How to Ward Off Retinal Toxicity of Perfluorooctane and Other Perfluorocarbon Liquids?

Abstract

PURPOSE. Reactive and underfluorinated impurities are acknowledged as a source of cytotoxicity of perfluorocarbon liquids (PFCLs) used as blood substitutes. To determine whether this is also a relevant factor in retinal toxicity, we analyzed eight PFO batches associated with adverse ocular events. METHODS. (A)The amount of reactive and underflurinated impurities was analyzed by fluorideselective potentiometry and expressed as H-value. (B) Cytotoxicity of these batches was determined by an ISO 10993-5-compliant extractive test and compared to published data generated with a direct-contact method. (C) A toxic PFO batch (061014) was purified to remove reactive and underfluorinated impurities. (A) and (B) -measurements were repeated after that. (D) The dose dependence of the H-value and cytotoxicity was determined in a dilution experiment. RESULTS. (A)The batches revealed H-values ranging from 1.400 ppm to 4.500 ppm. (B) All batches induced cell growth inhibition; seven must be classified as cytotoxic. Findings from ISO-conform extractive and direct-contact methods showed no difference. (C) After all reactive and underfluorinated impurities in batch 061014 were removed, the H-value dropped to <10 ppm and cytotoxicity disappeared. (D) Cytotoxicity increases gradually as the H-value rises.CONCLUSIONS. The clinical relevance of the H-value as a safety parameter for PFO endotamponades could be proven. The H-value is a measure for reactive and underfluorinated impurities that cause toxicity of PFCLs and should be incorporated in each endotamponade specification with a limit of 10 ppm to prove the effectiveness of the ultra-purification required and ensure a safe product. Despite the fact that an (ISO)-standard literally is a ''standard'' only, which cannot cover all imaginable possibilities, the incorporation of the Hvalue determination into the relevant ISO standard has been initiated. If a thorough risk assessment results in risks that cannot be detected and/or managed by the effective standard, additional investigations have to be performed.

Hydrofluoric Acid and Other Impurities in Toxic Perfluorooctane Batches

“…The H-value was originally developed as a quality criterion for PFCL as blood substitutes5 and was later also applied to ophthalmological application 6. Its clinical relevance has recently been demonstrated as a safety parameter for PFO/PFCL endotamponades 4. The retinal toxicity of hydrogen-containing PFCLs was reported by Sparrow at al 7.…”

“…Serious toxic complications reported in 2015 after the intraocular use of PFO-batches produced by the Alamedics company (Dornstadt, Germany) were investigated and documented intensively 3. Previous work has shown that the toxic complications are due to reactive underfluorinated impurities,4 proven by determining the H-value, which quantifies such impurities and can be used as safety measure. The H-value is a quality parameter for fluorinated compounds in which, ideally, all hydrogen atoms have been replaced by fluorine atoms (PFCL).…”

Author Response: Chemical Considerations Regarding the H-Value Methodology and Its Relation With Toxicity Determination

“…We thank Srivastava and colleagues 1 for their careful and extensive comments on our article, which emphasize the importance of this subject and the urgent need for more clarity. 2 Before going into the questions in detail, we will summarize our main findings.…”

Chemical Considerations Regarding the H-Value Methodology and Its Relation With Toxicity Determination

“…We are writing about the recently published paper ''How to ward off retinal toxicity of perfluorooctane and other perfluorocarbon liquids?'' by Menz et al 1 The article is of great interest to us and other vitreoretinal surgeons because of the huge number of cases in which blindness has occurred after vitreoretinal surgery during which perfl uorocarbon endotamponades were used. The perfluorocarbon (PFO) liquids were manufactured by different companies, one German, one Indian, and one Turkish.…”

“…In their article, Menz et al 1 reported an analytical method to determine the concentration of incompletely fluorinated compounds assuming that its presence is the cause of cytotoxicity, increasing in a dose-dependent manner. We found several aspects that need clarification in the referenced paper.…”