{"operation":"document","citation":"09-0186","title":"Oregon Health and Science University — Hazardous Materials Safety Interpretation","source_type":"guidance","agency":"Pipeline and Hazardous Materials Safety Administration","status":"guidance","official":true,"published_on":"2009-09-04","effective_on":null,"summary":"09-0186 response to Oregon Health and Science University concerning 173.134.","machine_formats":{"json":"https://regulus.evalyn.ai/document/phmsa-interpretation-09-0186.json","markdown":"https://regulus.evalyn.ai/document/phmsa-interpretation-09-0186.md"},"app_url":"https://regulus.evalyn.ai/document/phmsa-interpretation-09-0186","source_url":"https://www.phmsa.dot.gov/sites/phmsa.dot.gov/files/legacy/interpretations/Interpretations/2009/090186.pdf","body":"<<>>\n\nU.S. Department\nof Transportation\nPipeline and Hazardous Materials\nSafety Administration\nSEP - 4 2009\n1200 New Jersey Ave., SE\nWashington, DC 20590\nMs. Debra A. Brickey, PhD\nResponsible Official Select Agent Program,\nCentral and Waterfront Campuses\nOregon Health and Science University, PP- 1 70\n3 18 1 SW Sam Jackson Pk Rd\nPortland, OR 97239-3098\nRef. No. 09-0 186\nDear Dr. Brickey:\nThis responds to your June 3 1,2009 email requesting an interpretation of the applicability of\nthe Hazardous Materials Regulations (HMR; 49 CFR Parts 17 1-1 80) to the transport of\nDivision 6.2 materials. Specifically, you ask whether mice infected with a replication\ndefective adeno-associated virus (AAV) are subject to the requirements of the HMR.\nThe information attached to your email indicates that the mice are infected with a type of\nAAV that does not cause disease in humans or animals. The AAV injected into the mice is\ninactivated such that it does not replicate itself in the host; thus, the mice do not contain\ninfectious AAV viral particles.\nUnder tj 173.134, a Division 6.2 Infectious substance is defined as a material known to\ncontain or reasonably expected to contain a pathogen, such as a virus, that can cause disease\nin humans or animals. Additionally, under exceptions provided in 173.1 34(b), a material\ncontaining pathogens that have been neutralized or inactivated such that they no longer pose\na health risk is not subject to the requirements of the HMR as a Division 6.2 material. Based\non the information provided in your email, it is the opinion of this Office that the mice do not\nmeet the definition of a Division 6.2 material and are not subject to the HMR.\nI hope this information is helpful. If you have further questions, please contact this ofice.\nSincerely,\nief, Standards Development\nof Hazardous Materials Standards\n\n<<>>\n\nDer 6( r nde~eR age 1 of 4\nDrakeford, Carolyn (PHMSA)\nFrom: Gorsky, Susan (PHMSA)\nSent: Friday, August 07, 2009 3:00 PM\nTo: Drakeford, Carolyn (PHMSA)\nCc: Lavalle, Diane (PHMSA); Mazzullo, Ed (PHMSA)\nSubject: FW: OHSU Animal shipment to Germany\nFrom: Debra Brickey [mailto: brickeyd@ohsu.edu]\nSent: Friday, August 07, 2009 2:35 PM\nTo: Special Permits (PHMSA)\nCc: Sally Finch; Kim Saunders; John Brigande; Gwynn Daniels\nSubject: RE: OHSU Animal shipment to Germany\nHi Diane,\nThanh you for J our assistance. 1 talked thi:, over nith the OSHIJ director of the Deparl~lle~ll oTCornparative\nblt.dlcine and we both agreed that at thesc animals would not havc an) non-integrated ~,cplication-~ncompctent\nadeno-associated virus. I'liese nlice would 1101 pose a harard to humails or othcr ailirnals duc to the procedure\ndone to them as embrqos.\nIf you could provide us with an email approval and a written approval so that we may ship as soon as animals are\nready, it would be very appreciated by all of us here at OHSIJ.\nDebra\nI1cbr:i A. Hrickq. Phi)\nLaboratory Safety Ad\\ isor\nBiosafety & Chemical Hygiene Ofiicer\nKcsponsiblc Official Select Agent Program.\nCIentral and Waterfront Campuses\nOregon Health and Science I_Jniversilj\nPP- 1 70\n3 1 8 1 S&' Satn Sacl>>\n\nPage 2 of 4\nthe HMR.\nWe can respond by email immediately, a written response will take a bit.\nThanks,\nDiane LaValle\nTransportation Specialist\nFrom: Debra Brickey [mailto:brickeyd@ohsu.edu]\nSent: Thursday, August 06, 2009 3:23 PM\nTo: Special Permits (PHMSA)\nSubject: FW: OHSU Animal shipment to Germany\nImportance: High\n1'0 the atteritiori of l)arrell Kelcford. I'his In reference to the permit for Oregon Ilealth & Scicncc Llniversity\n(OlISU) to ship mice from thc US to Germany on passenger aircraft.\nFrom: Debra Brickey\nSent: Friday, July 31, 2009 10:45 AM\nTo: 'kenneth.herzog@DOT.gov'\nSubject: OHSU Animal shipment to Germany\nImportance: High\nKcnny,\nHere is Dr. Soh11 Rriga~ide'b explanation of his virul; work in these mice. What it boils down to is that the virus Is\nnot in the mice at the tirllc of shipping. 'nit genes carried by the virus are in tlic mice but a11 of the virus has been\neliminated by the mouse cells. The delays have lead to a lnillilnum cost oC$6000 dollars to the lab due to the age\nrequireriierlt for the mice needed for the experiment an expedited assessment uould be greatly appreciated by all\nthose involved in thc pcnriit process at 01 ISU and Gcnnatiy.\nIf based on this you decide that a permit is not required, could you givc us a written dcclar ation of this\nassessment? Do you think we could have resolution 011 this by earlj next ~ c c k ' ?\n'I'hanks.\nDebra\nDebra A. Hricl>>\n\nPage 3 of 4\nSubject: RE: Animal shipment to Germany\nDeb,\nThe nild type adeno-associated virus (AAV) is a member of the parvo\\rirus famil! that displays 110 pathogenicity\nin hu~llans. 1 hc t irus is composcd of a single strandcd l>KA gellome that comes in hio versions: sense or coding\nand anti-sense or non-coding. l'he wild type virus in humans can integrate into a specific site called AAVSl in\nhuman chromosome 10. Because i: is not associated with ally pathogenic or disease slate in humaris and because it\ndoes integrate, AAV has bee~i detclopcd as a gcnc tl~erapy vcctor for usc i l l trcat~ng hu~na~l discases through genc\nreplacement. Currently. there are cli~iical trials using AAV-based vectors for gene therapy for lipid storage\ndisease: muscular d j strophy; and C'anava~i disease. Completed hulnan cli~lical trial> using AAV-based gene\ntllcrapy ~cctors ]lave focused on cystic fibrosis. al-tllritis. and l~ereditary empllyscnla alllong other d~seascs.\nThe vector we are working with is a replication defective versio~~ of the non-pathogenic wild Qpe t irus. Our v i ~ us\nis also non-pathogenic, and it docs no1 lrlake more of itself in thc infected host. I'hc gellome of our virus has\ndeletions of DNA seqilelice that encode proleiris essential for the virus to replicate. Hence. our virus infects cells\nbut callnot replicate in them to produce more of itself. '[\"lie i~~fectior~ penl~lts our gene to bc esprcsscd in cells in\nthe inner ear so \\YC can learn if our pcrlc replacement restores hearing function. l'he infected cells cannot mahe\ntnore viral particles, and they therefore do not harbor infectious AAV viral particles.\nThe animals we seek to ship to our colleague in Germanj Mere infected with the replication defective A4V virus\nlien they were en~brjos groni~lg in the uterus of the tkmale mouse. Tliey are born about a week later, mature to\n31 days, and arc then tested for hca~ing function. 'The ncxt step is to have tlie scnsorq hair cells evaluated b)\nelectrophysiology: our colleague in (;ermanj is one of tlie only people on earth who does the specialized hind of\nrecordings ncccssary to validate hair cell function. 'I here arc no otller optio~ls for us to sccure the\nelcctrophysiological analyses.\nWc are higllly confident that the adult tnicc that wcre cvposcd to 11 AV wllcn thcy bere cml~rjos g ~ o n 111g in the\nuterus do not shed virus: thcy carinot since they arc unable to iiiakc riew tirus. 'She .4AV virus wc usc is simplj a\ngene shuttle to bring our cargo. the genes of interest. into the target cells in the i~i~ier ear. very sinlilar to the AAV\n\"\ntiral vectors used for human gene therapy. We bclie\\le our mice pose 110 risk wllatsoe\\.c~ to othcr nllce. ~odents.\nor humans.\nWc have gcileratcd 30 adult rr~icc to datc that ucrc csposed to cxpcrirrlcr~tal arid coiitrol virus. Wc had 4 possible\nship dates for these animals that have all passed. Estimating the cost of this extremely difficult. Each i11.iected\nmouse is worth about $200 US[> givc~l what it costs to generate the arlio~als. maintain them. and perform thc\nsurgery and irijections. 'l'liis is tliereforc about $6.000 lost thus Car, and it's probabl~ a lot\\ estimate. 1 have not\ntigured in the technician salary tirile to perform the preoperative and postoperative care. or my salarj as I do all of\nthe in-jcctions. t3ut more importa~lt than the money lost is the corlipletc breakdown of basic science research that\nhas occurred: we cannot adtance this project li~rlher without the electrophjsiological recording$.\nI hope that providing 1011 with tllcse details \\+ill help the 110 1' and FAA criticallj evaluate our request I b r a\npassenger flight permit to get these mice to Germany. 1 atn happy lo fly to the DOT or the FAA home offices at\nrnq expcrlse and present a scssion on replication detective AAV V I J us ~f requested.\n1 do appreciate your support of our efforts.\nJohn\nFrom: Debra Brickey\nSent: Thursday, July 30, 2009 12:53 PM\nTo: John Brigande; Sally Finch\nSubject: Animal shipment to Germany\n\n<<>>\n\nPage 4 of 4\nHey John,\nI spoke to Kenneth Herzog and he had heard from the FAA and their suggestions and then said it had to go to a\ntechnology advisor. I tried to explain more fully to Kenneth that the mice should not be categorized as Category\nB because there was no longer live virus in the animals.\nHe asked me to write up an explanation to give to their technology representative but I first wanted to confirm my\nunderstanding of what happens with you John and also give an estimate of cost including time spent on the missed\ntwo previous shipments due to delays in getting this approval.\nSo, my understanding is that the adenovirus construct is injected into embryos in the inner ear cells. The\nadenovirus expresses the prescribed proteins but since it cannot replicate it would be gradually degraded and\nexpression lost as the animal develops (it does not integrate into the DNA correct?). By the age of shipment the\nanimals would no longer have adenovirus in their bodies. So that the animals are essentially pathogen free.\nDo you want to add anything to that or clarify any part of that? Please let me know your costs and comments\nASAP since I would like to email this to him later today or early tomorrow?\nI apologize for all the hassle this has caused for you.\nDebra","truncated":false,"body_characters":10853}