In parallel with a larger experiment on 4080 rats fed 16 different concentrations of
N-nitrosodiethylamine (NDEA) or
N-nitrosodimethylamine (NDMA) from 6 weeks of age, a variety of smaller experiments on a total of 1040 rodents were undertaken and are the subject of the present report. Three separate subjects were addressed. Studies of 16 different concentrations of
N-nitrosopyrrolidine and
N-nitrosopiperidine given from age 6 weeks onwards to small groups of rats yielded dose-response relationships for the effects of
N-nitrosopyrrolidine on liver
tumors and for those of
N-nitrosopiperidine on
tumors of the liver and upper gastrointestinal tract that resembled those seen for NDMA and NDEA, respectively, except that
N-nitrosopyrrolidine and
N-nitrosopiperidine were less potent [the respective dose rates needed to halve the proportion of tumorless survivors after 2 years of treatment being approximately 0.4 (males) and 0.6 (females) mg/kg adult
body weight/day for each agent]. Alternatively, it was estimated that the risks to rats from lifelong exposure to 1 microgram/kg adult
body weight/day of each agent might be about 0.1%, and that the risks to rats from lower doses would be proportionately less. Studies of 16 different concentrations of NDEA on small groups of female mice and female hamsters yielded the types of dose response that would be expected for upper gastrointestinal
tumors, liver cell
tumors, and Kupffer cell
tumors in mice (no other types of liver
tumor being produced, in contrast with previous reports) and for tracheal and liver cell
tumors in hamsters (no clear effect on upper gastrointestinal
tumors being apparent in hamsters). The dose rates needed to halve the proportion of tumorless survivors after 2 years of treatment were approximately 0.3 mg/kg adult
body weight/day, i.e., 5 times that for the same agent in rats. In part, however, this may be because treatment started at an older age in these species. Studies were undertaken of the effects on esophageal and liver
tumorigenesis of starting the treatment of rats with NDEA at 3 or at 20 weeks of age instead of at 6 weeks of age (as in the main experiment). Earlier treatment resulted in slightly greater dosage rates, if dosage was measured in mg/kg/day, and hence in a correspondingly more rapid yield of esophageal
tumors, but the effect was not large. By contrast, an earlier start to treatment resulted, after a fixed
duration of treatment, in animals having a 3-fold higher incidence rate of liver
tumors, while a later start resulted in a 2-fold decrease.(ABSTRACT TRUNCATED AT 400 WORDS)