The Viracept (nelfinavir)—Ethyl methanesulfonate case : A threshold risk assessment for human exposure to a genotoxic drug contamination?

In May 2007, the F. Hoffmann-La Roche Company became aware of a contamination of Viracept (nelfinavir) tablets by the mutagenic DNA-ethylating agent ethyl methanesulfonate (EMS) as a result of a production incident. HIV-patients could have been exposed for 3 months to daily doses of up to 2.75 mg EMS, i.e., about 50 μg/kg per day. In this special issue, 12 manuscripts have been assembled to provide comprehensive insight in what happened and how the incident was managed by Roche and handled by the regulatory agencies. In the first four papers, the course of events and the toxicological information available at the outset are summarized and a traditional cancer risk assessment on the basis of a linear default dose–response is made. Three articles then report on the experiments performed for an improved risk assessment. A standard 4-week toxicity study with EMS in the rat indicated an NOAEL of 20 mg/kg per day. Extensive studies on the genotoxicity showed threshold-like dose responses for both chromosome damage (bone marrow micronucleus test) and gene mutation (lacZ transgenic MutaMouse test) in various organs of mice treated for up to 4 weeks, whereas ethylation of hemoglobin at the N-terminal valine increased linearly with dose. The difference between adduct formation in DNA and protein was interpreted by repair of DNA adducts that becomes saturated above a threshold concentration of EMS, regarded as the metrics for the rate of DNA ethylation. Elaborate toxicokinetic investigations in various animal species, coupled to appropriate modeling, were performed in order to extrapolate the animal data to humans. Using a threshold risk assessment based on estimated cmax of EMS, a safety factor of 370 was derived for maximum doses ingested by Viracept patients. A number of critical points are addressed in this editorial, concerning (i) definitions and types of “thresholds”, (ii) estimation of a confidence limit for a slope below the threshold dose, interpreted as an increment within background variation, (iii) implementation for other mutagens and for human risk assessment.