March 31, 1997.
4. Thorgeirsson, U. P., Dalgard, D. W., Reeves, J., and Adamson, R. H. Tumor incidence in a chemical carcinogenesis study in nonhuman primates. Regul. Toxicol. Pharmacol. 19: 130-151(1994).