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The guideline made it clear that only after the use of a genotoxic reagent had been justified and every effort had been made to reduce levels should a toxicological assessment be made. Different options were provided by which risk assessments could be carried out, these being through either:

1 1) Quantitative risk assessments – this being essentially based on the linear extrapolation of the dose–response curve from rodent cancer bioassays from a high dose to low dose region. In this case the low dose recommended being one associated with a 1 in 100 000 risk. (One excess cancer death per 100 000 people exposed to the agent concerned over a lifetime [70 years]).

2  2) Uncertainty factor approach –this approach, one that involves the determination of a no effect level (NOEL) from preclinical studies, along with the subsequent application of uncertainty factors would be appropriate where a threshold‐mediated mechanism has been established. Such an approach is consistent with that described within ICH Q3C – Residual Solvents [5].

The position paper in this initial form was a cause of significant concern to the industry. The main concern perhaps related to the safety testing requirements. For many reagents the only safety data available often relates to limited in vitro studies, e.g. an Ames test. Such data are unsuitable for establishing a NOEL or for performing a quantitative risk assessment. Thus, to generate data to support the determination of a NOEL or to carry out a quantitative risk assessment as prescribed in the concept paper would require the conduct of further significant in vivo studies. This could have resulted in a significant increase in animal studies, something considered potentially unacceptable both at the time and now as efforts are made to refine, reduce, and replace animal experimentation.

Thus, alternatives to this were immediately sought. An alternative approach, previously adopted within other spheres, such as the food arena, was the concept of a “virtually safe dose.” This had been developed to deal with low‐level contaminants within food. This concept itself was based on the principal of establishing a level at which any new impurity, even if it was subsequently shown to be carcinogenic, would not constitute a significant risk. This paved the way ultimately for the employment within subsequent versions of the guideline of the Threshold of Toxicological Concern (TTC) concept.