The use of genetically modified mice in cancer risk assessment: Challenges and limitations

Abstract

The use of genetically modified (GM) mice to assess carcinogenicity is playing an increasingly important role in the safety evaluation of chemicals. While progress has been made in developing and evaluating mouse models such as the Trp53+/−, Tg.AC and the rasH2, the suitability of these models as replacements for the conventional rodent cancer bioassay and for assessing human health risks remains uncertain. The objective of this research was to evaluate the use of accelerated cancer bioassays with GM mice for assessing the potential health risks associated with exposure to carcinogenic agents. We compared the published results from the GM bioassays to those obtained in the National Toxicology Program’s conventional chronic mouse bioassay for their potential use in risk assessment. Our analysis indicates that the GM models are less efficient in detecting carcinogenic agents but more consistent in identifying non-carcinogenic agents. We identified several issues of concern related to the design of the accelerated bioassays (e.g., sample size, study duration, genetic stability and reproducibility) as well as pathway-dependency of effects, and different carcinogenic mechanisms operable in GM and non-GM mice. The use of the GM models for dose-response assessment is particularly problematic as these models are, at times, much more or less sensitive than the conventional rodent cancer bioassays. Thus, the existing GM mouse models may be useful for hazard identification, but will be of limited use for dose-response assessment. Hence, caution should be exercised when using GM mouse models to assess the carcinogenic risks of chemicals.

Commentary on New Formaldehyde Studies in Trp53 Haploinsufficient Mice: Further Support for Nonlinear Risks From Inhaled Formaldehyde

“… 2 Tp53 +/− mice were designed such that shortened cancer bioassays could be conducted due to their increased sensitivity to carcinogens—particularly genotoxic carcinogens. 3 These mouse strains are also reported to develop spontaneous lymphomas 3 and serve as models for lymphohematopoietic tumors in short-term studies. 2 These findings lend additional weight to the evidence that inhaled formaldehyde is not leukemogenic—including reanalysis of epidemiological studies 4 and animal studies that indicate that inhaled formaldehyde does not distribute beyond the nasal cavity or reach the blood or bone marrow.…”

Advancing alternatives analysis: The role of predictive toxicology in selecting safer chemical products and processes

“…Nontraditional in vivo approaches can combine the integrative benefits of whole‐animal testing with the speed and reduced costs of in vitro and in silico approaches (Mesens ). Some types of short‐term rodent studies fall within the nontraditional category, for example, short‐term or accelerated cancer bioassays using rodents that have been genetically modified to exhibit high sensitivity to chemically induced cancers (Eastmond et al ). Other approaches involve the use of smaller animals as surrogates for higher, more complex ones.…”

Tg.rasH2 Mouse Model for Assessing Carcinogenic Potential of Pharmaceuticals: Industry Survey of Current Practices

“…These reviews have focused on responsiveness to genotoxic and nongenotoxic compounds, 2,16 the use of positive controls in typical study designs, dose selection criteria, and interpretative factors such as the influence of body weight parameters on spontaneous tumor incidence. [17][18][19][20][21][22][23][24][25] Despite the increased use of the Tg.rasH2 model, there has been no systematic survey of current practices in the design and interpretation of results from the bioassay. Therefore, the aim of this work was to poll the industry on Tg.rasH2 study design practices used in the dose range finding and definitive 6-month studies, and on results relevant to the ongoing negotiations toward revisions of ICH S1 in order to identify opportunities for refining the study design in ways that reduce animal usage and increase the value of study results for assessing human carcinogenic risk of pharmaceuticals.…”