# Human Health Risks With the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed(1989)

## Chapter: THE ESTIMATION OF RISK

« Previous: THE RISK MODEL: OVERVIEW OF THE PROBLEM AND NEED FOR A MODEL
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Suggested Citation:"THE ESTIMATION OF RISK." 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:"THE ESTIMATION OF RISK." 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:"THE ESTIMATION OF RISK." 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:"THE ESTIMATION OF RISK." 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 153
Suggested Citation:"THE ESTIMATION OF RISK." 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 154
Suggested Citation:"THE ESTIMATION OF RISK." 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 155
Suggested Citation:"THE ESTIMATION OF RISK." 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 156
Suggested Citation:"THE ESTIMATION OF RISK." 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 157
Suggested Citation:"THE ESTIMATION OF RISK." 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 158
Suggested Citation:"THE ESTIMATION OF RISK." 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 159
Suggested Citation:"THE ESTIMATION OF RISK." 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 160
Suggested Citation:"THE ESTIMATION OF RISK." 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 161
Suggested Citation:"THE ESTIMATION OF RISK." 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 162
Suggested Citation:"THE ESTIMATION OF RISK." 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 163
Suggested Citation:"THE ESTIMATION OF RISK." 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 164
Suggested Citation:"THE ESTIMATION OF RISK." 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 165
Suggested Citation:"THE ESTIMATION OF RISK." 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 166
Suggested Citation:"THE ESTIMATION OF RISK." 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 167
Suggested Citation:"THE ESTIMATION OF RISK." 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 168
Suggested Citation:"THE ESTIMATION OF RISK." 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 169
Suggested Citation:"THE ESTIMATION OF RISK." 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 170
Suggested Citation:"THE ESTIMATION OF RISK." 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 171
Suggested Citation:"THE ESTIMATION OF RISK." 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.
×
Page 172
Suggested Citation:"THE ESTIMATION OF RISK." 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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150 ranges . We caution that such numerical estimates are incomplete descriptions of risk and should not be used without citation of the associated uncerta inties , many o f which can not be expressed quant itatively . METHOD OF RISK CALCULATION Chapter VI I expla ined the risk model , provided a view o f the uncertainties associated with each parameters used by the committee and presented the committee ' s l ow , mid-range , and h igh estimates of these parameters required by the model . The estimates of risk presented in this chapter are l im ited to infections with ant ibiotic-res istant stra ins ( due to subtherapeutic uses of ant ib iotics in anima l s ) of Salmone l l a ( other infectious bacteria have been mentioned , but risks are not calculated for them ) and further l imited to annual numbers o f deaths from these infections ( risk due to morbidity and from non-lethal cases were not calculated ) . Annual numbers of deaths are estimated by a stra ightÂ­ forward multipl ication of combinations of parameter est imates , as il lustrated for the mid-range estimates alone at the opening of Chapter VI I . The committee could not select a s ingle "best estimate" of any of the parameters for use in describing risk . Al l poss ible combinat ions of the parameters were thus used to produce a range of poss ibl e risks . The various combinations sel ected for estimating d i f ferent risks are described in the text to fol l ow . I n each case the complete set of possible ri sks for each combination was calculated , and the results were converted to percent iles and pl otted on graphs as cumulat ive distributions ( Figures VI I I - 1 through VI I I - 12 ) . The committee attaches some importance to the 5th , 5 0th ( median ) and 9 5th percentiles as descriptions of the whol e set of estimates . However , the 5th and 9 5th percent i l es are not to be interpreted as confidence l imits , because they do not reflect any underlying probab i l ity distribution . A given percentile s imply describes the fraction of risk est imates that fal l bel ow it . Thus , for example , if a spec i f ic risk i s based o n multipl ication of five d i f ferent parameters , and there are three d i f ferent estimates of each parameter ( l ow , mid , and high-range ) then there are 2 4 3 d i f ferent possib l e ï¿½ estimates of r i s k ( 3 ) . The l owest five percent of these 2 4 3 estimates fal l s bel ow the 5th percent i l e , etc . The committee bel ieves that it is unl ikely that all ( or nearly a l l ) of the l ow or high estimates hold s imultaneously . Thus , combinations of parameters that are all ( or nearly a l l ) low , or high , are highly implaus ibl e . This i s based , i n part , on the improbab i l ity of being cons i stently wrong in the same direction , and in part on the committee ' s attempt to set the l ow and high estimates at the bounds of general plausib i l ity .

1005\t ï¿½ ï¿½ 70% IJ u 600; ï¿½ ï¿½IJ 50% Ja:1 'a 40% ï¿½ ti; t-J 30% 20% 1 0% ï¿½ 0 200 400 600 800 Eatilna.t.ed death/year Figure VI I I - 1 . Estimates o f annual numbers o f deaths from subtherapeutic uses o f any antibiotic for both prophylaxis and growth promotion ( multipl ication of l ines 1 , 2 a , 3 b , 4 , s a o f Table VI I I - 1 ) .

ï¿½ï¿½ ï¿½ ï¿½ 70. â¢ u 60Sll ï¿½ j â¢ 5o. fl1 ï¿½ 40Sll â¢ ...... U'l "' 30Sll 20. 10. 0. 0 1 00 200 300 400 Eatbna.ted death/year Figure VI I I - 2 . Estimates o f annual numbers o f deaths from subtherapeutic uses o f pen ic i l l in/tetracycl ine for both prophylaxis and growth promot ion ( multipl icat ion of l ines 1 , 2 b , 3 c , 4 , 6 a of T ab l e VI I I - 1 ) .

ï¿½ï¿½ 90Sll 8<* 7ï¿½ â¢ u ï¿½ ï¿½ ï¿½ â¢ ï¿½ ï¿½ '8 "'* â¢ ..... 1.11 w 3()Sl; 2ï¿½ 1ï¿½ ï¿½ 0 1 00 200 300 400 Eatbna.ted death/year Figure VI I I - 3 . Estimates of annual numbers of deaths from subtherapeut ic uses of any antibiotic for growth promot ion only (multipl ication of l ines 1 , 2 a , 3 b , 4 , s b of Table VI I I - 1 ) .

ï¿½ï¿½ ï¿½ 80S\; 7ï¿½ â¢ u ï¿½ ï¿½ ï¿½â¢ 50% J!;l -a 40S\I ï¿½ ..... 1.11 ol:oo ï¿½ 2ï¿½ 1ï¿½ ï¿½ 0 40 80 120 160 200 240 280 320 Estimated death/year Figure VI I I - 4 . Estimates of annual numbers o f deaths from subtherapeutic uses of penici l l injtetracycl ine for growth promot ion only ( multipl ication of l ines 1 , 2 b , 3 Â° , 4 , 6 b o f T ab l e VI I I - 1 ) .

100. ï¿½ ï¿½ 7<* â¢ u 6<* ï¿½ j â¢ 5<* ï¿½ "8 ï¿½ ï¿½ ï¿½ U1 3<* 2<Mll 1ï¿½ <* 0 40 80 120 160 200 Eatbnated death/year Figure VII I - 5 . Est imates of annual numbers of deaths in the etiologic fraction attributable to subtherapeutic use o f any antibiotic for both prophylaxis and growth promotion (multipl ication o f l ines 1 , 7 , 3 b , 4 , s a of Table VI I I - 1 ) .

100S\I 90\ll ï¿½ 7<* ID 6<* u +I ï¿½ s - 5<* +I ID IJ;1 ï¿½ 4<* ..... U1 0\ 30ï¿½ 2<* 1<* <* 0 4-0 80 1 20 160 200 Eatiln.ated death/year Figure VI I I - 6 . Est imates of annual numbers of deaths in the etiologic fraction attributable to subtherapeutic uses of penicill in /tetracycl ine for both prophylaxis and growth promot ion ( multip l icatio n o f l ines 1 , 7 , J c , 4 , 6 a of Table VI I I - 1 ) .

100ï¿½ ï¿½ 80ï¿½ 70ï¿½ l'l v .,J 60Sli d a ... .,J 50Sli Ill rz1 'M 0 40Sli ï¿½ .... U1 -..J 30ï¿½ 20ï¿½ l<>sli OSli 0 20 40 60 80 100 1 20 Eetilnated death/year Figure VI I I -7 . Estimates of annual numbers of deaths in the etiologic fraction attributable to subtherapeutic uses of any antibiotic for growth promotion only (multipl ication of l ines 1 , 7 , 3 b , 4 , s b of Table VI I I - 1 ) .

ï¿½ï¿½ 90ll ï¿½ 7ï¿½ Ill u 60ï¿½ +I Gl ï¿½ +I 50Sli II J-:1 '0 40loll ï¿½ .... U1 co 3ï¿½ 2ï¿½ Â·ï¿½ ï¿½ 0 20 40 60 80 100 1 20 140 Eetim.ated death/year Figure VI I I -8 . E st ima t e s o f annual numbers o f deaths in the et iologic fract ion attributabl e to subtherapeut ic uses of enic i l l injtetracycl ine for growth p romotio n only g (multipl ication of l i n es 1 , 7 , 3 Â° , 4 , 6 of Tabl e VI I I - 1 ) .

100. 9<* eo. 70. â¢ u 6o. ï¿½ ï¿½ â¢ so. ï¿½ '0 4o. ï¿½ ï¿½ \0 ao. 2o. 10. 0. 0 20 40 60 80 1 00 120 140 160 1 80 Estbna.ted death/year Figure VI II-9 . Estimates of annual numbers of deaths aris ing because of higher death rate and increased d i f ficulty of disease treatment attributable to subtherapeut ic uses of any ant ibiotic for both prophylaxis and growth promot ion (multipl icat ion of t imes 1 , 2 a , ( 3 b - 3 a ) , 4 , sa of Table VI I I - 1 ) .

1ï¿½ ï¿½ ao. 7ï¿½ â¢ u 60li ï¿½ j â¢ ï¿½ ï¿½ ï¿½ ï¿½ ï¿½ ...... 0\ 0 3ï¿½ 2ï¿½ 10S\i ï¿½ 0 20 .w 60 80 100 1 20 Eeti1118.te d death/year Figure VI I I - 1 0 . Estimates of annual numbers o f deaths aris ing because o f increased difficulty of disease treatment attributable to subtherapeutic uses o f penic i l l in/tetracycl ine for both prophylaxis and growth promotion (multipl ication of l ines 1 , 2 b , ( 3 c - 3 a ) , 4 , 6 a o f Ta b l e VI I I -1 ) .

1ï¿½ ï¿½ SOli 7ï¿½ â¢ u 60li ï¿½ ï¿½II ï¿½ r-:1 1M 0 Â·ï¿½ ï¿½ ..... 0\ ..... 3ï¿½ 2ï¿½ Â·ï¿½ ï¿½ 0 20 40 60 80 Eetiln.ated death/year Figure VI I I - 1 1 . Estimates of annual members of deaths aris ing because of increased d i f ficulty o f disease treatment attributable to subthera geutic uses of any ant ibiotic for growth promotion only ( multipl ication of l ines 1 , 2 a , ( 3 - J a ) , 4 , s b of Table VI I I - 1 ) .

1ï¿½ ï¿½ ï¿½ 70ll â¢ &I 60ll .., II ï¿½â¢ SOli Ja:1 'a 40ll ï¿½ ..... 0'\ t..) 30Sll 20ll lOll Oil 0 20 40 60 80 Eathnated death/year Figure VI I I - 1 2 . Estimates of annual numbers of deaths aris ing because of increased d i f f iculty o f disease treatment attributable to subtherapeutic uses of peni c i l l i n; t et racyc l ine f o r growth promot ion o n l y ( mult ipl icat ion o f l ines 1 , 2 b , ( J c - J a ) , 4 , 6 b o f Ta b l e VI I I - 1 ) .

163 The committee thus tends t o place greatest rel iance on estimates near the median value . ESTIMATION OF RISKS Chapter VI I , " The Risk Model " , provides the data on which the committee has based its estimates o f human health r i sk that may be assoc iated with the subtherapeut ic use o f antibiot ics in animal feed . Table VI I I - 1 gives the parameter estimates used in assess ing the whole o f the problem of exces s human salmone l l o s i s deaths that might be attributable to any low-level farm use of ant ib i ot ics . These estimates are taken d i rectly from the text and tables in Chapter VI I . Var ious combinat ion ' s o f these parameters are used to est imate d i fferent types of risk . Twelve d i fferent sets of r i sk est imates were produced from these data : these est imates are presented graph ical ly in F igures VI I I - 1 through VI I I - 1 2 , and are summari zed in Table VI I I -2 . The bas i s and meaning o f the twelve d i f ferent sets o f est imates that are shown in F igures VI I I - 1 through VI I I - 1 2 are described in the fol lowing text . MAXIMUM POS S I BLE NUMBERS OF EXCESS DEATHS F igure VI I I - 1 shows the cumulat ive d i stribut ion o f the 2 4 3 est imates o f annual deaths generated for drug res i stance of any type { Table VI I I - 1 , multipl icat ion of parameters from l ines 1 , 2 a , 3 b , 4 , s a ) . F igure VI I I -2 shows the corresponding d i stributions for res istance to penic i l l in andj or tetracycl ine spec i f ical ly { Table VI I I - 1 , mult ipl icat ion o f parameters from l ines 1 , 2 b , 3 c , 4 , 6 a ) . Est imates presented in Figures VI I I - 1 and VI I I -2 represent subtherapeut ic use of ant ib iot ics for both growth promot ion and prophylaxis . F igures VI I I - 3 and VI I I -4 are s imilar to F igures VI I I - 1 and VI I I - 2 except that the est imates are for farm use o f ant ibiotics for growth promot ion only , rather than for a l l subtherapeutic uses o n the farm . F igure VI I I - 3 descr ibes risks for use of any ant ibiotic and is based on mult ipl icat ion of l ines 1 , 2 a , 3 b , 4 , and s b of Table VI I I - 1 . F igure VI I I -4 descr ibes r isks for use of pen i c i l l in and tetracycl ine only and is based mult ipl icat ion of parameters from l ines 1 , 2 b , 3 c , 4 , and 6 b in Table VI I I - 1 . Readers are caut ioned that these are not necessarily " excess deaths " in the sense that the total number i s increased by the quant ity ind icated : they are rather est imates of the annual numbers of deaths attributable to salmonel los is of the spec i f ied origin . These may , to some extent , overlap or repl ace deaths { in these pat ients or

164 TABLE VI I I - 1 DATA USED TO ESTIMATE ANNUAL DEATHS FROM SUBTHERAPEUTI C USES O F ANTI BIOTICS IN ANIMAL FEED Estimates Low Mid-Banqe High 1) Reported S almone l l a per year 4 0 , 000 5 0 , 000 65 , 000 2) Re s i stance o f Salmone l l a to ant imicrobials a) Res istance to any antibiotic *0 . 16 0 . 24 0. 31 b) Res istance to penicil l in/ 0 . 10 0 . 15 0 . 20 tetracycl ine 3 ) Death Rate -- infection by strains a ) Not res istant to any antibiotic 0 . 002 0 . 005 0 . 01 * *b ) Res istant to any antibiotic 0 . 002 0 . 01 0 . 04 * *c ) Resistant to penici l l in/ 0 . 002 0 . 01 0 . 04 tetracycl ine 4 ) Fraction of those deaths 0.5 0.7 1.0 associated with strains of farm origin 5 ) Fraction of antibiotic res istance of farm origin caused by subtherapeutic use of any antib iotic in animal feed a ) Prophylaxis and growth promot ion 0 . 85 0 . 88 0 . 92 b) Growth promotion only 0 . 05 0 . 25 0 . 50 6) Fract ion of antibiot ic res istance caused by subtherapeut ic use of penic i l l in/tetracycl ine in animal feed a) Prophylaxis and growth promotion 0 . 86 0 . 90 0 . 94 b ) Growth promotion only 0 . 05 0 . 30 0 . 60 7 ) Etiologic Fract ion 0 . 005 0 . 02 0 . 09 Source : Table prepared by the committee . The bases for a l l estimates are provided i n Chapter VI I . Note : p e n icil l i n/ tet racycl i n e = p e n i c i l l in , amp icil l i n or t e tra cycl ines . * Deci ma l fract i on or pr opo rt i on . ** The c omm i tt e e could not find evidence su f f i c i ent to j ust i fy the use o f d i f ferent death rates for stra ins res istant to one drug rather than another , or for multire s i stant stra ins vs . strains res istant to only one drug .

165 TABLE VI I I -2 SUMMARY OF THE VARIOUS ESTIMATES OF ANNUAL NUMBERS OF DEATHS FROM SUBTHERAPEUTI C USES OF ANTIBIOTICS Sgyrce of Etti11te1 lett Ettllltt' ï¿½ <meslien> F i gure Â¥1 1 1 Â· 1: 70 5 Â· 700 F i gure Â¥1 1 1 Â·2 40 1 Â· 400 F i gure Â¥1 1 1 Â·3 ; 20 1 Â· 400 F i gure Â¥1 1 1 Â·4 15 1 Â· 300 F i gure V l l l Â·5ï¿½ 06 1 - 200 F i gure Vl l l -6 06 1 Â· 200 F i gure VI I I Â· 7f 02 0 Â· 1 00 F i gure Yi l t -aJ 02 0 Â· 1 00 F i gure Vl l l Â·9k 40 3 Â· 200 F i gure Vl l l Â· 10l 20 2 Â· 1 00 F i gure Vl l l Â· 1 1â¢ oa 1 Â· 1 00 F i gure vr r r - 1 2 n oa 1 Â· 1 00 source : Adapt ed by t h e com. i t t ee f rï¿½ T eb l e V I J I - 1 end F i gure! Â¥ 1 1 1 Â· 1 th rough Â¥ 1 1 1 Â· 1 2 . e SOl of ett i ., t et f e l l be l ow t h i t f i gure ( rounded t o one t f gn i f i cent f i gu r e ) . b 51 of ett i ., tet f e l l be l ow l ower end of the renee; 951 of ett i .. t et f e l l be l ow upper end . E t t i ., t et of ennue l nu.btrt of dee t h t : c f ro. tubtherepeut i c utet of eny a s t i b i ot i c for both prophy l ex i t and g rowt h pro.ot f on ( .u l t i p l i ce t i on of l i net 1 , 2 , 3 , 4 , 5 8 of T eb l e Â¥ 1 1 1 â¢ 1 ) . a d f ro. !Ubt herapeut i c Ute! Of pen i c i l l i n/ï¿½e t r acyc l i ne for both prophy l tX i l end g rOWt h pro.ot f on ( .u l t i p l i ca t i on of l i net 1 , 2 , 3 , 4 , 68 of T eb l e V l l l - 1 ) . c 8 f ro. tubthere ï¿½ t f c u&eâ¢ of eny ent i b f ot i c for g rowth pro.ot i on on l y ( .U l t i p l i ce t i on of l i ne! 1 , 2 8 , 3 , 4, 5 of T ab l e V I J J Â· 1 ) . f f ro. tubthertptUt i C Ute! Of esn i c i l l i n/ t st rtcyc l i nt for g rowth pro.ot i on on l y c ( .u l t i p l f ce t f on o f l f net 1 , 2 , 3 , 4 , 6 o f Teb l e Â¥ 1 1 1 Â· 1 ) . I i n the et f o l og f c f r ec t f on e t t r i but eb l e to tubtherapeut f c ute of 'BY ent f b i o t i c for both prophy l ex i t end growth pro.ot f on ( .u l t i p l i cat f on of l i net 1 , 7 , 3 , 4, s â¢ of T eb l e Y l l l - 1 ) . h f n the et i o l og i c f ract i on e t t r f but ebl e to tubtherepeut i c Ultl of pen i c i l l i n /tet recyc l i ne for both prophy l ex f t end g rowth pro.ot i on ( .u l t f pl f cet i on of l i nt! 1 , 7, 3 , 4 , 68 of T eb l e c Â¥1 1 1 Â· 1 ) . i n the et f o l og f c f re c t l on e t t r f but eb l e to tubth B rapeut &c utet o f eny ent f bf ot f c f o r grow t h pro.ot f on on l y ( .u l t f p l f c at i on of l i neâ¢ 1 , 7 , 3 , 4 , 5 o f T e b l e V l l l Â· 1 ) . f n t h e et f o l og f c f ract i on a t t r l bu t eb l e t o tubtherepeut i c utet of pen i c i l l i n/ t e t r ecyc l f ne f o r growth pro.ot i on on l y ( .u l t f p l i ce t f on of l i nt! 1 , 7 , 3 , 4 , 6 of T e b l e Y l l l â¢ 1 ) . c b k e r i t f ng beceute of h i gh e r dee th rete end l nc reeted d i f f i cu l ty of d i teate t re e t â¢ent a t t r f but e b l e to tubtherepeut i c utea of eny a s t i bf ot i c for bo t h prophy l ex f a and growth pro.ot i on ( .U l t i p l f c e t f on of t f .,a 1 , 2 8 â¢ ( 3 Â· 38 ) , 4, 5 8 of T tb l e V l l l Â· 1 ) . e r f a f ng because of f nc r eeatd d i f f i cu l ty o f d i aeeae t r ea t.,nt e t t r i bu t eb l e to aubt herepeu t l c uses of peG i c f l l i n/ t e t recyc l f ne for bot h prophy l ex f a end g rowth pro.ot f on ( .u l t f p l i c a t i on o f l f nea 1 , 2 , ( 3 - 3 ) , 4 , 68 o f T ab l e Y l l l - 1 ) . c a . â¢ e r i a i ng beceuae of I nc reased d i f f i cu l t y of d f aeaae t reat.,nt e t t r l bu t ab l e t o a ubt he ï¿½ apeut l c u&eâ¢ of eny ent i b i ot i c for g rowth promo t i on on l y ( .u l t f p l i c e t l on of l i nea 1 , 2 , ( 3 - e 3a ) , 4 , 5 of T eb l e V I I I - 1 ) . " E a t l .. tea o f annue l nu.btra o f dee tha e r l a i ng because Â·of f nc r eeaed d i f f i cu l t y o f d i sease t rea t.,nt e t t r i bu t eb l e to a ubt h e r a peut i c use & of ï¿½ n i c f'l l i n/ ,et recyc l i ne f o r g rowt h proï¿½t f on on l y ( .u l t f p l i ce t i on of l i nea 1 , 2 , (3 Â· 3 1 ) , 4 , 6 of T e b l e V I J I - 1 ) .

166 others ) from salmonellosis that would have occurred anyway with some other strain . Conversely , it is possible that these estimates underest imate the real number of excess deaths i f , for example , res istant strains tend to be more virulent than drug-susceptible stra ins , or i f the estimates in success ive l ines of Table VII I - 1 are not independent , ( see Chapter VI I regarding independence ) . ESTIMAtES OF DEAtH 8ASED ON ETIOLQGIC FRACTION As expla ined above , the est imates for deaths from all Salmonella strains with drug resistance attributable to l ow-level farm uses of antibiotics are not necessarily estimates o f the excess number of salmone l l os i s deaths from such use . A fraction of the excess can , however , be estimated--the " etiologic fraction" discussed in this sect ion and the death o f farm origin " harder-to-treat fraction di scuss ion in the fol l owing section . These two fractions may overlap ( e . g . , f igures for the etiologic fraction may ref lect some increase in the difficulty in providing effective treatment ) and , further , these two fractions do not necessarily account for the whole e f fect of farm use o f subtherapeutic leve l s of antibiotics ( e . g . there may b e a d i fference in virulence ) . Estimates for deaths attributable to the etiologic fraction--that is , cases o f salmonel losis that would s imply not have occurred in the absence o f res istance--requi re some modi f ication in approach . Parameter estimates are given in Table VII I - 1 . The odds ratios in Table VI I-7 are cal culated for the whol e population of exposed persons ; of these , some proport ion harbor res istant stra ins . The estimated odds ratios would be larger--perhaps substantially larger-- i f they were calculated to express the risk in persons who harbor such res istant stra ins . Use of the odds rat ios in Table V I I - 7 , therefore , a lready incorporate a reducat ion factor to express the risk in the population as a whole . Furthermore , thi s automatical ly reflects the actual proportion o f persons who have res istant stra ins ( perhaps in addition to susceptible stra ins ) and does not depend on the kind o f estimate in l ine 2 of Table VI I I - 1 , which dea l s with proport ions o f stra ins rather than with the whole set o f res istant stra ins that may inhab it one person . Thi s approach ignores the l ikel ihood that persons within fami l ies , within hosp ital wards , or otherwise in proximity may tend to carry the same stra ins of salmonel lae , but no data on thi s seems to be ava i l able for use here . Because of the frequency distribution of res i stant stra ins al ready incorporated into the odds ratios ( l ine 7 ) , no further adj ustment for res istance ( l ine 2 ) is needed or appropriate .

167 Perhaps future research studies can estimate odds ratios for the " etiologic fraction" of cases among persons who are hosts to one or more res istant stra ins . The odds ratios are l ikely to be substantial ly higher , but wi l l be reduced by the ( then appropriate ) inclus ion of such factors as those in l ine 2 . Unt i l thi s kind of additional information i s ava i l able , we bel ieve that our present analytic approach to the etiologic fraction is correct . In addition , the committee is concerned that death rates in the " etiologic fraction" : ( see l ine 3 ) may be above average , because some persons who rece ive antibiotics do so because of conditions related to immunosuppress i on , general debi l ity , or other i l l nesses that may damage normal body defenses . In the absence of data , however , the committee has chosen to apply the death rates in l ine 3 o f Table VII I - 1 to the " etiologic fract ion" . Two sets of estimates are presented for the " et iologic fraction" component of salmonel losis . F igure VI I I - 5 presents the 2 4 3 estimates for deaths in the etiologic fraction attributable to subtherapeutic farm use o f any ant ibiotic for both prophylaxis and growth promotion (mul t ip l ication of parameter in l ines 1 , 7 , 3 b , 4 , s a , of Table VI I I - 1 ) , and Figure VI I I - 6 presents s imilar estimates for penici l l in/amp i c i l l in andjor tetracycl ines uses only ( multip l ication of parameters in l ines 1 , 7 , 3 c , 4 , and s b o f Table VI I I - 1 ) . Figures VI I I -7 and VI I I -8 present s imi l ar estimates for growth promotion alone : Figure VI I I -7 concerns farm use of any antibiotic and Figure VI I I -8 concerns uses of pen ic i l l in/ampic i l l in and/or tetracycl ines only . EXCES S DEATHS DUE TO INCBEASED DIFFICULTY OF TREATMENT While few or no strains of sa lmonel lae are res istant to all cl inica l ly useful ant imicrobials in the modern therapeutic armamentarium , some individual drugs are potentially toxic , have unwanted e ffects in part icul ar groups of patients , may requi re parental administration , and some are very expens ive . Further , critical t ime i s required to determine patterns of res istance of bacterial isolates in spec i f i c infections . Thus , it would be medica l l y inappropriate , t o treat each suspected case of salmonel losis with the whole combination of antimicrobials that could conceivably be e f fective . More selective therapy is med ical ly appropriate , but it has the unfortunate e ffect in some cases of delaying or replacing treatment by the opt imum drug or drug comb inat ion , and as a result death rates may be higher in salmonellosis with res istant stra ins than with susceptible stra ins . Whatever the reason ( s ) , it has been commonly observed that infections with res istant stra ins of salmonellae more often end in death than infect ions with susceptible stra ins ,

168 suggested by l ines 3 a , 3 b , and 3 c of Table VI I I - 1 . The d i fference between these l ines can be interpreted as an index of the increased difficulty of providing effect ive therapy in cases of res istant salmonel losis . Because the est imates in l ines 3 a , and 3 b and 3 c are so cl osely l inked , the committee s imply worked with the three d i fferences ( at l ow , mid-range , and high level s ) rather than the 9 poss ible comb inations . Estimates of the s i z e of thi s effect for a l l subtherapeutic uses of any ant ibiotic are presented i n Figure VI I I -9 (mult ipl ication and parameters in l ines 1 , 2 a , ( 3 b - 3 a ) , 4 and s a , Table VI I I -1 ) and s imilarly in Figure VI I I - 1 0 for res istance to penic i l l in/ ampici l l in and/ or tetracycl ine antibiotics ( l ines 1 , 2 b ( 3 c -3 a ) , 4 , 6 a ) . S imilar figures , but l imited to drug use for growth promot ion , are given in F igure VI I I - 1 1 ( l ines 1 , 2 a , ( 3 b - 3 a ) , 4 s b ) for any drug res istance and F igure VI I I - 1 2 ( l ines 1 , 2 6 , ( 3 c -3 a ) , 4 , 6 b ) for peni c i l l in or tetracycl ine res istance . SUMMABY OF NQMERIC BESULTS Each o f the figures in this chapter presents a range of r isks , reported as annual numbers o f deaths . This procedure was used because the committee had no bas is for selecting any s ingle " best " est imate . This procedure produces , for the data in each f igure , a total of 2 4 3 estimates . The committee bel ieves that the best s ingle est imator is the median of the 2 4 3 estimates , and that the range from the 5th to 9 5th percentile is quite l ikely to contain the unknown true value . Because o f the way these estimates were devel oped they do not prov ide ordinary statistical confidence l imits ( as explained above ) , but they should in pract ice provide even greater certa inty than , say , 9 0 % or 9 5 % confidence l imits . The committee bel ieves that the minimum and maximum est imates presented in the f igures are not scient i f ical ly p l ausible because they would require that the mid-range estimates for the parameters ( Table VI I I - 1 ) a l l be cons istently or nearly consistently wrong by a large margin and all be in the same direction . Figures are presented to one decimal to emphas i ze that they are estimates , not counts . Data from the twelve figures are summa ri zed in Table VI I I -2 . The fol lowing is an i l lustration of how the f igures and data in Table VI I I - 1 are to be read : Figure VIII-1 . Est imates of annual numbers of deaths from subtherapeut ic uses of any ant ibiotic for both prophylaxis and growth promot ion . Figure VI I I - 1 is read as fol lows :

169 ( i) F ive percent of the estimates fal l below 5 to 6 deaths per year , and 9 5 % fal l below 7 0 0 deaths per yea r . Thus , the committee bel ieves that the true number is very l ikely to be between 5 and 7 0 0 deaths per year . ( i i ) The l ikel iest estimate is 7 0 deaths per year . Thi s i s the committee ' s best s ingle estimate for mortal ity in this category . The estimates in Table VI I I - 2 are derived from Figures VI I I - 1 through VI I I - 1 2 , and each range is based on d i fferent assumption ' s regarding uses ( e . g . , any ant ibiotic vs . penic i l l in/ampici l l in and , or tetracycl ines only , on prophylaxis and growth promotion uses vs . growth promotion only ) . The ranges a l so d i f fer with regard to other assumpt ions ( e . g . , inclus ion of " et iologic fract ion" , cons iderat ion of increased d i f f iculty of treatment ) . The spec i f ic meaning of each set of estimates i s indicated by the F igure headings , that are reproduce at the foot of thi s table . INTERPRETATION OF BESULTS The various estimates of risk presented in Table VII I -2 are based on somewhat d i fferent assumpt ions and have d i f ferent meanings , as indicated in the foregoing text and as summarized in the Figure headings ï¿½ For each set of estimates the committee p laces greatest rel iance upon the 5 0th percent i l e figure , which has been termed the " l ike l iest est imate " in Table VI I I -2 . The range shown in Table VI I I - 2 almost certa inly encompasses the true figures . The committee i s not able to ass ign a numerical probabi l ity to the l ikel ihood that the estimates shown are correct . As noted ea r l i e r , none o f the se e s t ima t e s h a s been veri f i ed by trad i t i on a l s c ient i f ic methodo l og i e s ( i . e . , exper iment a l o r we l l - c ontro l l ed f i e l d stud i e s ) , and thu s shou l d be i nterpreted as s c i ent i f i c hypothes e s about the pos s ib l e extent o f the prob l em that a re cons i stent w i th a l l ava i l ab l e s c i e nt i f i c i n f o rmat i on . The comm ittee knows o f no d i rect ev idence t o support the se est imate s . They shou l d be con s i dered as hav i ng s c i ent i f i c support rough l y comp a rab l e to that ava i l able for est imates of l ow dose carcinogen ic risk associated with chemical carcinogens subj ect to regul at ion . The est imates of death presented in Table VI I I - 1 can be placed in the context of other types o f risk est imates . FDA , f or example , general ly holds that , for carc inogenic drugs used in anima l s that l eave toxic food res idues , l i fet ime risks of cancer ( presumed to be equ ivalent to l i fetime r isks of death ) , of around 1 0 -6 or less are of ins ign i f icant pub l i c

170 Â· health consequence . Using thi s yardstick , and assuming the enti re populat i on of the United States to be potentially exposed to such res idues , the numbers o f excess annual cancers ( i . e . , deaths ) , a ssuming the risk to be accurately known , can be estimated for one such drug as fol l ows : 2 4 0 x 1 0 6 persons x 1 0 -6 = 2 4 0 l i fetime deaths , or = 3 - 4 deaths per year . The total number of deaths due to carcinogenic res idues depends on the number of such drugs in use . Actual numbers of deaths are probably much l ower than these f igures indicate , because actual res idue level s rarely approach the maximum a l l owabl e and because it is unl ikely that most o f the populat ion i s exposed to these drugs on a cont inuing bas i s . Moreover , the risk estimat ion method used for carc inogens is des igned to overstate risk . That i s , the procedures used to est imate excess cancer risk include adoption o f upper 9 5 % con f idence l imits on the dose-response curve and several other assumpt ions about interspecies and high-to-l ow dose extrapolation that almost guarantee that the actual numbers of deaths w i l l be l ess than those shown above . In fact , actual risk may be zero . The above f igures are helpful nonetheless , because they reflect the hypothetical number o f excess deaths that might be cons idered of negl igible pub l i c health consequences . The estimates o f annual numbers o f excess deaths presented in Table VI I I - 1 are derived by a method that is not strictly comparable to that used by FDA for carcinogenic drug residues , so care must be taken in comparing these two sources of risk . However , no better bas i s for comparison is known to the committee , and , with the appropriate qua l i f icat ions , the drug-res idue cancer risks , apparently cons idered acceptable by FDA , do prov ide a moderately useful yardstick aga inst which the r isks in F igure VI I I - 1 can be measured . Moreover , the committee does not mean to suggest that the r isks cons idered acceptabl e by FDA for carc inogenic an imal drug res idues are necessarily appl icable to the determinat ion of acceptab i l ity of the risks that are the subj ect of this report . Whether the ri sks presented in Table VI I I - 1 are to be cons idered acceptable or unacceptable depends on many factors that fal l outs ide the scope of the committee ' s charge . Such determinat ions of acceptabi l ity are risk-management decis ions and thus are properly l e ft to FDA .

17 1 EFFECTS OF DISCQNTINQATI ON Wil l the number of deaths from salmonel losi s and its compl ications be reduced or otherwise altered by the discont inuati on of the use of the subtherapeutic doses of antib iot i cs in farm animals , or by discontinuation of use speci fically for growth promotion? The committee , in the discuss ion that fol low below , is incl ined to think that the total number of deaths due to salmone l losis would decl ine . However , these matters are not at present subj ect to scient i f ic proof . The committee did not deal with the convers ion o f drugÂ­ susceptible bacterial organisms to drug-res istant clones ( by plasmid trans fer ) in s itu , but with the reduction in numbers of bacteria of drug-susceptible stra ins and the subsequent overgrowth with the more drug-resistant strains to f i l l the vacated ecologic niche . In thi s context , it may be useful to consider a s impl e diagram with two circles , one with deaths at some future t ime i f no discontinuation of antibiotics i s instituted , and one i f discontinuation has been put in pl ace as fol l ows : Deaths under D ea t h s i f aubt h e repe u t i c present po l i c i es , --+-- uses e r e banned bu t no t under a ben D ea t h s that wi l l occur e i t h e r way A ban then , would remove deaths in the left-hand lunule in thi s figure and replace them with by deaths in the r ightÂ­ hand lunule . The committee might pose the quest ion about whether thi s shi ft is worth making . The committee has not attempted any risk-management pol icy analys i s ( it was not part of the committee ' s mandate ) , but bel ieves that the fol lowing comments are within its mandate . The l eft-hand lunule a lone is approximated , for various facets of the prob l em , by Figures VI I I - 1 through VI I I - 6 , and certa in aspects of the net d i f ference of the l eft-hand minus the right-hand lunule ( the best benefits of discontinuation o f antibiotics ) should b e approximated by F igures VI I I -7 through VI I I - 1 2 . The committee bel ieves that overal l there would be a net bene fit in reduced mortal ity ( thus , the right lunule might be sma l l er than the left ) , but th is cannot be proved with mathematical certainty , nor can the s i z e of the net bene fit be estimated with precis ion . Crit ical to cons iderat ion o f a ban is the l ikel ihood of a l ong-term reduction in the proportion of salmone l l a stra ins

172 with resi stance t o ant ibiotics . The genie is out of the bottle ; wil l it return? Res istant stra ins appear to have no survival advantage in the absence of cha l lenge by ant ib iotics ( otherwise they would have driven out susceptible strai ns long before the modern era ) , but there is l ittle evidence that they have a survival disadvantage either . Further , other uses of antibiotics wil l continue including therapy of infect ions in both humans and animals , and compl iance with a ban on subtherapeutic uses might be incomplete . Thus , it may be that a ban would retard the increase in proportion o f res istant stra ins , but not stop o r reverse the increase . BEFEBENCES 1. National Research Counc i l , Committee on the I nstitutional Means for Assessment of Risks to Publ ic Health . Risk Assessment in the Federal Government : Managing the Process . washington , D . C . : Nat ional Academy Press , 1 9 8 3 .

IX DIScuSSION The use of tetracycl ine and penic i l l in in subtherapeut ic concentrations in anima l and poultry feeds has aroused concerns about the poss ibi l ity of a risk to human health . There are good reasons for concern : the known properties o f trans ferable res i stance plasmids and transposons among bacteria , the powerful action of antimicrobial drugs in selecting for antimicrobial -resistant bacteria , and the high level s of antimicrobial res istance found in ï¿½ ï¿½ and salmone l l a i sol ates from farm animals and humans . In addit ion , it i s now poss ible t o detect clona l ly salmone l l a stra ins from various sources i n the food production cha in ( from farm to consumer) and so establ ish l inkages between isolates from humans and from farm anima l s ( or animal food products ) . Th is report dea l s ma inly with the magnitude of the human health hazard and with whether suf ficient data are ava i l able to assess the risk . There is no direct evidence to quanti fy the human health hazard from antibiot ic-res i stant pathogenic bacteria created by the use o f subtherapeutic amounts of pen ic i l l in or the tetracycl ines in animal feed . Us ing the ava i l able ind i rect evidence shows these ant ibiot ics in subtherapeutic concentrations do present a haz ard to human health and may contribute to a percentage ( see F igure VI I - 2 ) of the approximately 5 0 0 deaths annual ly in the United States from salmonel l os i s . Although the focus in the analys i s of risk has been only on deaths attributed to salmonel l os i s , there are the same concerns about risk due to ï¿½ Â£Qli ( and other Enterobacteriaceae ) and to other pathogens ( both gramÂ­ negative and gram-positive ) known to be drug res istant that might infect both anima l s and humans . Human exposure to enteric organisms ( pathogens and commensal s ) of an imal origin is extens ive . In food-animal process ing plants , the inc idence of bacterial contamination has been reported as high as 3 4 % for chickens , 7 4 % for beef , and 8 4 % for pork . 1 0 Figures reported for comparable ï¿½ QQli contamination range from 7 3 % for beef carcasses , 8 1 % for chicken and 9 7 % for p ig carcasses . The ï¿½ Â£Qli contamination presumably is from feca l sources . I n studies from Great Brita in , 7 , 8 3 8 % o f ï¿½ QQli in cal f feces were res istant to one or more antimicrobial s , and other studies showed values of 4 9 % for pigs and 8 3 % for poultry . In the state o f Wash ington in surve i l l ance for enteric pathogens in a poultry process ing 17 3

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