The Multiple Chemicals and Actions Model of carcinogenesis. A possible new approach to developing prevention strategies for environmental carcinogenesis

Abstract

The number of definite and probable human chemical carcinogens identified by IARC approaches between 1987 and June 2004 is reported to be 50 agents. However, overall, given the rapid expansion in the number of chemicals in use, the throughput of the current approach to identifying potential environmental carcinogens is low. The long-term rodent bioassay, a key part of the current approach, identifies many chemicals which eventually turn out to be irrelevant for human health with regard to cancer. A new approach is suggested which focuses on identifying the potency of environmental mixtures for induction of toxicological changes relevant to carcinogenesis (e.g., cell proliferation, chronic inflammation, inhibition of apoptosis, mutagenicity). Details regarding a suggested strategy for prioritization of mixtures are provided with more detailed information regarding mutagenicity as an end point. The long-term rodent bioassay is not included in the proposal (although it is acknowledged that it will continue to be important in premarketing regulatory schemes) for hazard identification. The Multiple Chemicals and Actions Model (MCAM) is developed. In this model the chemical mixtures in the environment act via a number of mechanisms as ‘effectors’ or ‘inhibitors’ of a multistage carcinogenic process. Identifying effectors and inhibitors of the rate-limiting step would be important for preventive strategies. Genetic polymorphisms act as modulators of effector and inhibitor mixtures. It is suggested that the MCAM model could be used in public education programmes to help inform on public health issues regarding cancer and to help avoid future scares which tend to focus on single chemicals. It is acknowledged that there would need to be basic research undertaken to generate appropriate data to support the application of the proposal before it could be used in cancer prevention strategies.