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The Viracept (nelfinavir)--ethyl methanesulfonate case: a threshold risk assessment for human exposure to a genotoxic drug contamination?
Toxicol Lett. 2009 Nov 12; 190(3):239-42.TL

Abstract

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 microg/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 20mg/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 c(max) 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.

Authors+Show Affiliations

Department of Toxicology, University of Würzburg, Versbacher St. 9, 97078 Würzburg, Germany. lutz@toxi.uni-wuerzburg.de

Pub Type(s)

Editorial

Language

eng

PubMed ID

19695319

Citation

Lutz, Werner K.. "The Viracept (nelfinavir)--ethyl Methanesulfonate Case: a Threshold Risk Assessment for Human Exposure to a Genotoxic Drug Contamination?" Toxicology Letters, vol. 190, no. 3, 2009, pp. 239-42.
Lutz WK. The Viracept (nelfinavir)--ethyl methanesulfonate case: a threshold risk assessment for human exposure to a genotoxic drug contamination? Toxicol Lett. 2009;190(3):239-42.
Lutz, W. K. (2009). The Viracept (nelfinavir)--ethyl methanesulfonate case: a threshold risk assessment for human exposure to a genotoxic drug contamination? Toxicology Letters, 190(3), 239-42. https://doi.org/10.1016/j.toxlet.2009.07.032
Lutz WK. The Viracept (nelfinavir)--ethyl Methanesulfonate Case: a Threshold Risk Assessment for Human Exposure to a Genotoxic Drug Contamination. Toxicol Lett. 2009 Nov 12;190(3):239-42. PubMed PMID: 19695319.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Viracept (nelfinavir)--ethyl methanesulfonate case: a threshold risk assessment for human exposure to a genotoxic drug contamination? A1 - Lutz,Werner K, Y1 - 2009/08/18/ PY - 2009/07/27/received PY - 2009/07/30/accepted PY - 2009/8/22/entrez PY - 2009/8/22/pubmed PY - 2009/11/11/medline SP - 239 EP - 42 JF - Toxicology letters JO - Toxicol Lett VL - 190 IS - 3 N2 - 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 microg/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 20mg/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 c(max) 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. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/19695319/The_Viracept__nelfinavir___ethyl_methanesulfonate_case:_a_threshold_risk_assessment_for_human_exposure_to_a_genotoxic_drug_contamination DB - PRIME DP - Unbound Medicine ER -