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Appendix A Biosafety in Microbiological and Biomedical Laboratories C O N T E N TS Section I. Introduction 85 Section II. Principles of Biosafety 86 Laboratory practice and technique 86 Safety equipment (primary barriers). 86 Facility design (secondary barriers) 87 Biosafety levels Animal Biosafety levels Importation and interstate shipment of certain 87 88 biomedical materials 89 Section III. Laboratory Biosafety Level Criteria ................ Biosafety Level 1............... Biosafety Level 2....................... Biosafety Level 3............ Biosafety Level 4............. . . 89 ... . . ... 89 90 .92 94 - Section IV. Vertebrate Animal Biosafety Level Criteria 98 Animal Biosafety Level 1 98 Animal Biosafety Level 2 99 Animal Biosafety Level 3 . Animal Biosafety Level 4 . . .............. 100 ..102 Section V. Recommended Biosafety Levels for Infectious Agents and Infected Animab 104 Riskassessment 106 .... ... . ... ~ Agent Summary Statements Parasitic Agents......... Nematode parasites of humans . Protozoal parasites of humans . . Tremamde parasites of humans . Cestode parasites of humans . . . Fungal Agents ........................ Blastomyces dermatitidis ...... Coccidioides immitis ......... ..107 ..107 ..107 ..107 ..107 ..108 .108 ..108 ..108 .109 .109 109 Cryptococcus neoformans Histoplasma capsulatum Sporothrix schenc~i Pathogenic members of the genera Epidernmphyton, Microsporum, and Trichophyton 109 .110 110 Bacmnal Agents ...................... Bacillus anthracis .... Brucella (B. abortus, B. cants, B. rnelitensis, B. suds) .............. Chlamydia psittaci, C. trachomatis ..... Clostridium botulinum ............... Clostridium tetani................... Corynebacterium diphtheriae.......... Francisella tularensis................ Leptospira interrogans-fill strops .... Legionella pneumophila; other Legionella-like agents ............. Mycobacterium leprae ............... 0 0 111 111 2 2 2 3 3 Repnnted from J.H. Richardson and W.E. Baricley, Biosafety in Microbiological and Biomedical Laboratories, 1st ea., U.S. Public Health Service, HHS Publication No. (CDC) 84-8395, U.S. Govemment Printing Office, Washington, D.C., March 1984. Figures, tables, appendixes, and page numbers in this repented version have been renumbered to avoid confusion. 83

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84 Mycobacterium spp. other than M. tuberculosis, M. bovis, or M. Ieprae . . 113 Mycobacterium tuberculosis, M. bovis 114 Neisseria gonorrhoeae ................ Neisseria meningitidis ................. Pseudomonas pseudomallei ............ Salmonella cholera-suds, S. enteritidis" aDserotypes 115 Salmonella typhi ~ 115 Shigellaspp 116 Treponemapallidum 116 Vibrionic enteritis (Campylobacterfetus subsp. jejuni, Vibrio cholerae, V. parahaemolyticus) .114 .115 .115 . . .. .. . . .. . Yersinia pestis ........................ Rickettsial Agents . Coxiella burnetii 116 117 117 ...................... 117 Rickettsia akari, Rochalimaea quintana, end Rochalimaeavinsonii 117 Rickettsia prowaze~i, Rickettsia typhi (R. mooseri), Rickettsia tsutsugamushi, Rickettsia canada, and Spoued Fever Group agents of human disease other than Rickettsia rickettsii and Rickettsia akari..................... Rickettsm rickettsii .................... Viral Agents ......... Hepatitis A virus ...................... Hepatitis B9 hepatitis non-A non-B Herpesvirus sirruae (B-virus) .... Herpesviruses ................ Influenza virus............. Lymphocytic choriomeningitis ~CM) virus.................. Poliovirus e~ ee Poxviruses e-----~e~ APPENDIX A Rabies virus . . . . . . . . . . . . . . . . . eeeeee122 Transmissible spongiform encephalopathies (Creutzfeldt-Jakob and kuru agen~. . . . . . . . . . . . ee..ee122 Vesicular stomatitis virus (VSV) e e 123 Arbonruses ~ eee123 Arboviruses Assigned to Biosafe~r Level 2~ eeeeel23 Arboviruses and Arenaviruses Assigned to Bio~ety Level 3e~ A1bov~u~e,AUenavOu~es, or Filovinlses Assigned to Biosafety Level 4 . Appendix A.1. Biological Safety .......... 126 128 Cabinets ~ eeeeeee129 Appendix A.2. Immunoprophylaxis eee~131 AppendLx A.3. Surveillance of Personnel for Laboratory-Associated RickettsialInfections 131 . 118 Appendix A.4. Importation andInterstate . 118 Shipment of Human Pathogens and 119 .119 119 119 .. 120 120 Related Materials 132 Appendix A.5. Restricted Animal Pathogens 132 Appendix A.6. Resources for Information 133 . 121 121 Literature Cited 121

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APPENDIX A SECTIONI. INTRODUCTION Microbiology laboratories are special, often unique, work environments that may pose special infectious disease risks to persons in or near them. Personnel have contracted infections in the labora- tory throughout the history of microbiology. Pub- lished reports around the turn of the century described laboratory-associated cases of typhoid, cholera, "landers, brucellosis, and tetanus (123~. In 1941, Meyer and Eddie (75) published a survey of 74 laboratory-associated brucellosis infections that had occurred in the United States and concluded that the "handling of cultures or specimens or the inhalation of dust containing Brucella organisms is eminently dangerous to laboratory workers." A number of cases were attributed to carelessness or poor technique in the handling of infectious materials. In 1949, Sulkin and Pike (113) published the first in a series of surveys of laboratory-associated infections summarizing 222 viral infections 21 of which were fatal. In at least a third of the cases the probable source of infection was considered to be associated with the handling of infected animals and tissues. Known accidents were recorded in 27 (12%) of the reported cases. In 1951, Sulkin and Pike (114) published the second of a series of summaries of laboratory-associ- ated infections based on a questionnaire sent to 5,000 laboratories. Only one-third of the 1,342 cases cited had been reported in the literature. Brucellosis out- numbered all other reported laboratory-acquired in- fections and together with tuberculosis, tularemia, typhoid, and streptococcal infection accounted for 72% of all bacteria infections and for 31% of infec- tions caused by all agents. The overall case fatality rate was 3%. Only 16% of all infections reported were associated with a documented accident. The majority of these were related to mouth pipetting and the use of needle and syringe. This survey was updated in 1965 (93), adding 641 new or previously unreported cases, and again in 1976 (903, summarizing a cumulative total of 3,921 cases. Brucellosis, typhoid, tularemia, tuberculosis, hepatitis, and Venezuelan equine encephalitis were the most commonly reported. Fewer than 20% of all cases were associated with a known accident. Expo- sure to infectious aerosols was considered to be a plausible but unconfirmed source of infection for the 85 more than 80% of the reported cases in which the infected person had "worked with the agent." In 1967, Hanson et al. (53) reported 428 overt laboratory-associated infections with arboviruses. In some instances the ability of a given arbovirus to produce human disease was first confirmed as the result of unintentional infection of laboratory per- sonnel. Exposure to infectious aerosols was consid- ered the most common source of infection. In 1974, Skinhoj (104) published the results of a survey which showed that personnel in Danish clini- cal chemistry laboratories had a reported incidence of hepatitis (2.3 cases per year per 1,000 employees) seven times higher than that of the general popula- tion. Similarly, a 1976 survey by Hamngton and Shannon (55) indicated that medical laboratory work- ers in England had "a five times increased risk of acquiring tuberculosis compared with the general population." Hepatitis and shigellosis were also shown to be continuing occupational risks and together with tuberculosis were the three most commonly reported occupation-associated infections in Britain. Although these reports suggest that laboratory personnel are at increased risk of being infected by the agents they handle, actual rates of infection are typically not available. However, the studies of Har- rington and Shannon (55) and of Skinhoj (104) indi- cate that laboratory personnel have higher rates of tu- berculosis, shigellosis, and hepatitis than the general population. In contrast to the documented occurrence of labo- ratory-acquired infections in laboratory personnel, laboratories working with infectious agents have not been shown to represent a threat to the community. For example, although 109 laboratory-associated in- fections were recorded at the Center for Disease Control in 1947-1973 (97), no secondary cases were reported in family members or community contacts. The National Animal Disease Center has reported a similar experience (115), with no secondary cases occurring in laboratory and nonlaboratory contacts of 18 laboratory-associated cases occurring in 1960- 1975. A secondary case of Marburg disease in the wife of a primary case was presumed to have been transmitted sexually two months after his dismissal from the hospital (70~. Three secondary cases of smallpox were reported in two laboratoqy-associated outbreaks in England in 1973 (96) and 1978 (1303. There were earlier reports of six cases of Q fever in

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86 employees of a commercial laundry which handled linens and uniforms from a laboratory where work with the agent was conducted (84), and two cases of Q fever in household contacts of a rickettsiologist (5~. These cases are representative of the sporadic nature and infrequent association of community in- fections with laboratories working with infectious agents. In his 1979 review (92), Pike concluded, "the knowledge, the techniques, and the equipment to prevent most laboratory infections are available." No single code of practice, standards, guidelines, or other publication, however, provides detailed descriptions of techniques, equipment, and other considerations or recommendations for the broad scope of labora- tory activities conducted in the United States with a variety of indigenous and exotic infectious agents. The booklet Classification of Etiologic Agents on the Basis of Hazard (15) has, since 1969, served as a general reference for some laboratory activities util- izing infectious agents. That booklet and the concept of categorizing infectious agents and laboratory ac- tivities into four classes or levels served as a basic format for Biosafety in Microbiological and Biomedi- cal Laboratories. This publication will provide spe- cific descriptions of combinations of microbiological practices, laboratory facilities, and safety equipment and recommendations for use in four categories or biosafety levels of laboratory operation with selected infectious agents of man. The descriptions of biosafety levels 14 parallel those of P14 in the NIH Guidelines for Research Involving Recombinant DNA Molecules (43) and are consistent with the general criteria used in assigning agents to Classes 14 in Classification of Etiologic Agents on the Basis of Hazard (15~. Four biosafety levels are also described for infectious disease activi- ties utilizing small laboratory animals. Recommen- dations for biosafety levels for specific agents are made on the basis of the potential hazard of the agent and of the laboratory function or activity. SECTION II. PRINCIPLES OF BIOSAFETY The term 4'containment" is used in describing safe methods for managing infectious agents in the laboratory environment where they are being handled or maintained. Primary containment, the protection of personnel and the immediate laboratory environ- ment from exposure to infectious agents, is provided APPENDIX A by good microbiological technique and the use of appropriate safety equipment. The use of vaccines may provide an increased level of personal protec- tion. Secondary containment, the protection of the environment external to the laboratory from expo- sure to infectious materials, is provided by a combi- nation of facility design and operational practices. The purpose of containment is to reduce exposure of laboratory workers and other persons to, and to pre- vent escape into the outside environment of, poten- tially hazardous agents. The three elements of con- tainment include laboratory practice and technique, safety equipment, and facility design. Laboratory practice and technique. The most important element of containment is strict adherence to standard microbiological practices and techniques. Persons working with infectious agents or infected materials must be aware of potential hazards and must be trained and proficient in the practices and techniques required for safely handling such mate- rial. The director or person in charge of the labora- tory is responsible for providing or arranging for appropriate training of personnel. When standard laboratory practices are not suf- f~cient to control the hazard associated with a par- ticular agent or laboratory procedure, additional measures may be needed. The laboratory director is responsible for selecting additional safety practices, which must be in keeping with the hazard associated with the agent or procedure. Each laboratory should develop or adopt a bio- safety or operations manual which identifies the haz- ards that will or may be encountered and which speci- f~es practices and procedures designed to minimize or eliminate risks. Personnel should be advised of special hazards and should be required to read and to follow the required practices and procedures. A sci- entist trained and knowledgeable in appropriate labm ratory techniques, safety procedures, and hazards associated with handling infectious agents must di- rect laboratory activities. Laboratory personnel, safety practices, and tech- niques must be supplemented by appropriate facility design and engineering features, safety equipment, and management practices. Safety equipment (primary barriers). Safety equipment includes biological safety cabinets and a variety of enclosed containers. The biological safety

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APPENDIX A cabinet is the principal device used to provide con- tainment of infectious aerosols generated by many microbiological procedures. Three types of biologi- cal safety cabinets (Class I, II, III) used in microbio- logical laboratories are described and illustrated in Appendix A.1. Open-fronted Class I and Class II biological safety cabinets are partial containment cabinets which offer significant levels of protection to laboratory personnel and to the environment when used with good microbiological techniques. The gas- tight Class III biological safety cabinet provides the highest attainable level of protection to personnel and the environment. An example of an enclosed container is the safety centrifuge cup, which is designed to prevent aerosols from being released during centrifugation. Safety equipment also includes items for per- sonal protection such as gloves, coats, gowns, shoe covers, boots, respirators, face shields, and safety glasses. These personal protective devices are often used in combination with biological safety cabinets and other devices which contain the agents, animals, or materials being worked with. In some situations in which it is impractical to work in biological safety cabinets, personal protective devices may form the primary barrier between personnel and the infectious materials. Examples of such activities include certain animal studies, animal necropsy, production activi- ties, and activities relating to maintenance, service, or support of the laboratory facility. Facility design (secondary barriers). The de- sign of the facility is important in providing a barrier to protect persons working in the facility but outside the laboratory and those in the community from in- fectious agents which may be accidentally released from the laboratory. Laboratory management is re- sponsible for providing facilities commensurate with the laboratory's function. Three facility designs are described below, in ascending order by level of con- tainment. 1. The basic laboratory. This laboratory pro- vides general space in which work is done with vi- able agents which are not associated with disease in healthy adults. Basic laboratories include those fa- cilities described in the following pages as Biosafety Levels 1 and 2 facilities. This laboratory is also appropriate for work with 87 infectious agents or potentially infectious materials when the hazard levels are low and laboratory per- sonnel can be adequately protected by standard labm ratory practice. While work is commonly conducted on the open bench, certain operations are confined to biological safety cabinets. Conventional laboratory designs are adequate. Areas known to be sources of general contamination, such as animal rooms and waste staging areas, should not be adjacent to patient care activities. Public areas and general offices to which nonlaboratory staff require frequent access should be sepal from spaces which primarily support laboratory functions. 2. The containment laboratory. This laboratory has special engineering features which make it pos- sible for laboratory workers to handle hazardous materials without endangering themselves, the com- munity, or the environment. The containment labora- tory is described in the following pages as a Bio- safety Level 3 facility. The unique features which distinguish this laboratory from the basic laboratory are the provisions for access control and a special- ized ventilation system. The containment laboratory may be an entire building or a single module or complex of modules within a building. In all cases, the laboratory is separated by a controlled access zone from areas open to the public. 3. The maximum containment laboratory. This laboratory has special engineering and containment features that allow activities involving infectious agents that are extremely hazardous to the laboratory worker or that may cause serious epidemic disease to be conducted safely. The maximum containment labs ratory is described on the following pages as a Bio- safety Level 4 facility. Although the maximum con- tainment laboratory is generally a separate building, it can be constructed as an isolated area within a building. The laboratory's distinguishing character- istic is that it has secondary barriers to prevent haz- ardous materials from escaping into the environment. Such barriers include sealed openings into the labo- ratory, airlocks or liquid disinfectant barriers, a cloth- ing-change and shower room contiguous to the labo- ratory ventilation system, and a treatment system to decontaminate exhaust air. Biosafety levels. Four Biosafety levels are de- scribed which consist of combinations of laboratory practices and techniques, safety equipment, and labm ratory facilities appropriate for the operations per

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88 formed and the hazard posed by the infectious agents and for the laboratory function or activity. Biosafety Level 1. Biosafety level 1 practices, safety equipment, and facilities are appropriate for undergraduate and secondary educational training and teaching laboratories and for other facilities in which work is done with defined and characterized strains of viable microorganisms not known to cause disease in healthy adult humans. Bacillus subtilis, Naegleria gruberi, and infectious canine hepatitis virus are rep- resentative of those microorganisms meeting these criteria. Many agents not ordinarily associated with disease processes in humans are, however, opportun- istic pathogens and may cause infection in the young, the aged, and immunodef~cient or immunosuppressed individuals. Vaccine strains which have undergone multiple in viva passages should not be considered av~rulent simply because they are vaccine strains. Biosafety Level 2. Biosafety Level 2 practices, equipment, and facilities are applicable to clinical, diagnostic, teaching, and other facilities in which work is done with the broad spectrum of indigenous moderate-risk agents present in the community and associated with human disease of varying severity. With good microbiological techniques, these agents can be used safely in activities conducted on the open bench, provided the potential for producing aerosols is low. Hepatitis B virus, the salmonellae, and Toxoplasma spp. are representative of microor- ganisms assigned to this containment level. Primary hazards to personnel working with these agents may include accidental autoinoculation, ingestion, and skin or mucous membrane exposure to infectious materi- als. Procedures with high aerosol potential that may increase the risk of exposure of personnel must be conducted in primary containment equipment or de- vices. Biosafety Level 3. Biosafety Level 3 practices, safety equipment, and facilities are applicable to clini- cal, diagnostic, teaching, research, or production fa- cilities in which work is done with indigenous or exotic agents where the potential for infection by aerosols is real and the disease may have serious or lethal consequences. Autoinoculation and ingestion also represent primary hazards to personnel working with these agents. Examples of such agents for which Biosafety Level 3 safeguards are generally recom- mended include Mycobacterium tuberculosis, St. Louis encephalitis virus, and Coxiella burnetii. APPENDIX A Biosafety Level 4. Biosafety Level 4 practices, safety equipment, and facilities are applicable to work with dangerous and exotic agents which pose a high individual risk of life-threatening disease. All ma- nipulations of potentially infectious diagnostic materials, isolates, and naturally or experimentally infected animals pose a high risk of exposure and infection to laboratory personnel. Lassa fever virus is representative of the microorganisms assigned to Level 4. Animal Biosafety levels. Four Biosafety levels are also described for activities involving infectious disease activities with experimental mammals. These four combinations of practices, safety equipment, and facilities are designated Animal Biosafety Levels 1, 2, 3, and 4 and provide increasing levels of protec- tion to personnel and the environment. The laboratory director is directly and primarily responsible for the safe operation of the laboratory. Hisser knowledge and judgment are critical in as- sessing risks and appropriately applying these rec- ommendations. The recommended Biosafety level represents those conditions under which the agent can ordinarily be safely handled. Special characteris- tics of the agents used, the training and experience of personnel, and the nature or function of the labora- tory may further influence the director in applying these recommendations. Work with known agents should be conducted at the Biosafety level recommended in Section V unless specific information is available to suggest that viru- lence, pathogenicity, antibiotic resistance patterns, and other factors are significantly altered to require more stringent or allow less stringent practices to be used. Clinical laboratories, and especially those in health care facilities, receive clinical specimens with requests for a variety of diagnostic and clinical sup- port services. Typically, clinical laboratories receive specimens without pertinent information such as pa- tient history or clinical findings which may be sug- gestive of an infectious etiology. Furthermore, such specimens are often submitted with a broad request for microbiological examination for multiple agents (e.g., sputum samples submitted for"routine," acid- fast, and fungal cultures). It is the responsibility of the laboratory director to establish standard procedures in the laboratory which realistically address the issue of the infective

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APPENDIX A hazard of clinical specimens. Except in extraordinary circumstances (e.g., suspected hemorrhagic fever) the initial processing of clinical specimens and iden- tification of isolates can be and are safely conducted using a combination of practices, facilities, and safety equipment described as Biosafety Level 2. Biologi- cal safety cabinets (Class I or II) should be used for the initial processing of clinical specimens when the nature of the test requested or other information is suggestive that an agent readily transmissible by in- fectious aerosols is likely to be present. Class II biological safety cabinets are also used to protect the integrity of the specimens or cultures by preventing contamination from the laboratory environment. Segregating clinical laboratory functions and limiting or restricting access to laboratory areas are the responsibility of the laboratory director. Importation' and interstate shipment of cer- tain biomedical materials. The importation of etio- logic agents and vectors of human diseases is subject to the requirements of the Public Health Service For- eign Quarantine regulations. Companion regulations of the Public Health Service and the Department of Transportation specify packaging, labeling, and ship- ping requirements for etiologic agents and diagnostic specimens shipped in interstate commerce (see Ap- pendix A.4~. The U.S. Department of Agriculture regulates the importation and interstate shipment of animal 89 pathogens and prohibits the importation, possession, or use of certain exotic animal disease agents which pose a serious disease threat to domestic livestock and poultry (see Appendix Add. SECTION m. LABORATORY BIOSAFETY LEVEL CRITERIA The essential elements of the four Biosafety lev- els for activities involving infectious microorgan- isms and laboratory animals are summarized in Tables A.1 and A.2. The levels are designated in ascending order by degree of protection provided to personnel, the environment, and the community. Biosafety Level 1. Biosafety Level 1 is suitable for work involving agents of no known or minimal potential hazard to laboratory personnel and the en- vironment. The laboratory is not separated from the general traffic patterns in the building. Work is gen- erally conducted on open bench tops. Special con- tainment equipment is not required or generally used. Laboratory personnel have specific training in the procedures conducted in the laboratory and are su- pervised by a scientist with general training in micro- biology or a related science. The following standard and special practices, safety equipment, and facilities apply to agents as- signed to Biosafety Level 1. TABLE A.1 Summary of Recommended Biosafety Levels for Infectious Agents Biosafety level Practices and techniques Safety equipment None: primary containment provided by adherence to standard laboratory practices during open bench operations Facilities 1 Standard microbiological practices 2 3 Basic Level 1 practices plus: laboratory coats; decontamination of all infectious wastes; limited access; protective gloves and biohazard warning signs as indicated Level 2 practices plus: special labora- tory clothing; controlled access Partial containment equipment (i.e., Basic Class I or II Biological Safety Cabinets) used to conduct mechanical and manipulative procedures that have high aerosol potential which may in crease the risk of exposure to per sonnel Partial containment equipment used for Containment all manipulations of infectious material Level 3 practices plus: entrance Maximum containment equipment Maximum through change room where street clo- (i.e., Class III biological safety cabinet containment thing is removed and laboratory clo thing is put on; shower on exit; all wastes are decontaminated on exit from the facility ~ , ~ , _ _ . or partial containment equipment in combination with full-body, air- supplied, positive-pressure personnel suit) used for all procedures and activi- ties

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Do APPENDIX A TABLE A.2 Summary of Recommended Biosafety Levels for Activities in Which Experimentally or Naturally Infected Vertebrate Animals Are Used Biosafety level Practices and techniques Safety equipment Facilities Basic 1 Standard animal care and management None practices Laboratory coats; decontamination of all infectious wastes and of animal cages prior to washing; limited access; protective gloves and hazard warning signs as indicated 3 Level 2 practices plus: special labora tory clothing; controlled access Level 3 practices plus: entrance through clothes change room where street clothing is removed and labora tory clothing is put on shower on exit; all wastes are decontaminated before removal from the facility Partial containment equipment and/or personal protective devices used for activities and manipulations of agents or infected animals that produce aero- sols Basic Partial containment equipment and/or Containment personal protective devices used for all activities and manipulations of agents or infected animals Maximum containment equipment Maximum (i.e., Class III biological safety cabinet containment or partial containment equipment in combination with full-body, air sup plied, positive-pressure personnel suit) used for all procedures and activities A. Standard?rucrobiologicalpractices 1. Access to the laboratory is limited or re stricted at the discretion of the laboratory direc tor when experiments are in progress. 2. Work surfaces are decontaminated once a day and after any spill of viable material. 3. All contaminated liquid or solid wastes are decontaminated before disposal. 4. Mechanical pipetting devices are used; mouth pipetting is prohibited. 5. Eating, drinking, smoking, and apply ing cosmetics are not permitted in the work area. Food may be stored in cabinets or refrigerators designated and used for this purpose only. Food storage cabinets or refrigerators should be lo cated outside of the work area. 6. Persons wash their hands after they handle viable materials and animals and before leaving the laboratory. 7. All procedures are performed carefully to minimize the creation of aerosols. 8. It is recommended that laboratory coats, gowns, or uniforms be worn to prevent contami- washing. nation or soiling of street clothes. B. Specialpractices 1. Contaminated materials that are to be decontaminated at a site away from the labora tory are placed in a durable leakproof container which is closed before being removed from the laboratory. 2. An insect and rodent control program is in effect. C. Containment equipment Special containment equipment is generally not re- quired for manipulations of agents assigned to Bio- safety Level 1. D. Laboratoryfacilities 1. The laboratory is designed so that it can be easily cleaned. 2. Bench tops are impervious to water and resistant to acids, alkalis, organic solvents, and moderate heat. 3. Laboratory furniture is sturdy. Spaces between benches, cabinets, and equipment are accessible for cleaning. 4. Each laboratory contains a sink for hand 5. If the laboratory has windows that open, they are fitted with fly screens. Biosafety Level 2. Biosafety Level 2 is similar to Level 1 and is suitable for work involving agents

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APPENDIX A of moderate potential hazard to personnel and the environment. It differs in that (1) laboratory person- nel have specific training in handling pathogenic agents and are directed by competent scientists, (2) access to the laboratory is limited when work is being conducted, and (3) certain procedures in which infectious aerosols are created are conducted in bio- logical safety cabinets or other physical containment equipment. The following standard and special practices, safety equipment, and facilities apply to agents as- signed to Biosafety Level 2. A. Standard~ucrobiologicalpractices 1. Access to the laboratory is limited or restricted by the laboratory director when work with infectious agents is in progress. 2. Work surfaces are decontaminated at least once a day and after any spill of viable material. 3. All infectious liquid or solid wastes are decontaminated before disposal. 4. Mechanical pipetting devices are used; mouth pipetting is prohibited. 5. Eating, drinking, smoking, and apply- ing cosmetics are not permitted in the work area. Food may be stored in cabinets or refrigerators designated and used for this purpose only. Food storage cabinets or refrigerators should be lo- cated outside of the work area. 6. Persons wash their hands after handling infectious materials and animals and when they leave the laboratory. 7. All procedures are performed carefully to minimize the creation of aerosols. B. Specialpractices 1. Contaminated materials that are to be decontaminated at a site away from the labora- tory are placed in a durable leakproof container which is closed before being removed from the laboratory. 2. The laboratory director limits access to the laboratory. In general, persons who are at increased risk of acquiring infection or for whom infection may be unusually hazardous are not allowed in the laboratory or animal rooms. The director has the final responsibility for assessing 91 each circumstance and determining who may enter or work in the laboratory. 3. The laboratory director establishes poli- cies and procedures whereby only persons who have been advised of the potential hazard and meet any specific entry requirements (e.g., im- munization) enter the ldboramry or animal rooms. 4. When the infectious magentas) in use in the laboratory require special provisions for en- try (e.g., vaccination), a hazard warning sign, incorporating the universal biohazard symbol, is posted on the access door to the laboratory work area The hazard warning sign identifies the in- fectious agent, lists the name and telephone number of the laboratory director or other re- sponsible personas), and indicates the special requirementts) for entering the laboratory. 5. An insect and rodent control program is in effect. 6. Laboratory coats, gowns, smocks, or uniforms are worn while in the laboratory. Be- fore leaving the laboratory for nonlaboratory areas (e.g., cafeteria, library, administrative of- f~ces), this protective clothing is removed and left in the laboratory or covered with a clean coat not used in the laboratory. 7. Animals not involved in the work being performed are not permitted in the laboratory. 8. Special care is taken to avoid skin con- tamination with infectious materials; gloves should be worn when handling infected animals and when skin contact with infectious materials is unavoidable. 9. All wastes from laboratories and animal rooms are appropriately decontaminated before disposal. 10. Hypodermic needles and syringes are used only for parenteral injection and aspiration of fluids from laboratory animals and diaphragm bottles. Only needle-locking syringes or dispos- able syringe-needle units (i.e., needle is integral to the syringe) are used for the injection or aspi- ration of infectious fluids. Extreme caution should be used when handling needles and syringes to avoid autoinoculation and the generation of aero- sols during use and disposal. Needles should not be bent, sheared, replaced in the sheath or guard, or removed from the syringe following use. The needle and syringe should be promptly placed in a puncture-resistant container and decontami

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92 nated, preferably by autoclaving, before discard or reuse. 11. Spills and accidents which result in ovens exposures to infectious materials are immedi- ately reported to the laboratory director. Medi- cal evaluation, surveillance, and treatment are provided as appropriate, and written records are maintained. 12. When appropriate, considering the agentts) handled, base-line serum samples for laboratory and other at-risk personnel are col- lected periodically, depending on the agents handled or the function of the facility. 13. A Biosafety manual is prepared or adopted. Personnel are advised of special haz- ards and are required to read instructions on practices and procedures and to follow them. C. Containment equipment Biological safety cabinets (Class I or II) (see Appendix A.1) or other appropriate personal protec- tive or physical containment devices are used when- ever: 1. Procedures with a high potential for cre- ating infectious aerosols are conducted (821. These may include centrifuging, grinding, blend- ing, vigorous shaking or mixing, sonic disrup- tion, opening containers of infectious materials whose internal pressures may be different from ambient pressures, inoculating animals intrana- sally, and harvesting infected tissues from ani- mals or eggs. 2. High concentrations or large volumes of infectious agents are used. Such materials may be centrifuged in the open laboratory if sealed heads or centrifuge safety cups are used and if they are opened only in a biological safety cabi- net. D. Laboratoryfacilities 1. The laboratory is designed so that it can be easily cleaned. 2. Bench tops are impervious to water and resistant to acids, alkalis, organic solvents, and moderate heat. 3. Laboratory furniture is sturdy, and spaces between benches, cabinets, and equipment are accessible for cleaning. APPENDIX A 4. Each labo~auxy contains a sink for hand- washing. 5. If the laboratory has windows that open, they are fitted with fly screens. 6. An autoclave for decontaminating in- fectious laboratory wastes is available. Biosafety Level 3. Biosafety Level 3 is appli- cable to clinical, diagnostic, teaching, research, or production facilities in which work is done with in- digenous or exotic agents which may cause serious or potentially lethal disease as a result of exposure by the inhalation route. Laboratory personnel have spe- cif~c training in handling pathogenic and potentially lethal agents and are supervised by competent scien- tists who are experienced in working with these agents. All procedures involving the manipulation of infectious material are conducted within biological safety cabinets or other physical containment de- vices or by personnel wearing appropriate personal protective clothing and devices. The laboratory has special engineering and design features. It is recog- nized, however, that many existing facilities may not have all the facility safeguards recommended for Biosafety Level 3 (e.g., access zone, sealed penetra- tions, directional airflow, etc.~. In these circumstances, acceptable safety may be achieved for routine or repetitive operations (e.g., diagnostic procedures in- volving the propagation of an agent for identifica- tion, typing, and susceptibility testing) in laborato- ries where facility features satisfy Biosafety Level 2 recommendations, provided the recommended "Stan- dard Microbiological Practices," "Special Practices," and "Containment Equipment" for Biosafety Level 3 are rigorously followed. The decision to implement this modification of Biosafety Level 3 recommenda- tions should be made only by the laboratory director. The following standard and special safety prac- tices, equipment, and facilities apply to agents as- signed to Biosafety Level 3. A. Standard microbiologicalpractices 1. Work surfaces are decontaminated at least once a day and after any spill of viable material. 2. All infectious liquid or solid wastes are decontaminated before disposal. 3. Mechanical pipetting devices are used; mouth pipetting is prohibited.

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APPENDIX A 4. Eating, drinking, smoking, storing food, and applying cosmetics are not permitted in the work area 5. Persons wash their hands after handling infectious materials and animals and when they leave the laboratory. 6. All procedures are performed carefully to minimize the creation of aerosols. B. Specialpractices 1. Laboratory doors are kept closed when experiments are in progress. 2. Contaminated materials that are to be decontaminated at a site away from the labora- tory are placed in a durable leakproof container which is closed before being removed from the laboratory. 3. The laboratory director controls access to the laboratory and restricts access to persons whose presence is required for program or sup- port purposes. Persons who are at increased risk of acquiring infection or for whom infection may be unusually hazardous are not allowed in the laboratory or animal rooms. The director has the final responsibility for assessing each cir- cumstance and determining who may enter or work in the laboratory. 4. The laboratory director establishes poli- cies and procedures whereby only persons who have been advised of the potential biohazard, who meet any specific entry requirements (e.g., immunization), and who comply with all entry and exit procedures enter the laboratory or ani- mal rooms. 5. When infectious materials or infected animals are present in the laboratory or contain- ment module, a hazard warning sign, incorporat- ing the universal biohazard symbol, is posted on all laboratory and animal room access doors. The hazard warning sign identifies the agent, lists the name and telephone number of the labo- ratory director or other responsible personas), and indicates any special requirements for enter- ing the laboratory, such as the need for immuni- zations, respirators, or other personal protective measures. 6. All activities involving infectious mate- rials are conducted in biological safety cabinets or other physical containment devices within the 93 containment module. No work in open vessels is conducted on the open bench. 7. The work surfaces of biological safety cabinets and other containment equipment are decontaminated when work with infectious ma- terials is finished. Plastic-backed paper toweling used on nonperforated work surfaces within bio- logical safety cabinets facilitates cleanup. 8. An insect and rodent control program is in effect. 9. Laboratory clothing that protects street clothing (e.g., solid front or wrap-around gowns, scrub suits, coveralls) is worn in the laboratory. Laboratory clothing is not worn outside the labo- ratory, and it is decontaminated before being laundered. 10. Special care is taken to avoid skin con- tamination with infectious materials; gloves should be worn when handling infected animals and when skin contact with infectious materials is unavoidable. 11. Molded surgical masks or respirators are worn in rooms containing infected animals. 12. Animals and plants not related to the work being conducted are not permitted in the laboratory. 13. All wastes from laboratories and animal rooms are appropriately decontaminated before disposal. 14. Vacuum lines are protected with high efficiency particulate air (PAPA) filters and liq- uid disinfectant traps. 15. Hypodermic needles and syringes are used only for parenteral injection and aspiration of fluids from laboratory animals and diaphragm bottles. Only needle-locking syringes or dispos- able syringe-needle units (i.e., needle is integral to Be syringe) are used for the injection or aspi- ration of infectious fluids. Extreme caution should be used when handling needles and syringes to avoid autoinoculation and the generation of aero- sols during use and disposal. Needles should not be bent, sheared, replaced in the sheath or guard, or removed from the syringe following use. The needle and syringe should be promptly placed in a puncture-resistant container and decontami- nated, preferably by autoclaving, before discard or reuse. 16. Spills and accidents which result in overt or potential exposures to infectious materials are

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130 1~ ~-11 ~4J~ ~ ~ FIGURE A.1 Class I biological safety cabinet 1~ 1 rim ~ ~ ~ ~ 114~1 \ / ~ 1': Lit ~.~ Type A 1 1 ~-~,1 At\ \N 11 ...1- 1... ,: ~. ~'' ~ A. ~ I, ~ ~ ../.. ,..../ .::....'. . NEW li ~ ~ t ~ ;~1 \ ~\ ~ \\ IL I I I I ~ 11411 ~ , W~ ll Type B FIGURE A.2 Class II biological safety cabinets APPENDIX A Class III. The Class III cabinet (Figure A.3) is a totally enclosed ventilated cabinet of gas-tight con- s~uction. Operations within the Class III cabinet are conducted through attached nabber gloves. When in use, the Class III cabinet is maintained under nega- tive air pressure of at least 0.5 in. water gauge. Sup- ply air is drawn into the cabinet through HEPA fil- ters. The cabinet exhaust air is filtered by two HEPA falters, installed in series, before discharge outside of the facility. The exhaust fan for the Class III cabinet is generally separate from the exhaust fans of the facility's ventilation system. Use of cabinets. Personnel protection provided by Class I and Class II cabinets is dependent on the inward airflow. Since the face velocities are similar, they generally provide an equivalent level of person- nel protection. The use of these cabinets alone, however, is not appropriate for containment of highest-risk infectious agents because aerosols may accidentally escape through the open front. The use of a Class II cabinet in the microbiologi- cal laboratory offers the additional capability and advantage of protecting materials contained within it from extraneous airborne contaminants. This capa- bility is provided by the HEPA-filtered, recirculated mass airflow within the work space. The Class III cabinet provides the highest level of personnel and product protection. This protection is provided by the physical isolation of the space in which the infectious agent is maintained. When these cabinets are required, all procedures involving infec 1 7W 5Z5Z l Was 11 ~ \ f TV d, itt O O O O FIGURE AN Class m biological safety cabinet

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APPENDIX A tious agents are contained within them. Several Class III cabinets are therefore typically set up as an inter- connected system. All equipment required by the laboratory activity, such as incubators, refrigerators, and centrifuges, must be an integral part of the cabi- net system. Double-doored autoclaves and chemical dunk tanks are also attached to the cabinet system to allow supplies and equipment to be safely introduced and removed. Personnel protection equivalent to that provided by Class III cabinets can also be obtained with a personnel suit area and Class I or Class II cabinets. This area is one in which the laboratory worker is protected from a potentially contaminated environ- ment by a one-piece positive-pressure suit ventilated by a life-support system. This area is entered through an airlock fitted with airtight doors. A chemical shower is provided to decontaminate the surfaces of the suit as the worker leaves the area. The exhaust air from the suit area is filtered by two HEPA units installed in series. APPENDIX A.2. IMMUNOPROPHYLAXIS An additional level of protection for at-risk per- sonnel may be achieved with appropriate prophylactic vaccinations. A written organizational policy which defines at-risk personnel, which specifies risks as well as benefits of specific vaccines, and which dis- tinguishes between required and recommended vaccines is essential. In developing such an organiza- tional policy, these recommendations and require- ments should be specifically targeted at infectious diseases known or likely to be encountered in a par- ticular facility. Vaccines for which the benefits (levels of antibody considered to be protective) clearly exceed the risks (local or systemic reactions) should be re- quired for all clearly identified at-risk personnel. Examples of such preparations include vaccines against yellow fever, rabies, and poliomyelitis. Rec- ommendations for giving less efficacious vaccines, those associated with high rates of local or systemic reactions, or those that produce increasingly severe reactions with repeated use should be carefully con- sidered. Products with these characteristics (e.g., cholera, tularemia, and typhoid vaccines) may be recommended but should not ordinarily be required 131 for employment. A complete record of vaccines re- ceived on the basis of occupational requirements or recommendations should be maintained in the em- ployee's permanent medical file. Recommendations for the use of vaccines, adapted from those of the Public Health Service Advisory Committee on Immunization Practices, are included in the agent summary statements in Section V. APPENDIX Am. SURVEILLANCE OF PERSONNEL FOR LABORATORY ASSOCIATED RICKETTSIAL INFECTIONS Under natural circumstances, the severity of dis- ease caused by rickettsial agents varies considerably. In the laboratory, very large inocula which might produce unusual and perhaps very serious responses are possible. Surveillance of personnel for labora- tory-associated infections with rickettsial agents can dramatically reduce the risk of serious consequences of disease. Recent experience indicates that infections treated adequately with specific anti-rickettsial chemother- apy on the first day of disease do not generally pres- ent serious problems. Delay in instituting appropriate chemotherapy, however, may result in debilitating or severe acute disease ranging from increased periods of convalescence in typhus and scrub typhus to death in R. rickettsii infections. The key to reducing the severity of disease from laboratory-associated infec- tions is a reliable surveillance system which includes (1) round-the-clock availability of an experienced medical officer, (2) indoctrination of all personnel into the potential hazards of working with rickettsial agents and advantages of early therapy, (3) a report- ing system for all recognized overt exposures and accidents, (4) the reporting of all febrile illnesses, especially those associated with headache, malaise, prostration, when no other certain cause exists, and (5) a nonpunitive atmosphere that encourages report- ing of any febrile illness. Rickettsial agents can be handled in the labora- tory with minimal real danger to life when an ade- quate surveillance system complements a staff who are knowledgeable about the hazards of rickettsial infections and who put to use the safeguards recom- mended in the agent summary statements.

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132 APPENDIX A.4. IMPORTATION AND INTERSTATE SHIPMENT OF HUMAN PATHOGENS AND RELATED MATERIALS The importation or subsequent receipt of etio- logic agents and vectors of human disease is subject to the Public Health Service Foreign Quarantine Regulations (42 C:FR, Section 71.56~. Permits au- thorizing the importation or receipt of regulated ma- terials and specifying conditions under which the agent or vector is shipped, handled, and used are issued by the Centers for Disease Control. The interstate shipment of indigenous etiologic agents, diagnostic specimens, and biological prod- ucts is subject to applicable packaging, labeling, and shipping requirements of the Interstate Shipment of Etiologic Agents (42 CFR, Part 72~. Packaging and labeling requirements for interstate shipment of etio- logic agents are summarized and illustrated in Figure A.4. Additional information on the importation and interstate shipment of etiologic agents of human dis- ease and other related materials may be obtained by writing to: Centers for Disease Control Attention: Office of Biosafety 1600 Clifton Road, N.E. Atlanta, GA 30333 Telephone: (404) 329-3883 FTS: 23~3883 APPENDIX A.5. RESTRICTED ANIMAL PATHOGENS Nonindigenous pathogens of domestic livestock and poultry may require special laboratory design, operation, and containment features not generally addressed in this publication. The importation, pos- session, or use of the following agents is prohibited or restricted by law or by U.S. Department of Agri- culture regulations or administrative policies: African horse sickness virus African swine fever virus Besnoitia besnoia Boma disease virus APPENDIX A Bovine ephemeral fever Bovine infectious petechial fever agent Camelpax virus Foot and mouth disease virus Fowl plague virus Histoplasma (Zymonema) ~ . . larc~m~nosum Hog cholera virus Louping ill virus Lumpy skin disease virus Mycoplasma agalactiae Mycoplasma mycoides Nairobi sheep disease virus (Ganjam virus) Newcastle disease virus (velogenic strains) Pseudomonas mallet Rickettsia ruminantium Rift Valley fever virus Rinde~pest virus Swine vesicular disease virus Teschen disease virus Theileria annulata Theileria bovis Theileria hirci Theileria lawrencei ~. 1 rypanosoma Evans Trypanosoma vivax Vesicular exanthema virus Wesselsbron disease virus The importation, possession, use, or interstate shipment of animal pathogens other than those listed above may also be subject to regulations of the U.S. Deponent of Agriculture. Additional information may be obtained by writ- ing to: Chief Staff Veterinarian Organisms and Vectors Veterinary Services Animal and Plant Health Inspection Service U.S. Department of Agriculture Hyattsville, MO 20782 Telephone: (301) 436-8017 FTS 436-8017

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APPENDIX A APPENDIX A.6. RESOURCES FOR INFORMATION Resources for information, consultation, and advice on biohazard control, decontamination proce- dures, and other aspects of laboratory safety manage- ment include: Centers for Disease Control Attention: Office of Biosafety Atlanta, GA 30333 Telephone: (404) 329-3883 FTS 236-3883 133 National Institutes of Health Attention: Division of Safety Bethesda, MD 20892 Telephone: (301) 496-1357 FTS 496-1357 National Animal Disease Center U.S. Department of Agriculture Ames, IA 50010 Telephone: (515) 862-8258 FTS 862-8258

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APPENDIX A 63. Kiley, M. P., E. T. W. Bowel, G. A. Eddy, M. Isaacson, K. M. Johnson, J. B. McCormick, F. A. Murphy, S. R. Pattyn, D. Peters, W. Proz- esky, R. Regnery, D. I. H. Simpson, W. Slenczka, P. Sureau, G. van der Groen, P. A. Webb, and H. Sully. 1982. Filoviridae: taxo- nomic home for Marburg and Ebola viruses? Intervirology 18:24-32. 64. Klutsch, K., N. Hummer, U. Braun, A. Heid- land.1965. Zur Klinik der Coccidioidomykose. Dtsch. Med. Wochenschr. 90:1498-1501. 65. Kubica, G. P., W. Gross, J. E. Hawkins, H. M. Sommers, A. L. Vestal, and L. G. Wayne.1975. Laboratory services for mycobacterial diseases. Am. Rev. Respir. Dis. 112:773-787.5. 66. Larsh, H. W., and J. Schwartz. 1977. Acciden- tal inoculation blastomycosis. Cutis 19:334- 336. 67. Leifer, E., D. J. Gocke, and H. Bourne. 1970. Lassa fever, a new virus disease of man from West Africa. II. Report of a laboratory-acquired infection treated with plasma from a person recently recovered from the disease. Am. J. Trop. Med. Hyg. 19:677-679. 68. Looney, J. M., and T. Stein. 1950. Coccidioid- omycosis. N. Engl. J. Med. 242:77-82. 69. Marchoux, P. E. 1934. Un cas d'inoculation accidentelle du bacille de Hanson en pays non lepreux. Int. J. Leprosy 2: 1-7. 70. Martini, G. A., and H. A. Schmidt.1968. Sper- matogenic transmission of Marburg virus. Klin. Wochenschr.46:398400. McAleer, R. 1980. An epizootic in laboratory guinea pigs due to Trichophyton mentagro- phytes. Austral. Vet. J.56:234-236. 72. McDade, J. E., and C. C. Shepard. 1979. Viru- lent to avirulent conversion of Legionnaire's disease bacterium (Legionella pneumophila). Its effect on isolation techniques. J. Infect. Dis. 139:707-711. 137 73. Melnick, J. L., H. A. Wenner, and C. A. Phil- lips. 1979. Enterovauses, p. 471-534. In E. H. Lennette and N. J. Schmidt (ed.), Diagnostic procedures for viral, rickettsial and chlamydial infections, 5th ed. American Public Health As- sociation, Washington, D.C. 74. Meyer, K. F. 1915. The relationship of animal to human sporotrichosis: studies on American sporotrichosis III. J. Am. Med. Assoc. 65:579- 585. 75. Meyer, K. F., and B. Eddie. 1941. Laboratory infections due toBrucella. J. Infect. Dis.68:24- 32. 76. Meyers, W. M., G. P. Walsh, H. L. Brown, Y. Fukunishi, C. H. Binford, P. J. Gerone, and R. H. Wolf. 1980. Naturally acquired leprosy in a mangabey monkey (Cercocebus sp.~. Int. J. Leprosy 48:495496. 77. Morisset, R., and W. W. Spink. 1969. Epi- demic canine brucellosis due to a new species, Brucella cants. Lancet ii:l000-1002. 78. Murray, J. F., and D. H. Howard. 1964. Labo- ratory-acquired histoplasmosis. Am. Rev. Respir. Dis. 89:631-640. 79. Nabarro, J. D. N. 1948. Primary pulmonary coccidioidomycosis: case of laboratory infec- tion in England. Lancet i:982-984. 80. National Sanitation Foundation. 1983. Stan- dard 49. Class II (laminar flow) biohazard cabi- netry. National Sanitation Foundation, Ann Arbor, Mich. 81. Norden, A. 1951. Sporotrichosis: clinical and laboratory features and a serologic study in experimental animals and humans. Acta Pa- thol. Microbiol. Scand. Suppl. 89:3-119. 82. Off~ce of Research Safety, National Cancer In- stitute, and the Special Committee of Safety and Health Experts. 1978. Laboratory safety monograph: a supplement to the NIH Guide- lines for Recombinant DNA Research. National Institutes of Health, Bethesda, Ma{yland.

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138 83. Oliphant, J. W., and R. R. Parker. 1948. Q 95. fever: three cases of laboratory infection. Pub lic Health Rep. 63: 1364-1370. 84. Oliphant, J. W., D. A. Gordon, A. Meis, and R. R. Parker. 1949. Q fever in laundry workers, presumably transmitted from contaminated clothing. Am. J. Hyg.49:76-82. 85. Oliver, J., and T. R. Reusser. 1942. Rapid method for the concentration of tubercle ba cilli. Am. Rev. Tuberc. 45:450452. Oster, C. N., et al. 1977. Laboratory-acquired Rocky Mountain spotted fever. The hazard of aerosol transmission. N. Engl. J. Med.297:859 862. 87. Parritt, R. J., and R. E. Olsen. 1947. Two si multaneous cases of leprosy developing in tat toos. Am. J. Pathol. 23:805-817. 88. Patterson, W. C., L. O. Mott, and E. W. Jen ney. 1958. A study of vesicular stomatitis in man. J. Am. Vet. Med. Assoc. 133:57~2. 89. Perkins, F. T., and E. G. Hartley.1966. Precau tions against B virus infection. Br. Med. J. 1:899-901. 90. Pike, R. M.1976. Laboratory-associated infec tions: summary and analysis of 3,921 cases. Health Lab. Sci. 13:105-114. 91. 92. Pike, R. M. 1978. Past and present hazards of working with infectious agents. Arch. Pathol. Lab. Med. 102:333-336. Pike, R. M.1979. Laboratory-associated infec- tions: incidence, fatalities, causes and preven- tion. Annul Rev. Microbiol. 33:41-66. 93. Pike, R. M., S. E. Sulkin, and M. L. Schulze. 1965. Continuing importance of laboratory- acquired infections. Am. J. Public Health 55: 190-199. 94. Prescott, J. F., and M. A. Karmali. 1978. At- tempts to transmit Campylobacter enteritis to dogs and cats. Can. Med. Assoc. J. 119:1001- 1002. APPENDIX A Reid, D. D. 1957. Incidence of tuberculosis among workers in medical laboratories. Br. Med.J.2:10-14. 96. Report of the Committee of Inquiry into the Smallpox Outbreak in London in March and April 1973. 1974. Her Majesty's Stationery Office, London. 97. Richardson, J. H. 1973. Provisional summary of 109 laboratory-associated infections at the Center for Disease Control, 1947-1973. Pre- sented at the 16th Annual Biosafety Confer- ence, Ames, Iowa. 98. Riley, R. L. 1957. Aerial dissemination of pul- monary tuberculosis. Am. Rev. Tuberc.76:931- 941. 99. Riley, R. L. 1961. Airborne pulmonary tuber- culosis. Bacteriol. Rev. 25:243-248. 100. Robertson, D. H. H., S. Pickens, J. H. Lawson, and B. Lennex. 1980. An accidental laboratory infection with African trypanosomes of a de- fined stock. I and II. J. Infect. Dis. 2:105-112, 113-124. 101. Sastaw, S., and H. N. Carlisle. 1966. Aerosol infection of monkeys with Rickettsia rickettsii. Bacteriol. Rev. 30:636-645. 102. Schlech, W. F., J. B. Turchik, R. E. Westlake, G. C. Klein, J. D. Band, and R. E. Wever. 1981. Laboratory-acquired infection with Pseudon~nas pseudomallei (melioidosis). N. Engl. J. Med. 305:1133-1135. 103. Schwarz, J., and G. L. Baum. 1951. Blastomy- cosis. Am. J. Clin. Pathol. 21:999-1029. 1W. Skinhoj, P.1974. Occupational risks in Danish clinical chemical laboratories. II. Infections. Scand. J. Clin. Lab. Invest. 33:27-29. 105. Smith, C. E. 1950. The hazard of acquiring mycotic infections in the laboratory. Presented at 78th Annual Meeting, American Public Health Association, St. Louis, Missouri.

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APPENDIX A 106. Smith, C. E., D. Pappagianis, H. B. Levine, and M. Saito. 1961. Human coccidioidomyco- sis. Bacteriol. Rev. 25:310-320. 107. Smith, D. T., and E. R. Harrell, Jr. 1948. Fatal coccidioidomycosis: a case of laboratory in- fection. Am. Rev. Tuberc. 57:368-374. 108. Smithwick, R. W., and C. B. Stratigos. 1978. Preparation of acid-fast microscopy smears for proficiency testing and quality control. J. Clin. Microbiol. 8:110-111. 109. Spinelli, J. S., et al. 1981. Q fever crisis in San Francisco: controlling a sheep zoonosis in a lab animal facility. Lab. Anim. 10:24-27. 110. Spink, W. W. 1956. The nature of brucellosis, p. 106-108. University of Minnesota Press, Minneapolis. 111. Sterne, M., and L. M. Wertzel. 1950. A new method of large-scale production of high-titer botulinum formol-toxoid types C and D. J. Immunol. 65:175-183. 112. Subcommittee on Arbovirus Laboratory Safety of the American Committee on Arthropod- borne Viruses. 1980. Laboratory safety for ar- boviruses and certain other viruses of verte- brates. Am. J. Trop. Med. Hyg. 29:1359-1381. 113. Sulkin, S. E., and R. M. Pike. 1949. Viral in- fections contracted in the laboratory. N. Engl. J. Med. 241:205-213. 114. Sulkin, S. E., and R. M. Pike. 1951. Survey of laboratory-acquired infections. Am. J. Public Heals 41:769-781. 115. Sullivan, J. F., J. R. Songer, and I. E. Estrem. 1978. Laboratory-acquired infections at the National Animal Disease Center, 1960-1976. Health Lab. Sci. 15:58-64. 116. Tesh, R. B., and J. D. Schneidau, Jr. 1966. Primary cutaneous histoplasmosis. N. Engl. J. Med. 275:597-599. 139 117. Thompson, D. W., and W. Kaplan.1977. Lab~ ratory-acquired sporotrichosis. Sabouraudia 15:167-170. 118. Tomlinson, C. C., and P. Bancroft.1928. Gran- uloma coccidioides: report of a case respond- ing favorably to antimony and potassium tar- trate. J. Am. Med. Assoc. 91:947-951. 119. Tosh, F. E., J. Balhuizen, J. L. Yates, and C. A. Brasher. 1964. P~mary cutaneous histoplas- mosis: report of a case. Arch. Intern. Med. 114:118-119. 120. Walsh, G. P., E. E. Storrs, H. P. Burchfield, E. H. Cottrel, M. F. Vidrine, and C. H. Binford. 1975. Leprosy-like disease occurang naturally in armadillos. J. Reticuloendothel. Soc. 18:347- 351. 121. Wedum, A. G., and R. H. Kruse.1969. Assess- ment of risk of human infection in the microbi- ology laboratory. Miscellaneous Publication no. 30, Industrial Health and Safety Directorate, Fort Detrick, Frederick, Maryland. 122. Wedum, A. G., W. E. Barkley, and A. Hell- man. 1972. Handling of infectious agents. J. Am. Vet. Med. Assoc. 161:1557-1567. 123. Wedum, A. G. 1975. History of microbiologi- cal safety. 18th Biological Safety Conference. Lexington, Kentucky. 124. Weissenbacher, M. C., M. E. Grela, M. S. Sa- battini, J. I. Maiztegui, C. E. Coto, M. J. Frig- erio, P. M. Cossio, A. S. Rabinovich, and J. G. B. Oro. 1978. Inapparent infections with Junin vinlS among laboratory workers. J. Infect. Dis. 137:309-313. 125. Wilder, W. H., and C. P. McCullough. 1914. Sporotrichosis of the eye. J. Am. Med. Assoc. 62:1156-1160. 126. Willems, W. R., G. Kaluza, C. B. Boschek, and H. Bauer.1979. Semliki Forest virus: cause of a fatal case of human encephalitis. Science 203:1127-1129.

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140 127. Wilson, J. W., E. P. Cawley, F. D. Weidman, and W. S. Gilmer. 1955. Primary cutaneous Norm American blastomycosis. Arch. Derma- tol. 71:3945. 128. Wilson, J. W., C. E. Smith, and O. A. Plunked. 1953. Primary cutaneous coccidioidomycosis; the criteria for diagnosis and a report of a case. Calif. Med.79:233-239. APPENDIX A 129. Winkler, W. G. 1973. Airborne rabies ~ans- mission in a laboratory worker. J. Am. Med. Assoc. 226:1219-1221. 130. World Health Organization. 1978. Smallpox surveillance. Weekly Epidemiol. Rec. 53:265- 266.