Cefic-lri Programme | European Chemical Industry Council

The Basis for Species Differences in the Responses to Chemical Carcinogens

Background

Cancer hazard classification is almost solely derived from studies in laboratory rodents administered chemicals over their lifespan. Commonly two species, the rat and the mouse are used, and although positive results are found occasionally in both species, most commonly a response is only seen in one or the other. The task is then to put the positive, or negative, response into context and undertake a reasoned extrapolation as to what the risk would be if man were exposed. The approach to this extrapolation has been based upon a number of imprecisely-defined criteria that may be summarised in the following:

  • Understanding the mode of action by which the chemical induces cancer in rodents.
  • The relevance of the mechanism to man.
  • The nature of the dose response and extrapolations from high exposure levels in the bioassay to exposure levels relevant to humans.

 

Objectives

Proposals
Proposals submitted for consideration should follow the format of the application form'Application for a CEFIC-LRI Grant' and should address the following areas under individual headings:

  • The title of the research proposal
  • The name and affiliation of the principal investigator of the laboratory or laboratories in which the research will be conducted
  • Evidence of the principal investigator's knowledge, and contributions to, current understanding of the mechanisms through which chemicals induce cancer in animals and how this data is used in risk assessment to man
  • A detailed plan of investigation, including a clearly defined milestone plan which identifies all critical decision points in the research programme
  • A clear definition of the research objectives
  • A detailed breakdown of costs.

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Monitoring
The principal investigators will be required to submit a progress report annually during the course of the
programme. At the end of the project a detailed review of the project and the achievements made will be
provided by the principal investigators. It is expected that the results will be published in a peer-reviewed
journal; investigators are encouraged to present their preliminary findings in appropriate scientific
meetings.

 

Scope

Research proposals should be focused towards inter-species comparisons of how animal carcinogens
interact with biological systems at tissue, cellular and molecular levels. These will include:

  • Inter-species differences in chemical absorption, distribution, metabolism and excretion
  • Interactions of chemical carcinogens with key macromolecules including DNA, activating and deactivating receptors
  • Consequence of carcinogen-interactions with key macromolecules including induction of mutations and alterations in gene expression
  • The nature of dose-response relationships for investigating both genotoxic and nongenotoxic carcinogens
  • Comparative in vivo and in vitro approaches utilising rodent and primate/human viable tissues, isolated cells, cell fractions and purified proteins.

Proposals will ideally build upon the Principal Investigator's experience and current research activities;
collaborative or inter-disciplinary approaches are encouraged. Approaches that are broadly applicable to
multiple classes of chemicals will receive priority over those related to specific chemicals.
This programme will not solicit studies on the development of new models for the detection of carcinogens
but will be expected to develop or utilise already established in vivo and in vitro approaches .

 

Timing: between 3 - 5 years

Cost: * Provide support to a qualified graduate student and/or post-doctoral fellow in research centres active in any of the above areas: o US$ 30,000/year/graduate student, for up to 5 years; o US$ 50,000/year/post-doctoral fellow, for up to 3 years. * Supplement ongoing research programmes: o up to US$ 50,000/year, for 3 years. * Full research support o up to US$ 100,000/year/grant, 3 years.

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