Introduction

1. The International Conference on the Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for human use (ICH) has agreed that bioassay data from only one species, (i.e. the rat), would be required for regulatory submissions. This would be supported by appropriate mutagenicity and pharmacokinetic data and also information from one other study, that supplements the long term carcinogenicity study and provides information that is not readily available from the long term assay (1).The ICH guidelines cite the use of a neonatal rodent tumourigenicity model as one appropriate supporting study. Any decision regarding the use of this assay for pharmaceuticals could have significant implications for other categories of chemical (e.g. food additives, pesticides, industrial chemicals etc).

2. The Committee has recently reviewed the available information on a number of short-term bioassays using transgenic mice, which are also cited as suitable supporting studies in the ICH guidelines on the carcinogenicity evaluation of pharmaceuticals. The COC concluded, in respect of these short-term bioassays, that in view of the lack of appropriate validation data, it would not be appropriate to use the data from short-term transgenic bioassays considered (i.e. heterozygous p53+/- -deficient, Tg.AC, and Tg Hras 2 models) to support regulatory decisions at the present time(2).

3. The COC considered the available information on the neonatal rodent carcinogenicity bioassay models at its March and May 1998 meetings.

Conclusions

4. The following conclusions were finalised at the May 1998 COC meeting.

 i) The Committee reviewed the available published information (2-6) on the neonatal rat and mouse bioassays in the context of the proposal by the ICH for human medicines that these tests could be used to supplement information from pharmacokinetic, mutagenicity and one long-term rodent (usually rat) carcinogenicity bioassay. 

ii) Neonatal mouse and rat carcinogenicity bioassays have been shown to identify genotoxic carcinogens. The Committee agreed that there were very limited validation data on the neonatal mouse bioassay and even fewer data regarding the neonatal rat bioassay. The available information showed tumour yields with genotoxic carcinogens were highly dependent on the strain of animal, age at start of treatment, and treatment protocol.

iii) Some published information highlighted particular problems with regard to misclassification of carcinogens and non-carcinogens. There was also evidence of considerable animal mortality during studies, which raised animal welfare issues. Members also noted that there were potential difficulties in extrapolating from results in neonatal animals derived from parenteral dosing of the test material to other potential routes of human exposure.

iv) The Committee agreed that there were no validation data regarding the use of short-term neonatal rodent bioassays for the identification of non-genotoxic carcinogens. Furthermore, the use of appropriate mutagenicity testing in addition to one carcinogenicity bioassay in a rodent species would be expected to identify genotoxic carcinogens. Overall, the Committee concluded that there was no current evidence to support the use of the neonatal mouse or rat bioassays as apart of the regulatory testing strategy for human medicines.


References


1. ICH (1997). International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for human use (ICH). Harmonised Tripartite Guideline. Testing for Carcinogenicity of Pharmaceuticals. 

2. Blain. PG, Battershill JM, Venitt S, Cooper CC, and Fielder RJ (1998). Consideration of short-term carcinogenicity tests using transgenic mouse models. Mutation Research, 403, 259-263.

3. Flammang TJ, von Tungeln LS, Kadlubar FF and Fu PP. Neonatal mouse bioassay for tumourigenicity: Alternative to the chronic rodent bioassay. RegulatoryToxicology and Pharmacology, (1997), 26,230-240.

4. Odashima S (1976). The co-operative development in Japan of methods for screening chemicals for carcinogenicity. In Screening tests for chemical carcinogens, edited by Montesano R, Bartsch H and Tomatis L. IARC Scientific Publications, 12, pp 61- 75, Lyon.

5. Fujii K (1991). Evaluation of the newborn mouse model for chemical tumourigenesis. Carcinogenesis, 12, 1409-1415.

6. Sykora I and Vortel V (1993). Comparability of postnatal and long-term tests for carcinogenicity. Neoplasma, 40, 321-327

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