Cancer Research SABCS  Telomeres
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online

[Cancer Research 51, 6415-6451, December 2, 1991]
© 1991 American Association for Cancer Research

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Peto, R.
Right arrow Articles by Grasso, P.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Peto, R.
Right arrow Articles by Grasso, P.

Effects on 4080 Rats of Chronic Ingestion of N-Nitrosodiethylamine or N-Nitrosodimethylamine: A Detailed Dose-Response Study1

Richard Peto, Richard Gray, Paul Brantom and Paul Grasso2

ICRF Cancer Studies Unit, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford OX2 6HE [R. P., R. G.], and BIBRA Toxicology International, Woodmansterne Road, Carshalton, Surrey [P. B., P. G.], United Kingdom

Four thousand eighty inbred rats were maintained from weaning on various different concentrations of N-nitrosodiethylamine (NDEA) or N-nitrosodimethylamine (NDMA). The principal aim was to characterize the dose-response relationship for the effects of these agents on esophageal cancer (NDEA) or on various types of liver cancer (NDEA and NDMA), although NDEA also caused a few tumors of the nasopharynx and NDMA also caused a few tumors of the lung.

The numbers of tumors of mesenchymal and Kupffer cells in the liver were too few to allow easy characterization of the dose-response relationships, and although NDMA induced large numbers of bile duct neoplasms, NDEA did not. Thus, the four principal dose-response relationships studied were of NDEA on esophageal or liver cells and of NDMA on bile duct or liver cells.

At doses sufficiently high for the median time to death from the disease of interest to be estimated, relationships were observed of the general form (Dose rate) x (median)n = constant where n was about 2.3 for the first three relationships and about 1 for the last one (NDMA on liver cell tumors).

By contrast, at doses sufficiently low for longevity to be nearly normal (median survival about 2.5 years), there remained no material dependence on the dose rate of the age distribution of the induced neoplasms. At these low dose rates, the number of liver (but not of esophageal) neoplasms induced by treatment was simply proportional to the dose rate. This finding is not surprising, since the background incidence of liver (but not of esophageal) neoplasms was appreciable. The linear relationship observed at low dose rates (below 1 ppm) suggests that under these experimental conditions, among rats allowed to live their natural life span, a dose of 1 ppm of NDEA or NDMA in the drinking water will cause about 25% to develop a liver neoplasm, a dose of 0.1 ppm will cause about 2.5% to do so, and a dose of 0.01 ppm will cause about 0.25% to do so, etc., with no indication of any "threshold." (At these low dose rates, the incidence of liver neoplasms appears likely to exceed greatly that of esophageal neoplasms.)

In addition, even quite low dose rates of the test agents caused a variety of nonneoplastic liver abnormalities (e.g., hyperplastic nodules, or shrinkage of hepatocytes) at a frequency roughly proportional to the dose rate.

1 This experiment was commissioned by the Ministry of Agriculture, Fisheries and Food (MAFF) in consultation with the Department of Health and was executed at BIBRA and analyzed at Oxford.

2 Retired.




This article has been cited by other articles:


Home page
Toxicol Ind HealthHome page
J. Holder
Analysis of chloroethane toxicity and carcinogenicity including a comparison with bromoethane
Toxicology and Industrial Health, November 1, 2008; 24(10): 655 - 675.
[Abstract] [PDF]


Home page
Hum Exp ToxicolHome page
W J Waddell
Critique of dose response in carcinogenesis
Human and Experimental Toxicology, July 1, 2006; 25(7): 413 - 436.
[Abstract] [PDF]


Home page
Cancer Res.Home page
T. Chen, H. Hwang, M. E. Rose, R. G. Nines, and G. D. Stoner
Chemopreventive Properties of Black Raspberries in N-Nitrosomethylbenzylamine-Induced Rat Esophageal Tumorigenesis: Down-regulation of Cyclooxygenase-2, Inducible Nitric Oxide Synthase, and c-Jun.
Cancer Res., March 1, 2006; 66(5): 2853 - 2859.
[Abstract] [Full Text] [PDF]


Home page
Hum Exp ToxicolHome page
W. J Waddell
Comparisons of thresholds for carcinogenicity on linear and logarithmic dosage scales
Human and Experimental Toxicology, June 1, 2005; 24(6): 325 - 332.
[Abstract] [PDF]


Home page
Cancer Res.Home page
J. Faivre, J. Clerc, R. Gerolami, J. Herve, M. Longuet, B. Liu, J. Roux, F. Moal, M. Perricaudet, and C. Brechot
Long-Term Radioiodine Retention and Regression of Liver Cancer after Sodium Iodide Symporter Gene Transfer in Wistar Rats
Cancer Res., November 1, 2004; 64(21): 8045 - 8051.
[Abstract] [Full Text] [PDF]


Home page
Toxicol SciHome page
S. Fukushima, H. Wanibuchi, K. Morimura, S. Iwai, D. Nakae, H. Kishida, H. Tsuda, N. Uehara, K. Imaida, T. Shirai, et al.
Existence of a Threshold for Induction of Aberrant Crypt Foci in the Rat Colon with Low Doses of 2-Amino-1-methyl-6-phenolimidazo[4,5-b]pyridine
Toxicol. Sci., July 1, 2004; 80(1): 109 - 114.
[Abstract] [Full Text] [PDF]


Home page
Toxicol PatholHome page
G. M. Williams, M. J. Iatropoulos, and A. M. Jeffrey
Thresholds for the Effects of 2-Acetylaminofluorene in Rat Liver
Toxicol Pathol, February 1, 2004; 32(2_suppl): 85 - 91.
[Abstract] [PDF]


Home page
Toxicol SciHome page
E. Dybing and T. Sanner
Risk Assessment of Acrylamide in Foods
Toxicol. Sci., September 1, 2003; 75(1): 7 - 15.
[Abstract] [Full Text] [PDF]


Home page
Toxicol PatholHome page
W. J. Waddell
Thresholds in Chemical Carcinogenesis: What Are Animal Experiments Telling Us?
Toxicol Pathol, April 1, 2003; 31(3): 260 - 262.
[Abstract] [PDF]


Home page
CarcinogenesisHome page
P. E. Jackson, P. J. O'Connor, D. P. Cooper, G. P. Margison, and A. C. Povey
Associations between tissue-specific DNA alkylation, DNA repair and cell proliferation in the colon and colon tumour yield in mice treated with 1,2-dimethylhydrazine
Carcinogenesis, March 1, 2003; 24(3): 527 - 533.
[Abstract] [Full Text] [PDF]


Home page
Toxicol PatholHome page
H. Tsuda, S. Fukushima, H. Wanibuchi, K. Morimura, D. Nakae, K. Imaida, M. Tatematsu, M. Hirose, K. Wakabayashi, and M. A. Moore
Value of GST-P Positive Preneoplastic Hepatic Foci in Dose-Response Studies of Hepatocarcinogenesis: Evidence for Practical Thresholds with Both Genotoxic and Nongenotoxic Carcinogens. A Review of Recent Work
Toxicol Pathol, January 1, 2003; 31(1): 80 - 86.
[Abstract] [PDF]


Home page
Toxicol PatholHome page
A. Hagiwara, Y. Takesada, H. Tanaka, S. Tamano, M. Hirose, N. Ito, and T. Shirai
Dose-dependent Induction of Glandular Stomach Preneoplastic and Neoplastic Lesions in Male F344 Rats Treated with Catechol Chronically
Toxicol Pathol, February 1, 2001; 29(2): 180 - 186.
[Abstract] [PDF]


Home page
Toxicol PatholHome page
G. M. Williams, M. J. Iatropoulos, and A. M. Jeffrey
Mechanistic Basis for Nonlinearities and Thresholds in Rat Liver Carcinogenesis by the DNA-Reactive Carcinogens 2-Acetylaminofluorene and Diethylnitrosamine
Toxicol Pathol, May 1, 2000; 28(3): 388 - 395.
[Abstract] [PDF]


Home page
Toxicol SciHome page
N. Finnberg, U. Stenius, and J. Hogberg
Xenobiotics Modulate the p53 Response to DNA Damage in Preneoplastic Enzyme-Altered Foci in Rat Liver; Effects of Diethylnitrosamine and Phenobarbital
Toxicol. Sci., March 1, 2000; 54(1): 95 - 103.
[Abstract] [Full Text] [PDF]


Home page
International Journal of ToxicologyHome page
H. C. Pitot
The Progression of Neoplasia, Cell Replication, and Electromagnetic Fields
International Journal of Toxicology, January 1, 1998; 17(3_suppl): 59 - 108.
[PDF]


Home page
Hum Exp ToxicolHome page
R.L. Maynard, K.M. Cameron, R. Fielder, A. McDonald, and A. Wadge
Setting air quality standards for carcinogens: an alternative to mathematical quantitative risk assessment -- discussion paper
Human and Experimental Toxicology, February 1, 1995; 14(2): 175 - 186.
[Abstract] [PDF]




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 1991 by the American Association for Cancer Research.