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Introduction

1. The proper conduct of carcinogenicity studies in rats is an important part of the evaluation and prediction of potential human carcinogens. Significant reductions in the number of control rats surviving to termination have been widely reported in the scientific literature. (1-5) This is a matter of concern since inadequate carcinogenicity studies could be important in decisions regarding the identification of potential human carcinogens and in particular the failure to identify such compounds. In addition there is a possibility that inadequate studies could be rejected by regulatory agencies with the consequent need for use of further animals to obtain a valid result. For a negative result from a rat carcinogenicity bioassay to be considered acceptable, survival at 24 months should be 50% or greater in all groups (see OECD, EPA and EC guidelines).

COC consideration of database prepared by Pesticides Safety Directorate(PSD)

2. PSD reviewed survival in control animals from 26 carcinogenicity studies in rats which had been submitted over the period 1993-1998. These carcinogenicity tests had been undertaken between 1983 and 1995. Of these studies 18 had used Sprague-Dawley rats (from various sources), six Wistar rats and two Fischer 344 rats. Adequate survival was reported for 3/18 studies in Sprague-Dawley rats, all of the studies in Wistar rats, and one study undertaken in Fischer 344 rats. Most inadequate studies had been undertaken using Charles-River Sprague-Dawley rats. There was no evidence to support previous suggestion (6) that Virus Antibody status had an effect on survival.

COC consideration of FDA proposals for dietary restriction

3. The FDA published a Points-to-Consider document in 1996.(1) It was recommended that ..."sponsors and petitioners consider variability in outcome that results from ad-libitum feeding and other factors influencing body weight such as multiple housing, feeder type, and cage type, and take appropriate steps to control these variables to improve the interpretation and regulatory utility of studies conducted in support of submissions, through dietary control and establishment of idealised body weight growth curves."

4. The COC considered some recently published information on diet and caloric restriction in rodent carcinogenicity bioassays.(5) The Committee reiterated the conclusion published its 1991 "..the most suitable nutritional regime, or the desirable body weight, have yet to be agreed because of the paucity of information. There is, therefore, no general agreement about the value of altering the dietary regime in carcinogenicity tests.The decision to do so must rest at present with the individual toxicologist".(7) The Committee considered that individual housing of animals such as that required for dietary restriction was not desirable for animal welfare reasons. Other relevant points to note were that the consequences of dietary restriction even on responses to known carcinogens, for instance in terms of their kinetics and metabolism, are insufficiently documented. In addition the appropriate duration of experiments in such longer-lived animals is also not known.

Conclusions

5. The Committee reached the following conclusions;

A. Information from the database of rat carcinogenicity studies reviewed by PSD supports the view that unacceptable survival at termination (<50%) in carcinogenicity tests is predominantly confined to Charles-River Sprague-Dawley rats. Survival in long-term carcinogenicity bioassays should be compliant with current UK and EC guidelines for the acceptability of a negative result from such studies.

B. The available information supports the view reached by the COC in its guidelines published in 1991 that dietary restriction in carcinogenicity studies should be applied with caution and is the responsibility of the toxicologist undertaking the study. This subject may be reviewed when more information is available.

April 2000



References

1. Allaben WT, Turturro A, Leakey JEA, Seng JE and Hart RW (1996). FDA Points to consider Documents: The need for dietary control for reduction of experimental variability within animal assays and the use of dietary restriction to achieve dietary control. Toxicologic Pathology, 24, 776-781.

2. Roe FJC, Lee PN, Conybeare G, Kelly D, Matter B, Prentice D and Tobin G (1995). The Biosure study: Influence of composition of diet and food consumption on longevity, degenerative diseases and neoplasia in Wistar rats studied for up to 30 months post weaning. Fd Chem Tox, 33, suppl 1, 1S-100S.

3. Keenan KP et al (1996). The effects of diet, ad-libitum overfeeding, and moderate dietary restriction on the rodent bioassay: The uncontrolled variable in safety assessment. Toxicologic pathology, 24 (6), 757-768.

4. Haseman JK (1995). Statistical considerations in long-term dietary restriction studies. In Dietary Restriction. Implications for the design and interpretation of toxicity and carcinogenicity studies. Edited Hart R, Neumann DA and Robertson RT. Published ILSI Press, Washington DC, U.S.A., pp141-153.

5. Keenan KP, Ballam GC, Soper KA, Laroque P, Coleman JB and Dixit R (1999). Diet, caloric restriction and the rodent bioassay. Toxicological Science, 52, (supplement), 24-34.

6. Nohynek GJ, Longeart L, Geffray B, Provost J P and Lodola A (1993). Fat, frail and dying young: survival, body weight and pathology of the Charles River Sprague-Dawley-derived rat prior to and since the introduction of the VAFR variant in 1988. Human and Experimental Toxicology, 12, 87-98.

7. Department of Health (1991). Guidelines for the evaluation of chemicals for carcinogenicity. Committee on Carcinogenicity of Chemicals in Food, Consumer Products and the Environment. Report on Health and Social Subjects 42. London, HMSO.

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