Risk assessment on the carcinogenic potential of hybridoma cell DNA. Implications for residual contaminating cellular DNA in biological products
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Series / Report no.
Open Access
Type
Report
Language
en
Date
1995-12-31
Research Projects
Organizational Units
Journal Issue
Title
Risk assessment on the carcinogenic potential of
hybridoma cell DNA. Implications for residual contaminating cellular DNA in
biological products
Translated Title
Risico-evaluatie van de carcinogeniteit van
hybridoma cel DNA. Implicaties voor contaminatie van biologische produkten
met cellulair DNA
Published in
Abstract
Dit rapport beschrijft een onderzoek naar mogelijk
tumor-inducerend vermogen van rest DNA afkomstig van geimmortaliseerde en
mogelijk tumorigene cellijnen door de aanwezigheid van geactiveerde
oncogenen. Deze cellijnen worden gebruikt voor produktie van bijv.
monoclonale antistoffen, lymphokines en vaccins. DNA, afkomstig van Balb/c
hybridoma-cellen, werd gebruikt als model. De lokale (s.c.) tumorigene
capaciteit werd onderzocht in Balb/c muizen (speenlingen, n=200, 250 mug
DNA) en pasgeboren Riv:TOX ratten (n=9, 50 mug DNA). Doses van 5 mug
plasmide pPy1 DNA (Polyoma-virus genoom als positieve controle), werden s.c.
geinjecteerd 20 muizen en 9 ratten. Op de hybridoma DNA injectieplaats werd
bij geen van de 9 ratten en bij 1 van de 200 muizen een (haemangiomateuze)
laesie aangetroffen. Na pPy1 toediening werd bij 1 van de 20 muizen en bij
3 van de 9 ratten lokale tumorvorming waargenomen. Lokale tumorontwikkeling
na toediening van uitsluitend de oplosbuffer werd bij twee van de 200 muizen
en 0 van de 9 ratten waargenomen. De conclusie is dat toediening van zeer
hoge doses hybridoma DNA niet leidt tot lokale tumorvorming op de
injectieplaats. Tevens werden geen aanwijzingen voor systemische tumorigene
effecten gevonden. Uitgaande van het meest ongunstige scenario, werd het
oncogene risico van 100 pg rest DNA op 2*10 macht-9) berekend. Deze waarde
is gelegen tussen de risicoschattingen van de WHO (5*10 macht-11) en de
Gezondheidsraad (2*10 macht-7). Het is daarom niet aannemelijk, dat
toediening van 100 pg DNA afkomstig van andere geimmortaliseerde cellijnen
het algemeen geaccepteerde carcinogene risico van 10 macht-6
overschrijdt.
The aim of this study was to evaluate the possible carcinogenic potential of residual DNA derived from immortalized and possibly tumorigenic cell lines due to activated oncogenic sequences (oncogenes). These cell lines have been used for production of biologicals i.e. monoclonal antibodies, lymphokines and vaccines. DNA, derived from Balb/c hybridoma cells, has been used as a model. Local s.c. tumorigenicity experiments were performed in 3-4 week old female Balb/c mice (n=200, 250 mug DNA) and newborn Riv:TOX rats (n=9, 50 mug DNA). Doses of 5 mg plasmid pPy1 DNA (Polyoma virus genome as positive control) were injected s.c. in 20 mice and 9 rats. At the s.c. hybridoma DNA injection site of none of the 9 rats and in one out of 200 mice a (haemangioma-like) lesion was observed. At the pPy1 injection site tumour development was observed in one out of 20 mice and 3 out of 9 rats. Local tumour development at the injection site of the solvent only was observed in 2 out of 200 mice. The conclusion is that parenteral high dose administration of hybridoma DNA does not induce local tumour development. Furthermore, indications for systemic carcinogenic potential of the hybridoma DNA used were absent. The oncogenic risk of 100 pg residual DNA to be 2*10 power-9 (worst case approach) has been estimated, a value intermediate of the estimations of the WHO ( 5*10 power-11) and the Dutch Health Council (2*10 power-7). Therefore it is unlikely, that the risk of 100 pg of DNA derived from other immortalised cell lines will exceed the level of generally accepted cancer risk of 10 power-6.
The aim of this study was to evaluate the possible carcinogenic potential of residual DNA derived from immortalized and possibly tumorigenic cell lines due to activated oncogenic sequences (oncogenes). These cell lines have been used for production of biologicals i.e. monoclonal antibodies, lymphokines and vaccines. DNA, derived from Balb/c hybridoma cells, has been used as a model. Local s.c. tumorigenicity experiments were performed in 3-4 week old female Balb/c mice (n=200, 250 mug DNA) and newborn Riv:TOX rats (n=9, 50 mug DNA). Doses of 5 mg plasmid pPy1 DNA (Polyoma virus genome as positive control) were injected s.c. in 20 mice and 9 rats. At the s.c. hybridoma DNA injection site of none of the 9 rats and in one out of 200 mice a (haemangioma-like) lesion was observed. At the pPy1 injection site tumour development was observed in one out of 20 mice and 3 out of 9 rats. Local tumour development at the injection site of the solvent only was observed in 2 out of 200 mice. The conclusion is that parenteral high dose administration of hybridoma DNA does not induce local tumour development. Furthermore, indications for systemic carcinogenic potential of the hybridoma DNA used were absent. The oncogenic risk of 100 pg residual DNA to be 2*10 power-9 (worst case approach) has been estimated, a value intermediate of the estimations of the WHO ( 5*10 power-11) and the Dutch Health Council (2*10 power-7). Therefore it is unlikely, that the risk of 100 pg of DNA derived from other immortalised cell lines will exceed the level of generally accepted cancer risk of 10 power-6.
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