Carcinogenicity models, alternative

The traditional second long-term carcinogenicity study can be replaced by a shorter-term alternative model. In practical terms, this guideline is beginning to result in sponsors conducting a two-year study in the rat and a six-month study in an alternative mouse model, such as the P53 or the TG.AC genetically manipulated mouse strains. 

A mutated cell may reproduce and begin the formation of a carcinogenic mass (tumor), and mutations may occur after acute or chronic exposure. The specific relationship between acute or chronic exposure rate and cancer risk is hotly debated, although current U.S. regulations conservatively adopted the linear no threshold (LNT) model. This model states that risk is linearly proportional to the total dose even at the smallest possible dose levels (risk is associated with all levels of dose no matter how small). An alternate model theorizes that no measurable adverse health effects appear below doses of about 10 to 25 rem (0.1 to 0.25 Sv). Data supporting both models are limited and, to be conservative, levels of exposure should be kept as low as reasonably achievable (ALARA). Victim and emergency responder doses and dose rate may not be easily controlled in the event of a terrorist attack. However, methods to achieve ALARA exposures are described in Chapters 4 and 5. 

Cohen SM. Alternative models for carcinogenicity testing weight of evidence evaluation across models. Toxicol Pathol 2001 29 183-90. 

Hastings KL. Assessment of immunosuppressant drug carcinogenicity standard and alternative models. Hum Exp Toxicol 2000 19 261-5. 

Cohen SM, Robinson D, MacDonald J. Alternative models for carcinogenicity testing. Toxicol Sci 2001 64 14-19. 

Goodman JI. A perspective on current and future uses of alternative models for carcinogenicity testing. Toxicol Pathol 2001 29 173-6. 

Robinson DE, MacDonald JS. Background and framework for ILSI s collaborative evaluation program on alternative models for carcinogenicity assessment. Toxicol Pathol. 2001 29S 13-19. 

In this chapter we will introduce and discuss the use of alternative methods to evaluate the carcinogenic potential of some PFCs. In detail, in silico (QSAR) models and BALB/c 3T3 CTA will be used to investigate the issue. 

CTAs are possible in vitro alternatives to the standard approach for the assessment of carcinogenicity (the 2-year bioassay in rodents), which have been shown to be a multistage process able to model the most important stages of in vivo carcinogenesis [50]. CTAs are faster and more economic than in vivo assay and they could be a valid and useful screening tool for chemicals. 

In the experimental evaluation of substances for carcinogenesis based on experimental results of studies in a nonhuman species at some relatively high dose or exposure level, an attempt is made to predict the occurrence and level of tumorogenesis in humans at much lower levels. In this chapter we will examine the assumptions involved in this undertaking and review the aspects of design and interpretation of traditional long-term (lifetime) animal carcinogenicity studies as well as some alternative short-term models. 

There has been extensive debate and consideration on the relevance and value of the traditional long-term rodent bioassays. The FDA looked at rat and mouse studies for 282 human pharmaceuticals, resulting in the conclusion that sufficient evidence is now available for some alternative in vivo carcinogenicity models to support their application as complimentary studies in combination with a single two-year carcinogenicity study [emphasis added] to identify trans-species tumorigens (Contrera et al., 1997). 

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