drs. I.M.M. (Ingeborg) van Leeuwen
Realistic characterizations of the tumor induction potential of
It is a frightening fact, but despite improvements in prevention, diagnosis and treatment, cancer still strikes one in three people, and one in four will die of the disease. Throughout the 20th Century many experimental tests and epidemiological studies have revealed a clear causal relationship between cancer incidence and exposure to definite chemical compounds. Nowadays the ability of chemicals to increase tumor incidence and to reduce survival is crucial for restrictions on handling chemicals and emissions into the environment. Therefore, from the perspective of human health, there is a need for a strategy to accurately evaluate the carcinogenic potency of chemicals. However, the quantitative risk assessment of carcinogens still suffers from difficulties such as:
- Mouse-to-human extrapolation: Human data are seldom available and are often inadequate to obtain cancer risk estimates. Indeed, most risk assessment is currently performed on the basis of animal cancer bioassays. Interspecies extrapolation in most cases also implies extrapolation across routes of exposure and/or tumor induction.
- Low-dose extrapolation: High doses are used in animal tests for practical reasons such as reducing the number of animals required or improving the signal-to-noise ratio. Low-dose extrapolation implies the extrapolation of both tissue dosimetry and response.
A series of physiologically based mathematical models, ranging from simple to complex, will be developed to estimate the tumor induction potential of chemicals from standardized carcinogenicity tests.
The process of carcinogenesis will be divided into five phases. The first phase, referred to as exposure, describes both external concentration of (pro-)carcinogen and exposure route. The second phase, referred to as kinetics, links exposure to an effective internal concentration. It includes processes such as uptake and elimination, metabolic transformation and distribution among body compartments. The third phase, referred to as induction, corresponds to the effects of the internal concentration on the process of malignant transformation of normal cells into tumor cells. The fourth phase, referred to as growth, relates to the process of tumor growth, starting from one initial tumor cell. The last phase, referred to as effects, involves the consequences of both toxic effects and tumor development for a host individual (e.g. survival, body weight and aging).
The different phases and the relationships between phases will be modelled on the basis of the Dynamic Energy Budget (DEB) theory. This approach will allow us to analyze the relevance of several physiological processes (such as food uptake, body growth or aging) on the different phases of carcinogenesis. Moreover, because the DEB theory is not-species specific, it will provide us a fresh mechanistic insight into the reasons underlying the significant differences in carcinogenic potency observed in different species.