1、Designation: F1439 03 (Reapproved 2018)Standard Guide forPerformance of Lifetime Bioassay for the TumorigenicPotential of Implant Materials1This standard is issued under the fixed designation F1439; the number immediately following the designation indicates the year oforiginal adoption or, in the ca
2、se of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon () indicates an editorial change since the last revision or reapproval.1. Scope1.1 This guide is intended to assist the biomaterials testinglaboratory in the conduct and eva
3、luation of tumorigenicity teststo evaluate the potential for new materials to evoke a neoplasticresponse. The procedure is generally reserved only for thosematerials which have not previously been used for humanimplantation for a significant period of time.1.2 Assessment of tumorigenicity is one of
4、several proce-dures employed in determining the biological response to amaterial as recommended in Practice F748. It is assumed thatthe investigator has already determined that this type of testingis necessary for a particular material before consulting thisguide. The recommendations of Practice F74
5、8 should beconsidered before a study is commenced.1.3 Whenever possible, it is recommended that a battery ofgenotoxicity procedures be initiated and proposed as an alter-native to an in-vivo tumorigenicity bioassay. Genotoxicityassays may also be considered as initial screening proceduresdue to the
6、sensitivity of the assays, the significant reduction intime to gain valuable data, and the desire to reduce the use ofanimals for testing. Genotoxicity assays that may be consid-ered are outlined in Guides E1262, E1263, E1280, and E2186,and Practices E1397 and E1398. Additionally, other genotox-icit
7、y testing which might be considered (but which do not yethave ASTM test methods) include Salmonella/Mammalian-Microsomal Plate Incorporation Mutagenicity Assay, In VivoCytogenetics Bone Marrow Chromosomal Damage Assay,BALB/3T3 Morphological Transformation of Mouse EmbryoCells, and the Mouse Micronuc
8、leus Assay. The investigator isadvised to consider carefully the appropriateness of a particularmethod for his application after a review of the publishedliterature.1.4 This standard does not purport to address all of thesafety concerns, if any, associated with its use. It is theresponsibility of th
9、e user of this standard to establish appro-priate safety, health, and environmental practices and deter-mine the applicability of regulatory limitations prior to use.1.5 This international standard was developed in accor-dance with internationally recognized principles on standard-ization establishe
10、d in the Decision on Principles for theDevelopment of International Standards, Guides and Recom-mendations issued by the World Trade Organization TechnicalBarriers to Trade (TBT) Committee.2. Referenced Documents2.1 ASTM Standards:2E1262 Guide for Performance of Chinese Hamster OvaryCell/Hypoxanthin
11、e Guanine Phosphoribosyl TransferaseGene Mutation AssayE1263 Guide for Conduct of Micronucleus Assays in Mam-malian Bone Marrow Erythrocytes (Withdrawn 2014)3E1280 Guide for Performing the Mouse Lymphoma Assayfor Mammalian Cell Mutagenicity (Withdrawn 2014)3E1397 Practice for In Vitro Rat Hepatocyte
12、 DNA RepairAssay (Withdrawn 2013)3E1398 Practice for In Vivo Rat Hepatocyte DNA RepairAssay (Withdrawn 2013)3E2186 Guide for Determining DNA Single-Strand Damagein Eukaryotic Cells Using the Comet AssayF748 Practice for Selecting Generic Biological Test Methodsfor Materials and Devices2.2 Other Docu
13、ments:National Toxicology Program General Statement of Workfor the Conduct of Toxicity and Carcinogenicity Studies inLaboratory Animals4OECD Guidelines for Testing of Chemicals: Guideline 451,1This guide is under the jurisdiction of ASTM Committee F04 on Medical andSurgical Materials and Devices and
14、 is the direct responsibility of SubcommitteeF04.16 on Biocompatibility Test Methods.Current edition approved Feb. 1, 2018. Published April 2018. Originallyapproved in 1992. Last previous edition approved in 2013 as F1439 03 (2013).DOI: 10.1520/F1439-03R18.2For referenced ASTM standards, visit the A
15、STM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMStandards volume information, refer to the standards Document Summary page onthe ASTM website.3The last approved version of this historical standard is referenced onwww.astm.org.4Available from Nati
16、onal Institute of Environmental Health Sciences, 111 T. W.Alexander Drive, Research Triangle Park, NC, August 1988. http:/www.niehs.nih.gov/.Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United StatesThis international standard was developed in a
17、ccordance with internationally recognized principles on standardization established in the Decision on Principles for theDevelopment of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.1Carcinogenicity Studies5OECD
18、 Guidelines for Testing of Chemicals: Guideline 453,Combined Chronic Toxicity/Carcinogenicity Studies5Good Laboratory Practice for Nonclinical Laboratory Stud-ies63. Terminology3.1 Definitions of Terms Specific to This Standard:3.1.1 carcinogenica substance is considered to be carci-nogenic if it ca
19、n be shown to be causally related to an increasedincidence of malignant neoplastic formation.3.1.2 maximum implantable dosethe maximum weight orvolume of the test article which can be reasonably implantedinto the test site taking into account the gross distention oftissue which can occur and its pos
20、sible effects on test results.3.1.3 mutagenica substance is said to be mutagenic if itinduces alterations in the genetic code of the cell.3.1.4 tumorigenica substance is said to be tumorigenic ifit can be shown to be causally related to an increased incidenceof neoplastic formation whether malignant
21、 or benign.4. Significance and Use4.1 This guide is not intended to specify the exact method ofconducting a test for any particular material but only to presentsome of the criteria that should be considered in method designand possible problems that could lead to misleading results. Inthe developmen
22、t of the actual test protocol, it is recommendedthat recognized tumorigenesis bioassay procedures be con-sulted.4.2 The recommendations given in this guide may not beappropriate for all applications or types of implant materials.These recommendations should be utilized by experiencedtesting personne
23、l in conjunction with other pertinent informa-tion and the requirements of the specific material application.5. Choice of Animal Model5.1 These types of bioassays for chemical substances havetraditionally been performed in mice or rats, or both, becauseof their small size, relative cost factors, and
24、 lifespan. For thetesting of biomaterials, mice are not recommended because thesmall animal size is not conducive to the placement of solidimplants. The investigator should seriously consider the use ofone of the traditional models in order to draw upon theextensive information available about typic
25、al tumor formationrates and sites in control animals. The National ToxicologyProgram4recommends the use of Fischer 344 (F344/N) rats.However, other readily available species and strains may alsobe acceptable for the performance of these studies. Other ratspecies which have been recommended include S
26、prague-Dawley, Long-Evans, and Wistar. Some investigators haverecommended the use of Long-Evans or Wistar Rats because ofthe difficulty of achieving a two-year lifespan for Fischer andSprague-Dawley rats.5.2 The currently accepted level of testing in a particularsite of implantation or medical speci
27、alty should be carefullyresearched and regulatory requirements determined before astudy design is finalized to ensure acceptability of the finalresults.5.3 The appropriate choice of male or female animals or acombination should be carefully considered in light of theparticular material and applicati
28、on being investigated. If thedevice will ultimately be used only in the male or female, onlyone sex may need to be evaluated. Otherwise, both sexesshould be used.5.4 The decision to use other species for study should becarefully documented in terms of a clear need. The use ofspecies which have not p
29、reviously been used may reduce theamount of comparative data available on control animals.Typical tumor rates for hamsters, rats, and mice have beentabulated and are available in Refs. (1, 2, 3).76. Selection of Size and Form of Implant6.1 Tumorigenicity bioassays have traditionally been per-formed
30、using chemical substances as the challenge. Theevaluation of implant materials requires that solid material beimplanted in some form. It is important to realize that thedown-sized implants necessary for use in animals will have agreater surface area to volume ratio, and this difference must beconsid
31、ered in experimental design.6.2 It may be important to determine the site of administra-tion of the test material that is most appropriate to the end usebefore determining implant size. The site of implantationshould be the paravertebral muscle unless the size of theimplant causes this site to be un
32、acceptable. Alternatively, thesite of implantation should mimic the anticipated end use, ifpossible. Where a specific material may be utilized in morethan one type of device, multiple sites of administration shouldbe considered if different types of tissue will be contacted. (Forinstance, materials
33、that may be in contact with bone orimplanted into internal organ tissue might be tested in bothtissues.)6.3 It should be recognized that the response of the testanimal to an extract of a material may not fully represent theresponse that might be seen if the material itself were to beimplanted. In ge
34、neral, an extract should not be used as asubstitute for the actual material of interest.6.4 The physical form of the test material should be repre-sentative of that intended for use in human patients and shouldconsider potential material debris, if appropriate. The investi-gator should be aware that
35、 tests have shown (4) that powderedpolymeric materials may not elicit a tumorigenic responsesubcutaneously even when prepared from polymers that doinduce tumors when implanted in the form of a film. The5Available from Organization for Economic Cooperation and Development,2001 L Street, N.W., Suite 6
36、50, Washington, D.C. 20036-4922. http:/www.oecd.org/washington/contact.htm.6Available from 21 CFR, Part 58, U.S. Government Printing Office Superinten-dent of Documents, 732 N. Capitol St., NW, Mail Stop: SDE, Washington, DC20401, http:/www.access.gpo.gov.7The boldface numbers in parentheses refer t
37、o the list of references at the end ofthis guide.F1439 03 (2018)2impact of physical form and surface properties on tumorigen-esis must be carefully considered, in making decisions aboutthe physical form of the implants (5, 6, 7, 8, 9, 10).6.5 Researchers have found that the aspect ratio (length/diam
38、eter) of fiber materials may play a role in the tumorigen-esis of a particular material (11, 12). When new fibrousmaterials are being tested, the actual fiber length to beanticipated in practice should be studied. If fragmentation canbe anticipated or is a worse case possibility, an attempt shouldbe
39、 made to document a clinically relevant fiber length.6.6 The material to be tested should originate fromsample(s) representative of all processing including surfacefinishing, passivation, and sterilization or other final processingthat will occur to a finished device.6.7 Dosage:6.7.1 In most materia
40、ls, the ratio between the surface area ofthe implant and the body weight of the animal or person willhave an effect on the amount of extractable substances (if any)which leach out of the material. The total weight or volume ofmaterial used in each animal should be in excess of theanticipated dosages
41、 to be seen in clinical practice whencalculated based upon the ratio of surface area of sample tobody weight of the animal. Consideration should be given tousing the maximum implantable dose as the dosage or as oneof multiple dosage levels. For the special case of degradablematerials, the sample siz
42、e should be calculated based on theratio of sample weight to animal body weight.6.7.2 Whenever possible, more than one exposure levelshould be considered to evaluate a dose-response effect.7. Choice of Control7.1 Control groups for this type of study will usually consistof identical animals that hav
43、e not received an implant of thetest material but have been subjected to the remainder of thesurgical procedures. Additional groups such as housing (ani-mals which receive no treatment but are housed with the testanimals) and reference control groups may be included in thestudy design.7.2 The invest
44、igator should consider a negative controlgroup in addition to the sham or untreated controls. Theseanimals would receive an implant or treatment identical to thetest animals but the implant would be manufactured from aselected negative reference material. This group would thenserve to isolate any re
45、sults due to the implant trauma ormechanically induced changes.8. Size of Test Groups8.1 The test group and the control group should eachcontain enough animals which will be scheduled to survive tothe end of the study to allow statistically valid conclusions tobe drawn from the study. If both male a
46、nd female animals arebeing used, each group should contain an equal number ofanimals of each sex. The National Toxicology Program4requires 60 animals/sex/group for chemical studies with tenanimals being sacrificed earlier than two years. Other interna-tional organizations recommend 50 animals/sex/gr
47、oup.5Theinvestigator should ascertain that the number of animals ineach group is adequate for statistical and regulatory purposesbefore proceeding. In order to ensure valid data analysis, theanimals should be randomly assigned to control and experi-mental groups. Considerations specific to the parti
48、cular implantapplication or medical specialty may mandate a greater numberof animals in each group. Additional animals in interimsacrifice groups or satellite groups may be added.8.2 The number of test animals in each group shall bedetermined based upon a sound statistical analysis of thescientific
49、questions to be addressed by the study. This analysisshould take into account predicted survival rates (if available)for the species being used as well as being consistent withresponsible use of experimental animals. If a statistically validexperiment can be performed with fewer than the usual numberof animals per group, that fact should be documented and thestudy design should proceed accordingly.9. Duration of Study9.1 Recommended durations for evaluation of tumorigenic-ity in rats is two years.9.2 Depending upon the material being evaluated, the earlyresults may suggest th
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