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Suggested Citation:"CONCLUSIONS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Suggested Citation:"CONCLUSIONS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Suggested Citation:"CONCLUSIONS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Page 195
Suggested Citation:"CONCLUSIONS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Page 196
Suggested Citation:"CONCLUSIONS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Page 197
Suggested Citation:"CONCLUSIONS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Page 198
Suggested Citation:"CONCLUSIONS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Page 199
Suggested Citation:"CONCLUSIONS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Page 200
Suggested Citation:"CONCLUSIONS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Page 201
Suggested Citation:"CONCLUSIONS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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Page 202
Suggested Citation:"CONCLUSIONS." Institute of Medicine. 1989. Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed. Washington, DC: The National Academies Press. doi: 10.17226/19030.
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194 the Animal Health Institute , microbiologists , and representatives of the pharmaceutical industry . Us ing a l l the resources noted above , we were unabl e to find a substantial body of direct evidence that establ i shed the existence of a def inite human health hazard in the use o f subtherapeutic concentrations of penici l l in and the tetracycl ines in animal feeds . However , we bel ieve that important--but as yet scant--data indicate the flow o f distinct salmonel l a strains from farm anima l s , through the food process ing cha in , to humans in whom they cause cl inica l salmone l l osis . In the one compel l ing instance o f such a clear l ink , the multiple-antibiotic-resistant � newport originated in farm animals exposed to chl oramphenicol , a drug not approved by the Food and Drug Administrat ion for use in feed . The committee bel ieves that the molecular f ingerprinting techniques used in this study can provide (when unique markers are present ) the direct evidence needed to trace the source of antibacteria l - resi stant bacteria to human in fection . I f records of amounts of antibiotic use are ma inta ined on farms producing food for human consumption , better evidence can be estab l i shed for incriminating subtherapeut icjtherapeut ic doses in disease outbreaks . The committee bel ieves that there is indirect evidence impl icating subtherapeutic use of antimicrobia l s in producing res i stance in infectious bacteria that causes a potential human health hazard . The ev idence is of several kinds : o There are extens ive experimental data on the propert ies of R pl asmids and the ir capacity for trans fer o f antimicrobial-resistance determinants , both i n the test tube and in the intestinal tract , particularly in the presence of antimicrobial sel ective pressure . o There is evidence of widespread use o f subtherapeut ic concentrations of pen ic i l l in and the tetracycl ines ( and other antimicrobia l s ) on farms and feedlots . o There i s ample evidence o f high leve l s o f antimicrobial res i stance among animal isol ates of sa lmone l l ae . o Animal and poultry carcasses in meat-process ing pl ants are o ften contaminated with Escher ichia coli and other enteric pathogens . Few data are ava ilable on the frequency of antimicrob ial res istance among such isol ates . I f the preva lence of antimicrob ial res istance among reported isol ates from d iagnostic laboratories is a true representation of antimicrobial resi stance in farm anima l s going to sl aughter , the frequency of resi stance among enteric pathogens in animal and poultry carcasses would be expected to be high . However , if the salmone l l a isolates reported

195 f rom diagnostic laboratories are principal ly from anima l s that are i l l and have received antimicrobial s , the figures would clearly overestimate the frequency of resistant i solates from meat and poultry carcasses . o Handl ing and ingestion o f improperly cooked , packaged f ro z en or refrigerated meat and poultry contaminated with bacterial pathogens provides exposure to an in fecting i noculum . o Experience with antimicrobial drugs in humans over the last 4 5 years has revealed the emergence o f res i stant stra ins associated with extens ive drug use and the need to avoid unnecessary and prolonged use , particularly "prophylactic" use without clear and proven indications . I n addition , the committee has used the results provided by the risk assessment model presented to estimate quantitatively the poss ible risk of mortal ity associated with ant ib iotic-res istant salmone l lae due to the subtherapeutic use o f penic i l l in or the tetracycl ines in anima l s . In the 1 9 8 0 NRC report , the committee to study the Human Health E ffects o f Subtherapeutic Antibiotic use in Animal Feeds concluded that " the postul ated ha zards to human health from a subtherapeut ic use o f antimicrobials in animal feeds were ne ither proven nor di sproven . " In other words , the risk o f human health as a result of subtherapeutic use o f antimicrobials i n feed was not estimated . We found the ava i lable data base on some aspects of the problem to be l imited in qual ity and quantity : indeed , the data had not been gathered prospectively for the purpose of thi s type o f analys is . The committee has used what it cons iders the best ava i lable information , indicating , where appropriate , the inherent weaknesses in the data . Admittedly , in some instances , we used only the best estimates ava i l able in the risk assessment . The assessment does indicate the presence of risk . Although it does not provide a distinct numerical " answer" to the quest ion of the magnitude of the human hea lth risk involved , it does provide some indication o f the probable s i z e of the risk in terms o f numerical estimates o r ranges . These are presented bel ow a s numbers o f deaths per year attributabl e t o the subtherapeutic use o f antimicrobials ( or penici l l in and tetracycl ine s ) in the l i sting of speci fic conclus i ons : BIOLQGIC IMPACTS o Use of each new antimicrobial agent over the last hal f-century has eventual ly mobi l i zed genes that encode res istance to the agent and disseminated them widely through

196 the world ' s interconnectinq bacterial populations . U s e o f the ant imicrobial aqent disseminates the res istance qenes in staqes , each of which beqins with a rare molecular event that faci l itates further dissemination . Althouqh use o f ant imicrobials i n a patient or the patient ' s neiqhbors miqht have triqqered overqrowth and cl inical mani festat ion of the res istant strain , the evolution and del ivery o f its res istance qenome was the result of prior use in many , probably distant , bacterial populations . o Results of surveys of isolates of salmonel lae from animals and humans in the United States and restriction­ endonuclease fraqment patterns of res istance plasmids from selected isolates suqqest that clones of resistant salmonel lae are endemic in animal s and sporadic or occas ional ly ep idemic in humans . o Herds of farm an imals qiven subtherapeutic amounts of antimicrobial aqents have more antimicrobial -res istant intestinal bacteria than herds qiven no antimicrobial s . o The most important determinant in the selection o f ant imicrobial -resistant stra ins i n a bacterial population i s exposure of that population to antimicrobial s . Tota l duration and concentration of antimicrob ial use are important in selection for res istance . Any measure that fa i l s to reduce tota l use apprec iably is unl ikely to a ffect the preval ence of antimicrobial-resistant stra ins . o Res istance to ant imicrobial druqs amonq sa lmonel l a stra ins can interfere with the eff icacy of antimicrobial therapy o f human salmonel losis . ( Such res istance i s usual ly R-plasmid-mediated , so it can involve other druqs , such as trimethoprim-sul famethoxa zole , chl oramphen icol , and ampicil l in . ) Althouqh such interference with the e f f icacy of therapy almost certa inly occurs ( i . e . , patients are treated with an antimicrobial that is ine f fective because of druq res istance ) , it is probably quite uncommon in nontyphoidal sa lmonel los i s . o The ava i l able data are inadequate to conclude that either subtherapeutic or therapeut ic concentrat ions o f antimicrobials are more sel ect ive of druq-resistant bacteria . On theoretical qrounds , it is l ikely that therapeut ic and subtherapeut ic dosaqes exert equal sel ective pressure for cl onal expans ion of res istance , but subtherapeutic dosaqes exert more pressure for conj uqative trans fer of druq res i stance , because of the dosaqes and the durat ions o f administrat ion .

197 o An imal and poultry products ( includinq veal , bee f , pork , chicken , eqqs , and milk) are the princ ipal sources o f human nontyphoidal salmonel losis . Also , some � QQli serotypes can also be found in the intestinal flora both o f humans and of farm animals . Thus , there could be an interconnect inq l ink between these two larqe pools o f enteric m icroorqanisms , facil itated by the h iqh frequency of contamination o f anima l and poultry carcasses in s lauqhterhouses . Such a potential l ink would provide a means of movement of R plasmids of farm oriqin to the human a l imentary tract . The interconnection , because of its nature , would constitute an almost exclus ively one-way passaqe . o The overal l prevalence of res istance to any of five commonly used antimicrobials is about 4 times as qreat in col lections of salmonella isolates from farm anima l and poultry ( 6 5 % ) as those in col lections of isolates from humans ( 15 . 5% ) . This d i fference suqqests that the predominant pool of res istant salmonel lae is in farm animals . Because ult imately almost a l l human infections with nontyphoidal salmonel lae result from stra ins oriqinat inq in farm animal s , the ant imicrobial res istance observed in human isolates most l ikely is derived from the anima l pool of res istance qenes , rather than from selection due to antimicrobial use in humans . EPI DEMIOLOGIC FINDINGS o Evidence is sparse that directly l inks the use of penici l l in and tetracycl ine in subtherapeutic concentrations in animal feeds to human infections . several studies have yielded rel iable evidence of spread , from farm animal s and poultry to humans , of � col i stra ins in which antimicrobial res istance had been induced by administrat ion of subtherapeut ic concentrations of antimicrobials as feed add itives . There is evidence from only one study of the direct spread of multiple-antimicrobial-res istant salmone l l ae from farm animals to humans via meat products . However , the ant imicrobial used on the farm was chl oramphenicol , a druq not approved by FDA as a feed addit ive in animals used for food production . It miqht be diff icult , or imposs ible , to provide a total cha in of evidence directly relatinq the maj ority of cases of human infection with antimicrobial­ res i stant salmonel l ae to a source on the farm or feedlot or to relate the presence of the res istance to the use of spec i f ic ant imicrobials in subtherapeutic concentrations in feed . By the t ime a deta iled invest iqation o f an outbreak of human salmonel losis occurs , evidence of prior antimicrobial use patterns miqht not be ava i lable .

198 o It has not been poss ible to determine whether antimicrobial res istance of salmone l l ae caused by the administrat ion of subtherapeutic concentrations o f antimicrobials i n animal feed increases the number o f cases of human salmonel losis . o Whether the presence of antimicrobial res istance in salmone l l ae increases virul ence i s uncerta in ; the avai l able data are l imited and confl icting . I n special circumstances , as when R plasmids are l inked with virul ence genes ( e . g . , those for enterotoxin or hemolys in in � �) , selection by antimicrobial agents might promote spread of v i rulent stra ins ; however , such an occurrence has only rarely been reported . It is not clear whether the overal l prevalence o f salmonel l ae i n food products i s increased b y v irtue o f antimicrobial res istance . However , the incidence of human sa lmone l l o s i s in the United States is increas ing , and the increase is unl ikely to be an arti fact of better reporting . As long as most stra ins of Salmonel l a are susceptible to the antimicrobials to which they are exposed , subtherapeutic administration of antimicrobials might reduce the preval ence of salmonel l ae in meat and poultry products that humans ingest . However , as the preval ence of res i stant stra ins increases because of repeated and prol onged exposure to antimicrobial s , subtherapeutic administration might actual ly favor the increase by suppress ing the normal compet ing flora and promoting R-plasmid spread . Direct proof of this pattern in sa lmone l l ae in farm animals is lacking . o The current frequency of R-plasmid-mediated ant imicrobial res istance among isolates of � QQli and salmone l l ae in the intestinal contents of farm animals and poultry is h igh--much higher than in human isolates . It would be d i f f icult to predict the period required , after curta i lment of the use of subtherapeutic concentrations o f penic i l l in and the tetracycl ines i n animal feed , for R­ plasmid-mediated ant imicrobial res istance to decrease in any extent in salmonel lae and � � strains . Maj or decreases might occur only a fter the passage of years , in view o f ( 1 ) the current degree of res istance , ( 2 ) the extensive environmental contaminat ion on farms and feedlots with res istant organisms , ( 3 ) the prolonged prior subtherapeutic use of antimicrobial s , which has a l l owed extens ive permeation of res istance genes ( transposons ) throughout the h ighly col on i z ation-adapted col i form fl ora of farm animals , and ( 4 ) the need to introduce competing , ant imicrobial­ suscept ible col i form bacteria . Results of studies in conf ined populations of swine indicate that it could take many years for maj or decreases in level s of res istance to occur .

199 o Althouqh the extent of antimicrobial res istance amonq salmone l l a strains isolated from humans is probably qrowinq , it i s sti l l low enouqh for suitable intervention to forestal l pos s ible further increases and eventual ly t o lower the overa l l extent of antimicrobial res istance . ANtiBIOTIC USE PATTEBNS o The use o f subtherapeutic dosaqes of penici l l in and the tetracycl ines in animal feeds is extens ive in the United states . Such use is for the purpose of e ither qrowth promotion or disease prevention and often continues for a substant ial port ion of the qrowth cycle of farm animal s . The spec i fic rationale for use in a qiven herd at a qiven time is not always clear . Of over 3 1 m i l l ion pounds o f antimicrobials produced each year i n the Un ited States , about 4 2 -4 8 % is des iqnated for addition to anima l feeds or other unspeci f ied (minor ) uses . The best estimates ( they are only est imates ) indicate that penici l l in and the tetracycl ines account for almost 6 0 % of the antimicrobial s sold to the feed trade ( and presumably ultimately used on farms and in feedlots ) . Of the total amount of tetracycl ines produced in thi s country , for use in both humans and animals , approximately 7 0 % i s sold for use in l ivestock and poultry feeds . An estimated 8 8 % of all antimicrob ial use in l ivestock and poultry i s in subtherapeutic concentrations . Thus , subtherapeutic use of pen ic il l in , the tetracycl ines , and other ant imicrobials in animal feeds --wh ich accounts for some 4 0% of antimicrob ial production in the United States-­ constitutes a s i z able seqment of the total antimicrobial selective pressure ( for res istant enteric microorqanisms ) exerted on the combined human and farm-animal intestinal bacterial populations . o Interpretation of the results in Great Brita in a fter banninq the subtherapeutic use of penici l l in and the tetracycl ines in animal feed is d i f ficult , in part because total farm use o f these antimicrobials miqht not have decreased because use could have taken the form of therapeutic or prophylactic doses in feed for disease treatment or prevention as prescribed by a veterinarian . The appearance of new epidemic stra ins of ant imicrobial -resistant salmonella serotypes durinq the period of interd iction of subtherapeutic use further confounds interpretation . It miqht take years for d ilution of antimicrobial -res i stant stra ins of Salmonella and � � in the farm animal population be fore any substantial chanqes miqht be observable .

2 00 RISK ANALYSIS o The committee has been unable to f ind substantial direct evidence that bacterial res istance resulting from the use o f subtherapeutic concentrations of penici l l in or the tetracycl ines in animal feed causes an excess risk to human health as a result of consumption of food products derived from the treated an imals , as a result of contact with such animals , or as a result of exposure to an env ironment contaminated by res istant enteric bacteria from such an imals . Lacking this direct evidence , the committee turned to the tools of risk assessment to develop some quantitative estimate of the probable risk to human heal th associated with this form of the subtherapeutic use o f these antimicrobial s . o Use of penicil l in and the tetracycl ines in subtherapeutic concentrations in animal feed has led to increased antimicrobial res istance in foodborne commensal s and pathogens . The risk analys is i n thi s report focused only on human infection with salmonel la serotypes , because ava i lable data on other species were insuffic ient . The committee has not assessed the potential risk to human health associated with drug res istance in other gram-negat ive bac i l lary species (Campylobacter jei uni , Yersinia enterocolitica , and enterohemorrhagic � £Qli ) of animal origin , because the data on human cases are too l imited and because antimicrobial suscept ib il ity data on those bacteria are not routinely obta ined . o Because the committee ' s risk assessments are based on estimates us ing sparse data , these estimates should be interpreted and used with caution . Such estimates are best seen as scienti fic hypotheses about the possible extent of a problem . Th is does not mean that they are "hypothet ica l " in the weak sense of be ing speculative . Rather , they are hypotheses that are cons istent with a l l ava i l able informat ion and scient i f ic understanding , but they have not been tested by traditional scienti fic methods . Al l the est imates presented in this report should be viewed in that perspective . o Annual numbers of deaths from salmone l l o s i s attributable t o subtherapeutic uses of any antimicrobials for prophylaxis and growth promotion have been estimated . · The l ikel iest estimate is 7 0 deaths per year . o The l ikel iest estimate of mortal ity from salmonel los is attributable to subtherapeutic uses of penici l l in/ampicil l in andj or tetracycl ine for prophylaxis and growth promotion is 4 0 deaths per year . Caveat--these are not necessari ly " excess deaths , " but rather estimates of the

2 01 yearly mortal ity attributable to salmonellosis o f the indicated origin . The deaths might to some extent replace deaths ( in the same patients or others ) that occur from infections due to salmonellae susceptible to penici l l in/ ampici l l in and tetracycl ine i f subtherapeutic dosages of these antimicrobials had not been used in animal feed . Estimation of such " replacement" o f deaths is not poss ible with the evidence at hand . o The l ikel iest estimate o f mortal ity from salmonellosis attributable to subtherapeutic uses of any antimicrob ial for growth promotion only is 2 0 deaths per year . As in the preceding ( and fol l owing ) estimates , the caveat regarding " excess deaths " appl ies . o The l ikel iest estimate o f mortal ity from salmone l l osis attributable to subtherapeutic uses o f penicil l in/ampici l l in andj or tetracycl ine only for growth promotion is 1 5 deaths per year . o The l ikel iest estimate of mortal ity from salmonellosis in the " etiologic fraction " attributable to subtherapeutic uses of any antimicrobial for prophylaxis and growth promotion is 6 deaths per year . The " etiologic fraction " is the proportion of persons exposed to an antimicrobial-res i stant salmonel la stra in who are at increased risk o f i l lness by virtue of recent use of antimicrobial drugs for whatever reason . Therefore , such deaths can be cons idered as " excess deaths " ; i . e . , they would not occur if the in fecting salmonel l a strain were not ant imicrobial -res istant and i f its multipl ication were not promoted , presumably , by suppress ion of growth of the competing normal antimicrobial-susceptible normal f lora . In the same way , the number of foodborne pathogens ( inoculum s i z e ) needed to precipitate disease might have been decreased . Whether a s imilar e ffect can be produced by prior antimicrobial use in persons infected with antimicrobial ­ susceptible salmonel lae ( due to poss ible d i fferential ant imicrobial susceptibi l ity between susceptible salmonellae and normal components of the intestinal flora ) is unknown , and the committee has not been able to f ind data bearing on this question . o The l ikel iest estimate of mortal ity from salmonel losis in the " etiologic fraction " attributable to subtherapeutic uses of penici l l in/ ampic i l l in andjor tetracycl ine for prophylaxis and growth promotion is 6 deaths per year . o The l ikel iest estimate of mortal ity from salmonel l os i s in the " etiologic faction" attributable to

2 02 subtherapeutic uses of any antimicrobial only for growth promotion is 2 deaths per year . o The l ikel iest estimate of mortal ity from salmonellosis in the " etiologic fraction" attributable to subtherapeutic uses of penic i l l in/ampic i l l in and/or tetracycl ine only for growth promotion is 2 deaths per year . o Infections with antimicrobial -res istant strains o f Salmonella are more o ften fatal than infections with susceptible Salmonella . Therefore , the increased d i f f iculty o f providing e ffective therapy for human disease can be estimated . The increased d i f ficulty in providing e ffective treatment may be due to increased virulence of ant imicrobial­ res istant stra ins , to the presence of res istance to one o f the ant imicrobials ordinari ly used t o treat such infect ions when they are severe or when they occur in particularly vulnerable persons , or to some other factor . The l ikel iest estimate of mortal ity from salmone l l osis arising because of increased d i f ficulty of treatment attributable to subtherapeutic uses of any antimicrobial for prophylaxis and growth promotion is 4 0 deaths per year . o The l ikel iest estimate of mortal ity from salmonel losis aris ing because of increased d i f ficulty o f treatment attributable t o subtherapeut ic uses o f penic i l l in/ampici l l in and/ or tetracycl ine for prophylaxis and growth promotion is 2 0 deaths per year . o The l ikel iest estimate of mortal ity from salmonel losis aris ing because of increased d i f f iculty o f treatment attributable t o subtherapeutic uses o f any antimicrobial only for growth promotion is 8 deaths per year . o The l ikel iest estimate of mortal ity form salmonel l osis aris ing because of increased difficulty of treatment attributable to subtherapeutic uses of penici l l in/ ampici l l in and/or the tetracycl ines only for growth promotion is 8 deaths per year . o Evaluation of the foregoing estimates o f mortal ity from salmonel losis attributable to subtherapeutic uses of antimicrobials in animal feed requires cons iderat ion in a broader context . What possible bene fits accrue from such subtherapeutic use of antimicrobials in food product ion? Would human deaths from salmone l l os i s be reduced by the discontinuation of subtherapeutic use of penici l l in/ ampici l l in andjor the tetracycl ines? The committee ' s thesis is that , although some deaths due to antimicrobial -res i stant stra ins might be " replaced " by deaths due to suscept ible stra ins , the tota l number of deaths would decrease , however ,

203 this cannot now be proved . The committee o f fers no recommendat ions regarding pol icy-making because that was not part of its mandate .

XI RECOMMENDATIONS FOR FUTURE RESEARCH The committee offers no recommendations o f poss ible solut ions to risk manaqement of the overal l problem under cons ideration . It has directed its attention mostly to its charqe to review the human health consequences and the ri sk assoc iated with the use of penic i l l in and the tetracycl ines at subtherapeutic concentrations in animal feed . Recommendation of any action would be appropriate only a fter requlatory aqency review and we iqhinq of both the benef its and risks o f use of these antib iotics in subtherapeut ic dosaqes . The committee does , however , offer recommendations concerninq further investiqations that would be helpful in resolvinq the issue , which has been intensely debated for some 15-2 0 years . Many of the recommendations for study would remain appropriate whether current pol icies reqardinq subtherapeutic antimicrobial use rema in in e f fect or are chanqed by a requlatory aqency . In the former instance , the data obta ined would serve to strenqthen the informat ional underpinninq of risk estimation . In the latter instance , they would make it poss ible to compare data on the prevalence of antimicrobial res istance amonq enteric pathoqens and human health risks before and after institution o f any chanqe in approved antimicrobial use . STQDIES TO SUPPLEMJNT THE QATA 8ASE FOR RISK ANALYSIS The risk assessment performed by thi s committee used the best avai l able data rel ated to the six essential elements in its risk estimates : res istance of human salmonel l a isolates to antimicrobia ls , annual reports of cases of salmonellosis , death rates associated with antimicrobial-susceptibl e and antimicrobial -res istant stra ins , fraction of human salmonel losis deaths associated with stra ins o f farm oriqin , fraction o f antibiotic res istance in stra ins o f farm oriqin caused by subtherapeutic use of antimicrobials in anima l feed , and " etioloqic fract ion . " In compil inq its risk estimates the committee was l imited by the pauc ity of some types of data and the consequent need to extrapolate from the results of sma l l studies to the qloba l problem , by the fact that in some subj ects rel iable data were almost total ly lackinq and had to be substituted for with " best estimates , " 2 04

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