Carcinogenicity studies models

Carcinogenicity Studies. These are generally inappropriate for biotechnology-derived pharmaceuticals however, some products may have the potential to support or induce proliferation of transformed cells... possibly leading to neoplasia. When this concern is present, further studies in relevant animal models may be needed. 

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. 

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). 

Susceptibility to tumor induction is an important criterion. There would be little justification for doing carcinogenicity studies in an animal model that did not respond when treated with a true carcinogen. Ideally, the perfect species/strain would have the same susceptibility to tumor induction as the human. Unfortunately, this information is usually unavailable, and the tendency has been to choose animal models that are highly sensitive to tumor induction to minimize the probability of false negatives. 

Carcinogenicity studies are a time-consuming (up to 3 years to complete) and expensive (can be in excess of 1 million dollars each) proposition and are typically carried out in rats and mice. Their purpose is to determine if the drug possesses the capability to initiate or promote the development of tumors. The application of the results of these studies to the human safety has been debated for many years. In many instances over the past two decades, mechanistic studies have shown that positive responses in these rodent models do not have specific relevance for humans, and drugs have been approved on the basis of these explanations. While the scientific debate about relevance of these studies continues, they remain required by regulations. Positive responses without adequate explanation or safety margin can result in nonapproval of the product. 

Adequacy of the carcinogenicity study and appropriateness of the test model... 

The effects of genotoxic compounds are considered non-threshold. Thus, risk assessment for a given exposure is usually performed by a linear or sub-linear extrapolation from the high dose effects observed in animals to the lower human exposure. Since the outcome of the extrapolation depends on the model applied and extrapolation over different orders of magnitude is error prone, the European Food and Safety Authority (EFSA 2005) recommended to avoid this extrapolation and proposed the MOE approach. This approach uses the benchmark dose, or the T25 calculated from a carcinogenicity study and compares this with human exposure. A MOE of 10,000 and more is considered to be of minor concern. The advantage is that neither a debatable extrapolation from high to low doses needs to be performed nor are hypothetical cancer cases calculated. For details of the different approaches see, SCHER, SCCP, SCENIHR (2008). 

Short-term toxicity studies simulate the exposure of workers or farmers to the products they use on a regular basis. They are performed with rats and dogs and last 1 to 6 months. Chronic and carcinogenicity studies last up to 2 years and simulate the long-term exposure of consumers to small concentrations of pesticides in food. Rats, mice, and dogs are used as animal models. The final result is the... 

Mutagenicity studies of isoniazid have yielded mixed results. Some models of sister-chromatid exchange were positive. Salmonella assays have been positive and negative. In vivo nonhuman primate carcinogenicity studies have been positive. 

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