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Editorial
The acute toxicity problem with some perfluorooctanes
El problema de la toxicidad aguda de algunos perfluoro-octanos
J.C. Pastor Jimenoa,b, R.M. Coco Martinb,
Corresponding author
rosa@ioba.med.uva.es

Corresponding author.
a Servicio de Oftalmología, Hospital Clínico Universitario de Valladolid, Valladolid, Spain
b Instituto Universitario de Oftalmobiología Aplicada (IOBA), Grupo de Retina, Universidad de Valladolid, Valladolid, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">In mid-2014&#44; a group of experienced Spanish retinologists had a series of dramatic experiences with patients who had undergone vitreoretinal surgery assisted with liquid perfluoro-octane &#40;PFO&#41; apparently completed without problems but with relatively sudden complications appearing in the immediate postop&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Said ophthalmologists&#44; worried about these cases&#44; shared their experiences in June 2015 and reached the conclusion that all those surgeries shared the same brand of PFO&#44; i&#46;e&#46;&#44; AlaOcta<span class="elsevierStyleSup">&#174;</span> &#40;Alamedics&#44; Dornstadt&#44; Germany&#41; for which reason they suspected that said complications could be due to acute toxicity caused by said product&#46; Accordingly&#44; they set in motion the established procedure for communicating adverse effects to the Medicaments and Health Products Agency of Spain &#40;MHPAS&#41; which published a health alert and seized the unused units of said product&#46; The Agency requested from Alamedics compulsory cytotoxicity tests that were carried out by another German company specialized in testing biosanitary products&#46; The results showed that the analyzed AlaOcta<span class="elsevierStyleSup">&#174;</span> samples did not exhibit any toxic behavior&#46; At that point in time&#44; an executive of the company explained to the press that as the product was safe toxicity must have been produced by incorrect use of PFO by the surgeons&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Far from accepting said explanations&#44; some colleagues insisted with the health authorities and finally&#44; in October 2015&#44; the Health Department of the Basque Country and the Innova Ocular Clinic requested IOBA to perform a counter-analysis&#44; providing samples of the suspect products under the supervision of the MHPAS&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The first surprise was that the utilized cytotoxicity tests&#44; carried out in accordance with ISO 10993-1&#58;2009&#59; ISO 10993-5&#58;2009 and ISO 10993-12&#58;2012 standards&#44; did not reproduce at all the clinic use of the product&#44; as recommended in said standards&#46; One of the possible analyses methods explained and accepted by said standards consisted in mixing the PFO with a cell culture&#44; agitating the mixture during 24<span class="elsevierStyleHsp" style=""></span>h at 37<span class="elsevierStyleHsp" style=""></span>&#176;<span class="elsevierStyleSmallCaps">C</span>and subsequently extracting the supernatant culture medium&#44; and the extract &#40;free of PFO&#41; placed in contact with a mouse fibroblasts culture&#46; In addition&#44; only the prime material was analyzed instead of the marketed products&#44; which is also recommended by said standards&#46; However&#44; the recommendations are not compulsory at least at this date&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">We suspect that the problem was that&#44; as PFO and water do not mix &#40;therefore the same occurs in the culture medium&#41;&#44; if the toxic substance was the modified PFO it would be very unlikely to dissolve in the culture medium&#46; The only molecules to go into the extract would be hydro-soluble&#46; Accordingly&#44; we decided to perform the tests with a different methodology&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">To this end&#44; our researchers designed 2 procedures for analyzing the cytotoxicity in conditions closer to the actual clinic use &#40;patent protected&#41;&#46; Said procedures were approved by the Medicaments Agency and they also matched both feasible procedures admitted by the ISO standards&#46; Both studies confirmed that&#44; as suspected by the surgeons&#44; the AlaOcta<span class="elsevierStyleSup">&#174;</span> products were toxic as they killed 100&#37; of the cells after&#44; in some cases&#44; only 30<span class="elsevierStyleHsp" style=""></span>min of contact&#44; thus confirming our hypothesis that the extraction method was not adequate for testing this type of products&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Subsequently&#44; our colleagues from the Sciences College of Valladolid University began a number of mass spectrometry studies that identified the presence of several compounds with no toxicity such as aldehyde alcohols&#44; traces of other compounds &#40;mainly ethylbencene and p-xylene&#41; and more importantly perfluoro-octanoic acid that has demonstrated in subsequent experiments to possess intensely acute toxicity at the minimum concentrations found in said products&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">In truth&#44; we are still in the dark about the cause of the problem&#46; We don&#8217;t know how a compound with highly stable links between fluoride and carbon is able to comprise OH radicals&#46; We also ignore at which point said transformation may have occurred&#46; However&#44; we believe that the cause is a self-feedback event as the amount of said substances progressively increased while the raw material was in storage&#46; The most toxic batches were those in which the raw material had been stored longer in the company&#46; Alamedics acquired the product from a German chemical company who in turn obtained it from a Russian company and for this reason the European health authorities found it impossible to obtain information about the manufacturing process because the latter country is beyond their scope of action&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Meanwhile&#44; the company has declared bankruptcy although new cases of patients with blindness have sprung up throughout Spain and the government has initiated lawsuits for damages which we doubt will be paid by Alamedics&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">It is highly worrying that in 2013 similar cases were reported in Spain and in Chile with compounds originated in Turkey &#40;Meroctane<span class="elsevierStyleSup">&#174;</span>&#44; Meran&#44; Istanbul&#44; Turkey&#41;&#46; The sole response was the withdrawal of a product and an analysis to establish the causes of acute toxicity which shed no light at all about the problem&#46; And&#44; as could be expected&#44; no references on these cases are to be found in scientific literature&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">It is true that&#44; since said compounds began to be used&#44; their toxicity was known but only in the long-term<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">1&#44;2</span></a> and some companies make it clear that they submit the compounds to purification procedures that reduce the concentration of incompletely fluorinated hydrocarbons&#44; thus allegedly improving their quality&#46; However it does not seem that said &#8220;impurities&#8221; are the cause of acute toxicity&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">In the majority of cases&#44; the observed clinical spectrum has produced amaurosis or light perception documented in the first week after surgery&#44; optic nerve atrophy within the first month&#44; conditions similar to acute retinal necrosis with giant retinal holes and friable retinas that are practically impossible to manage in reinterventions&#44; patients with extensive arterial and venous vascular occlusions with vascular tortuosity that in many cases gave rise to proliferative vitreoretinopathy&#46; In addition&#44; some patients experienced ocular and&#47;or orbitary inflammations while others developed rubeosis&#46; Finally&#44; the only reported case exhibiting a small PFO bubble in the anterior chamber produced significant corneal toxicity&#46; All the above clinic conditions mean that only a small percentage of patients were able to preserve some visual function&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">3</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">To make matters worse&#44; in December 2016 at least 4 acute toxicity cases were reported after the use of another PFO&#44; this time manufactured in India&#44; which was again withdrawn from the market and that&#44; after the appropriate analyses&#44; has demonstrated to be equally toxic &#40;Bio-Octane-Plus<span class="elsevierStyleSup">&#174;</span>&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The summary of affected patients&#44; if it can be summarized at all&#44; is as follows&#58; at least 4 blind patients caused by the Turkish product&#44; 120 by the German product and at least 4 additional cases caused by the Indian product&#46; In all&#44; 29 hospitals or clinics&#44; 21 Spanish cities and virtually all Autonomous Communities with patients affected by these products&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">And what about Europe&#63;</span><p id="par0075" class="elsevierStylePara elsevierViewall">In 2016 we had to insist repeatedly to be authorized to report this problem at a European meeting because we were told this was a Spanish problem&#46; Not the case&#46; After visiting some European manufacturers we were able to obtain completely off-the-record information about cases in Germany&#44; France&#44; Italy&#44; Switzerland&#44; Sweden and Saudi Arabia&#44; among others&#46; However&#44; the Spanish ophthalmologists&#44; acting in a very responsible and professional manner&#44; have reported every suspect case to the health authorities&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">At this point&#44; we suppose that the big question ought to be&#58; is PFO safe&#63; After more than 25 years of use&#44; our reply is affirmative&#44; provided that the entire European regulations on manufacture&#44; transport&#44; storage and mainly cytotoxicity evaluation of these compounds is overhauled&#46; That is what we are focusing on now&#44; together with the MHPAS&#46; For a number of weeks we have requested European authorities to analyze and modify the ISO standards regulating said evaluations prior to marketing endotamponade agents applied in ocular surgery&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">We trust that the response of some manufacturers&#44; who until now has only been holding on to the message that &#8220;my product is safe&#8221;&#44; will become collaborative so that together we can obtain the legislative changes in order to avoid another catastrophic episode in the future&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Our admiration goes to all Spanish ophthalmologists who&#44; suspecting cases&#44; reported them to the Agency&#44; and our solidarity goes to our patients who&#44; ultimately&#44; are the main victims of this problem&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Funding</span><p id="par0095" class="elsevierStylePara elsevierViewall">The cytotoxicity studies were funded by the <span class="elsevierStyleGrantSponsor" id="gs1">Donostia Hospital</span> and the management of the <span class="elsevierStyleGrantSponsor" id="gs2">Innova Ocular Clinics</span>&#46; The chemical studies were carried out by the MHPAS&#46;</p></span></span>"
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Article information
ISSN: 21735794
Original language: English
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