No\wIlt,t~r l!I!IO FOOD SAFETY AND QUALITY FDA Surveys Not Adequate to Demonstrate Safety of Milk SUPPlY illllll~~lllll 142662 RELEASED RESTRICTED--Not to be released outside the General Accounting OlTlce unless epeclf’lcally approved by the Office of Congressional Relations. GAO/H( xn-9 1-N united states , GA!!!0 General Accounting Office Washington, DE. 20548 Resources, Community, and Economic Development Division B-241106 November 1,199O The Honorable Ted Weiss Chairman, Human Resourcesand Intergovernmental Relations Subcommittee Committee on Government Operations Houseof Representatives Dear Mr. Chairman: In your April 2,1990, letter, and in subsequentdiscussionswith your office, you asked us to review the adequacy of the surveys the Food and Drug Administration (FJ&Y) conducted in 1988 and 1990 to determine the presenceof selectedantibiotic drug residues in milk and whether the information developedprovided a sufficient basis for FDA’spublic state- ments on the safety of the milk supply. FI~Ais responsible for assuring the safety of the billions of gallons of milk produced in the United States each year, as well as numerous other food, drug, and cosmetic products. m overseesthe nation’s milk supply through a cooperative program with all states and the District of Columbia (states). Generally, the states carry out the day-to-day over- sight of the milk supply. FDAmonitors the overall cooperative program, provides technical assistance,approves animal drugs for use in dairy cows, and performs studies, takes samples,and does additional testing when agency officials believe it is needed. Concernedabout media reports that independent surveys had found a variety of animal drugs (primarily antibiotics) contaminating the milk supply, FDA conducted three efforts to determine the presenceof selectedantibiotic drug residues in milk between 1988 and 1990. These efforts were necessarybecause,except for penicillins, there is no routine testing required to screenmilk for such drugs, many of which are not approved for use in milk-producing dairy cows (dairy cows). FDA stated that the results of these three surveys confirmed its belief that the nation’s milk supply was safe. FDAstatements that the nation’s milk supply was not contaminated with Results in Brief unsafe animal drug residues cannot be supported becauselimitations in Y the survey methodologies precluded any overall conclusions.Specifi- tally, the surveys were not statistically valid and present, at best, “snapshots in time” of a small number of milk samplestested for the Page 1 GAO/RCED91-26Drug Jtesiduesin Milk E241106 presenceof a small number of drug residues.However, collectively, becausethe surveys show instancesof drug residues in milk, they sug- gest a need for more thorough examination by FDAto identify the types and amounts of animal drug residuesthat may be contaminating milk. Even if the surveys had been statistically valid, the results would still be of limited use becauseFDAdoesnot have test methods to detect and con- firm many drugs believed to be used in dairy cows. Generally, compa- nies submitting drugs to rn~ for approval for use in food-producing animals must develop tests to identify any residues left by the drug in edible tissues or milk. However, many of the drugs believed to be used by the dairy industry were not submitted to m for use in dairy cows, and the tests to detect their residues in milk have not been developed.In other cases,the test methods FDAhas are not sensitive enough to confirm the presenceof drug residues at the health concern levels set for human consumption. Our review, which was limited to FDA’smilk surveys conducted between 1988 and 1990, raised other questions about the adequacy of routine monitoring of the milk supply by FDAand cooperating state agencies, m’s “extra-label use” policy that permits the use of drugs not specifi- cally approved for dairy cows, and the setting of health concern levels for unapproved drugs. Under the Federal Food, Drug, and CosmeticAct (FFDCA), as amended, Background FVA,part of the US. Department of Health and Human Services(HHS), is responsible for ensuring the safety of the nation’s milk supply. The FIN’S milk safety program is a collaborative federal/state effort that dates back to the mid-1920s. Most milk is produced and marketed under the Grade A Pasteurized Milk Ordinance (the Milk Ordinance). The Milk Ordinance is recognizedby public health agencies,the milk industry, and many others as a national standard for milk sanitation. The only official test for detecting animal drugs in milk, under the Milk Ordinance, is the Bacillus Stearothermophilus Disk Assay test (disk assay). While the disk assay effectively detects the residues of several drugs in the penicillin family, it is much less effective in detecting many of the other drugs now being used by the dairy industry. For instance, the disk assay detects sulfa drugs at levels of 16 parts-per-million (ppm) or higher-l,600 times the 10 parts-per-billion (ppb)concern level set by a for milk. Somestates and industry groups supplement the disk assay with other tests that are more sensitive to sulfa and other drugs. F’I)A Page 2 GAO/ECED-Bl-26Drug Beeiduar in Milk . E!441106 itself doesnot routinely test milk samplesfor drug rosiduos but relies instead on the states and industry for such testing. However, according to FDAMilk Safety Branch officials, FQAdoesnot routinely receive state or industry test results. FDAis also responsible for determining whether new animal drugs, such as antibiotics, are safe and effective for those animals and whether the food products (including milk) from treated animals will be safe for human consumption. Generally, new animal drugs may be legally mar- keted in the United States only if FI%has determined that they are safe and effective and has established tolerances for their intended uses. A tolerance defines the amount of residues of a new animal drug from treated animals that is demonstrated to be safe in the human diet.1F+W also sets withdrawal periods for approved drugs during which time meat or milk products from the treated animal cannot be marketed. The intent is to allow the drug to be purged from the animal’s system so that any residues are below the tolerance level (see app. I for more informa- tion on how FDAestablishestolerances for drug residues in milk). Residuesof drugs, including antibiotics, can occur in milk as the result of legal or illegal use of drugs. FDAhas approved 63 drugs for use in or on dairy cows, including 20 antibiotic drugs. In addition, FDAhas estab- lished tolerances in milk for 21 of these 63 approved drugs. Generally, an illegal use occurs when a drug residue is found that exceedsits toler- ance level, when misuse of a drug approved for use in dairy cows results in residues in milk for which no tolerance has been established, or when residues of a drug not approved for use in dairy cows results in residues in milk. Actual or intended use of a new animal drug in a food-producing animal in a manner inconsistent with the approved labeling can result in FDA taking regulatory action against the veterinarian, producer, or other personsinvolved. However, FDAhas established guidelines for veterinar- ians to treat food-producing animals with drugs in an unapproved manner, if suffering and/or death would result from not treating the affected animal. %?dncemostof the drugs FDAtestedfor in its surveys are not approved for usein dairy cowsand have no official tolerancelevels,FDAset unofficial “concern1eveWfor usein the surveys.Generally, theseconcernlevels were estimatedon the bssisof tolerancelevels establishedfor the drugs in other animal speciesand tissues. Page 8 GAO/ltCED&24I Drug Iteddn~ in Milk , E241106 In establishing what is known as the extra-label use policy, FDA stated that it would ordinarily refrain from taking regulatory action against licensed veterinarians for using or prescribing any drugs they could legally obtain provided certain criteria are met. FW’Spolicy doesnot permit non-veterinarians (e*g.,dairymen) to treat food-producing ani- mals with drugs in an unapproved manner. In addition, FDA has declared that certain drugs cannot be used under the extra-label use policy becauseof public health concerns. Between 1988 and 1990, FDAconducted three efforts to determine the FDA Milk Survey presenceof selectedantibiotic drug residues in milk in responseto Methodologies and reports from the media and others that drugs were contaminating the Results milk supply. In March 1988, FDA tested a total of 49 retail milk samples from 10 cities in the United States to determine the presenceof sulfamethazine (SMZ), an antibiotic sulfa drug, in milk. SMZ is not approved for use in dairy cows, and its residues in milk may pose a risk for individuals allergic to sulfa-baseddrugs. SMZ is also a suspectedcar- cinogen (cancer-causingagent). FDAfound that 73 percent of the samples tested (36 of 49) contained SMZ levels ranging from 0.8 ppb to 40.3 ppb. Five of the 36 samplescontained SMZ residues above 10 ppb, FDA’sunoffi- cial concern level for SMZ at that time. Prompted by the 1988 survey results, FDAtook several steps intended to eliminate SMZ residues in milk, including an educational campaign aimed at dairy farmers. FDA coordinated this educational effort with the National Conferenceon Interstate Milk Shipments (the National Confer- ence).2In October 1988, the National Conferencesent a questionnaire to all state milk regulatory laboratories asking for data on raw milk sam- ples tested for SMZ from May to September 1988 to assessthe effective- nessof FDA’S educational program. FDA’sanalysis of this follow-up survey indicated that 6 percent of reported samplestested (247 out of 4,887) contained SMZ residues and 1 percent (64 out of 4,887) contained SMZ residues above 10 ppb.Basedon these results, FDAconcluded that SMZuse in dairy cows had decreased significantly since its 1988 survey and the SMZ problem had been resolved. ?he National Conferenceis a voluntary organizationof federal and statehealth and agricultural officials and the dairy industry that, alongwith FDA,overseesa cooperative,federal-stateprogram (the Interstate Milk ShippersProgram)to ensurethe sanitary quality of milk and milk products shippedinterstate. Page 4 GAO/ICED-91-26 Drug Residue6in Milk E!u1105 FDA’Sconclusion was subsequently questioned in December1989, when the Wall Street Journal (the Journal) reported the results of two surveys of animal drug residues in milk, one sponsoredby the Journal and the other sponsoredby the Center for Sciencein the Public Interest (CSPI), a consumer food safety and nutrition organization, The Journal survey found that 38 percent of 60 retail milk samplescontained antibiotic resi- dues, possibly including SMZand other unapproved drugs. The CSPI survey foundthat 20 percent of 20 retail milk samplescollected in the Washington, D.C., area contained sulfa drugs, again possibly including SMZand other unapproved drugs. Both surveys used an analytical method called “Charm II.” This method is considereda screeningtest becauseit reportedly detects the presenceof seven classesof antibiotic drug residues,but generally cannot identify individual drugs within these classes. In responseto media reports of contaminated milk, FDAconducted another survey in 1990 to test the reliability of the independent surveys and to determine for itself the presenceof animal drug residues in milk. FDAcollected 70 retail milk product samples3-5 each from 14 cities sampled in its 1988 survey and/or the Journal survey. FDAalso used the Charm II, as well ‘asother methods, to test the milk samples. FDA, as a matter of policy, requires further, more specific tests of all positive screeningtest results such as those obtained from Charm II to conclusively identify and confirm the presenceof the specific drug resi- dues present. These more specific tests include high pressure liquid chromatography (HPLC), thin layer chromatography, gas chromatog- raphy, and mass spectrometry test methods. FDAofficials consider the more costly and difficult mass spectrometry testing to be the most reli- able confirmation method for identifying specific drug residues for enforcement purposes. FDA’sresults using the Charm II test were similar to the results from the Journal and CSPIsurveys in that the presenceof antibiotic drug residues was indicated in many of the samplestested. In addition, the results of HPLc testing at FDA’S Beltsville laboratory indicated that almost 86 per- cent of the samplestested (60 of 70) contained sulfa drug residues and that 11 of the samples(16 percent) had residues above the concern levels for the drugs analyzed. However, upon subsequentconfirmation testing with mass spectrometry methods, FDAdid not find any of the 3FJMcollected2 identical containersfrom eachof 6 storesin 14 different cities and sentoneof each to its Beltsville and Philadelphia laboratories,respectively. Page 5 GAO/WED-91-26Drug Residuesin Milk . 5&(llW antibiotics it tested for above established health concern levels, or above the level of detection sensitivity of the methods used. FR.% initially reported, in a February 61990, press release,that it could not confirm the presenceof any antibiotics in the milk samplestested in the 1990 survey. However, FDA’spress releasewas premature because the agency had not completed its analysis of the milk samplesat the time it was issued.Upon subsequenttesting, FDAconfirmed the presence of SMZat levels less than 6 ppb in three milk samplestested. FDAlater modified its presentation of the 1990 survey results to report this finding. ~~4’sefforts and the independent surveys were basedon a limited FDA’s Survey Results number of milk samplesthat were not selectedin a manner that would Not Representative of allow drawing statistically valid conclusionsabout the overall milk the Nation’s Milk supply. At best, m’s efforts and the independent surveys were snap- shots in time of a small number of milk samplestested for the presence SUPPlY of a small number of drug residues. With specific regard to FIN’Sinitial 1988 survey and its 1990 effort, a total of 119 milk sampleswere tested-a very small percentageof the overall milk supply. In addition, the milk products and sampleswere not randomly selectedfor these surveys. FIIA’S1988 follow-up to its initial 1988 survey is not comparable and doesnot show that the SMZproblem initially found in its survey of 10 cities was corrected. First, the 23 states that respondedto the survey that tested milk samplesproduce only about 66 percent of the nation’s milk supply annually. More importantly, FDAcould not provide docu- mentation to show how the responding states had sampled milk prod- ucts. If the testing states did not use statistical methods to obtain sample data, then the resulting state and national data are highly suspect.FDA also did not know whether the analytical methods and calibration stan- dards used by the testing states to detect SMZresidues were similar or whether the methods used were all capable of detecting SMZ residues at the 10 ppb health concern level used by FDAat that time. We cannot state definitely that the SMZresults FIN developed from its 1988 follow-up effort are flawed. However, with a sample representing only 66 percent of the milk supply, no assurancesthat state samples were statistically drawn, and questions regarding the comparability of Page 6 GAO/ltCJD91-26 Drug Residuesin Milk E!241105 the testing performed, for the FDAestimates to be correct would likely be coincidence. In FDA’S1988 and 1990 survey efforts, only a limited number of drugs Limited Number of were tested in comparison to the total nymber of animal drugs that Drugs Tested might have been present in milk products. Approximately 78 drugs, approved and unapproved, are believed to be used in the dairy industry. During its surveys, FDAdid not test milk samplesto determine generally whether many of the 63 drugs approved for use in or on dairy cows were present, or for many of the approximately 26 drugs not approved for use in dairy cows but believed to be used in the dairy industry. In its 1988 survey and subsequentfollow-up effort, FDAonly tested for or collected information on one drug-SMZ. Also, while FDAused the Charm II test to screenthe 1990 survey samples for the presenceof sevenclassesof antibiotics, FDAonly had methods available to confirm the presenceof six of the antibiotics included in its survey. FDAhas also observedthat drugs used to treat dairy cows are to some extent chosenbecausetesting is not being performed to detect them, or the drugs cannot be detected by available test methods. Consequently, testing for a limited number of drug residues in sampled milk products doesnot provide information on the presenceof other drugs that might be in milk and may not provide sufficient information to support broad conclusionson the safety of the milk supply. m doesnot know what additional test methods states use to sample SomeDrugs Not milk or whether such tests can detect somedrugs at their concern level. Deteckd at Their For instance, regarding the 1988 follow-up survey, FDAdid not have Concern Level information on whether the 23 states that reported test results data used test methods sensitive enough to detect SMZresidues at the then 10 ppb concern level. Somestates may have used only the disk assay which is the only official screeningtest for detecting antibiotic drug residues in milk under the Milk Ordinance. While the disk assay is effective for detecting penicillins, it cannot detect many other antibiotics (including SMZ)at the concern levels established by FN Although FDAofficials believe that somestates had other test methods available to detect SMZ residues, they do not know what methods the states used. If the reported results were basedon the official disk assay method alone, then the results might have understated the number of samplescon- taining SMZabove the FLNconcern level. Page7 GAO/RCED-Bl-26Ihag lteoiduer in MU . B!241106 In addition, someof the analytical methods used in FDA’s1990 survey efforts were unable to detect and/or confirm somedrug residues at con- cern levels. For example, FDAdiscounted Charm II screeningtest results which indicated the presenceof novobiocin residues in five of the sam- ples tested on the basis of another screeningtest method that was not as sensitive as the detection capability claimed for the Charm II. Further- more, this secondscreeningmethod could not detect novobiocin at the health concern level established by FDA. FIX also requires that survey screeningtest results indicating the pres- enceof illegal or unapproved drug residues be confirmed using mass spectrometry testing, to facilitate its ability to take regulatory action. However, in its 1990 survey, FDAonly had mass spectrometry methods for six drugs, and three of these methods were incapable of confirming the presenceof their drugs at the health concern levels established. Spe- cifically, three of the six drugs for which FDAhad confirmatory tests were chlortetracycline, oxytetracycline, and tetracycline. m-established concern levels for these three antibiotics were/are 30, 30, and 80 ppb, respectively. However, FDA's mass spectrometry methods could only confirm the presenceof these drugs at levels of 100 ppbor more. Thus, although FDAreported that it could not confirm the presence of any tetracycline drugs, the drugs may still have been present in amounts exceedingthe concern level, but below the level of the con- firming test’s sensitivity. Additional questions have been raised about FDA's handling of the milk samples and use of analytical procedures in its 1990 survey. These and other limitations are discussedfurther in appendix II. During this review, several related issueswere identified that we believe Other Concerns merit further study. However, they were beyond the scopeand time Relating to Drug available for completing this work. Specific issuesinclude the (1) ade- Residuesin Milk quacy of routine drug residue screeningin milk by m and the states, (2) impact of FDA’Sextra-label use policy as it relates to dairy cows, and (3) setting of unofficial concern levels for unapproved drugs basedon limited data. Routine Drug Residue Neither FDAnor the states routinely screenmilk for many of the drugs, Testing May Be”Inadequate approved or unapproved, that might be used by the dairy industry. With regard to antibiotic drugs, the only screeningtest officially sanc- tioned by the Milk Ordinance is effective primarily for detecting the Page 8 GAO/RCEDBl-26 Dnqj Residuesin Milk , B-241106 penicillin family of drugs, not the sulfa, tetracycline, or other drug fami- lies. FDAis also aware that the choice of unapproved drug used is often guided by the fact that regulators cannot detect or are not checking for that drug. For these reasonsFDAhad to undertake the surveys discussed in this report. Somestates, veterinarians, and industry organizations, concernedthat the Milk Ordinance’s official screeningtest for antibiotic drug residues is not effective in detecting drugs other than penicillins, have asked FDAto either develop reliable and inexpensive methods for their use or offi- cially sanction someof the commercial tests that somestates already use such as the Charm II method. However, according to the Deputy Director, Center for Veterinary Medicine, m doesnot have the legisla- tive authority to approve or sanction screeningtests that are not sub- mitted as part of a sponsor’sapplication for a new animal drug approval. According to FDAattorneys, screeningtest kits by themselvesare consid- ered animal devicesunder FFLXAand, as such, are not subject to pre- market review and approval by FDA.However, such kits are subject to post-marketing controls under the law. Thus, for example, the labeling of screeningtest kits must be truthful, accurate, non-misleading, and must bear adequate directions for use. FDAdoeshave the authority to evaluate commercially available screeningtest kits and publish the results of such evaluations. FDAplans to exercise its evaluation authority in order to assist the states and the dairy industry in determining/obtaining effective and reliable analytical methods for detecting animal drug residues in milk. Starting with sulfa drugs, FDAintends to collect information on commercially available screeningtests, conduct limited evaluations of such tests- including their capabilities to detect residues at or above the tolerance or other levels established by FDA,and make the results of these evalua- tions publicly available. Extra-Label Drug Use IQA’Sefforts to overseethe safety of the nation’s milk supply are com- Makes Oversight Difficult plicated by the use of drugs not specifically approved for use in dairy cows and the extra-label use policy that allows it. In brief, this policy allows veterinarians to use drugs in an unapproved manner on animals i if that animal’s life is in danger, and no other effective approved drugs are available. Page 9 GAO/WED-91-26Drug Residuesin Milk &241106 No illegal drug residues are supposedto result from the extra-label use of drugs in dairy cows. However, neither FDAnor drug companieshave performed the studies necessaryto establish the dosagelevels and with- drawal periods neededto ensure that illegal/unsafe residue levels do not result in milk from extra-label uses.The lack of such scientific data makes it difficult for veterinarians to determine and prescribe dosages and withdrawal times that will assureillegal residues do not occur. Another concern is that someof these drugs are available to the layman “over-the-counter,” As such, the veterinarian/client relationship on which the extra-label drug use policy is basedoften may not exist. FDAalso has not determined what “safe” milk residue levels are for many of the drugs used in extra-label dairy applications. Instead, FDA has set unofficial concern levels for a limited number of these drugs, primarily for the 1990 survey. FDA’sgeneral practice is to not take regu- latory action when residues are found at levels below the concern level. Many of the residues detected in FW’S1988 and 1990 milk surveys were from drugs not approved for use in dairy cows. Becauseof FDA’spolicy that allows the extra-label use of drugs by veterinarians and its general practice not to take action when drug residues are below the concern level, it is difficult to determine whether residues found in milk result from the improper use of drugs by veterinarians under the extra-label use policy or from illegal use by non-veterinarians. The Adequacy of Concern Many of the drugs tested for in FDA’S1990 survey are not approved for Levels Is Questionable use in dairy cows and there are no official tolerance levels established for their presencein milk. As a result, FIX conducted a health risk assessmentto determine unofficial drug residue concern levels for selecteddrugs targeted in its survey efforts. m estimated the concern levels for residues in milk on the basis of tolerances established for the drugs in other animal speciesor tissues or on other data. Questionsexist about (1) the reliability of setting levels in this manner, (2) how factors such as the aggregateand synergistic health effects of the drugs were handled, and (3) whether drug metabolites,* both individually and those of closely related drugs, should be included in assessinghealth effects. *Drug compoundsadministeredto food-producinganimalscan form or be brokendown into new substance8(metaboliteaand degradationproductsof the compound)by the animal’sbiologicalsy% tans, which can poset.oxic&gical concernsof their own. Therefore,the total residueof a drug pro- posedfor we in food-producinganimalsconsIstaof the parent drug and 1t.ametaboliteaand any other substanceformedin or on food becauseof the useof the parent compound. Page 10 GAO/RCJiXWl-28Drue Residueain Milk E241106 FDAregards allergic responsesto penicillin, tetracycline, and/or sulfa drugs as a serious public health concern.Studies conducted by FDA’s National Center for Toxicological Researchalso indicate that moderate- to-high dosesof the sulfa drug SMZ causethyroid cancer in somelabora- tory animals. In addition, FDAdata suggestthat if a structural feature in one compound is found to causecancer,the presenceof that samestruc- tural feature in other compoundsgreatly increasesthe probability that they too can causecancer.All of the sulfa drugs have very similar struc- tures. According to FDAdata, someof these drugs exhibit toxic effects similar to those produced by SMZ. In setting concern levels for the 1990 milk survey, however, FM allowed residues of up to 10 ppb for each sulfa drug and did not consider the aggregateor synergistic effect of these drugs. The results of FLW’S HPLC screeningtests for the 1990 survey indicated that 46 percent (32 out of 70) of the samplestested contained more than one sulfa drug residue. FDAdata also indicate that drug metabolite residues in food are an important consideration. FLMstates that the importance of any metabo- lite in terms of its level, persistence,structure, relationship to the parent drug, and the anticipated human exposure must be consideredin deciding about the need for separate toxicity testing. According to FM, drug metabolites are likely to present health risks which may be as important as residues from the parent drug becauseof their amount, persistence,or potential for toxicity. For example, according to FM data, the SMZ metabolite levels that develop in pork are 3 to 10 times higher than the detectable residue level of the parent drug. FDAsuspectsthat metabolites may also be present in milk when drug residues are found and is currently attempting to determine the amount of SMZ metabolites that may be “hidden” in milk. According to FDAdata, several of the metabolites that develop from this drug in milk may pre- sent carcinogenicrisks similar to those associatedwith SMZ itself. How- ever, metabolites could not be detected by the analytical methods FDA used in the milk surveys, and, as a result, the metabolite levels that might be found in milk were not considered. FDA’sefforts to determine the presenceof animal drug residues in milk, Conclusions as well as the independent surveys, were not statistically designedto be Y representative of the nation’s milk supply. Thus, the surveys do not pro- vide an adequate basis for the statements made by FDAregarding the nation’s milk supply. However, collectively, becausethe surveys show Page 11 GAO/ltCEWl-28 Drug Residuesln Milk 1 B-241105 instancesof drug residues in milk, they suggestthe need for more thor- ough examination to identify the types and amounts of animal drug resi- dues that may be present in milk. Furthermore, if FDA had designedand undertaken a statistically valid random sample of milk products to test for drug residues that was rep- resentative of the nation’s milk supply-a difficult and costly endeavor-the results would still be of limited value becauseFDAlacks test methods to detect and confirm most of the drugs believed to be used in dairy cows, and someof FDA’S test methods cannot detect drug resi- dues at the concern level set for human consumption. The only screeningmethod sanctioned by the Milk Ordinance for antibi- otic drug residues in milk, by itself, will not effectively detect most drugs currently used by the dairy industry. Somestates are supple- menting the Milk Ordinance’ssanctioned screeningtest with other com- mercially available methods that are reportedly capable of detecting more drug types. Although FDA may lack sufficient legislative authority to officially sanc- tion screeningtest methods that are not part of an application for new drug approval, FDA can exercise its authority to evaluate commercially available screeningtest kits and share the results of its evaluations with the states, industry, and others. Beginning with sulfa drugs, FIIAplans to assist the states and others by conducting these evaluations and pub- licizing the results. FDAhas also begun to develop new test methods capable of detecting and confirming specific drugs at established concern levels. However, there are many additional drugs, approved and unapproved, for which ade- quate tests do not exist. These and other limitations in testing capability detract from FDA’sability to ensure the safety of the milk supply. Finally, FDA’sregulatory efforts to ensure a safe milk supply are made more difficult by the extra-label use of drugs in an unapproved manner in dairy cows and by questions regarding the basis for setting unofficial concern levels and how to treat factors like the cumulative effect of closely related drugs and drug metabolites. Becauseof insufficient data to fully addressmany of the issuesdis- Recommendations cussedin this report, and recognizing that it is unlikely that FDA could Page 12 GAO/RCED-91-26Drug Residuesln Milk E241106 devote a large amount of its limited resourcesto this one issue,we rec- ommend that the Secretary, HHS,direct the Commissioner,FDA,to take several incremental actions to provide greater assurancethat the milk supply is safe. First, FDAshould,develop more complete information on the incidence of drug residues in milk. FDAshould begin by asking the states under their cooperative agreementsand the dairy industry to routinely provide them with the results of their screeningtests for drug residues in milk, as well as information regarding their sampling plan and the types and sensitivities of test methods employed. Second,to further assist state regulatory efforts, FDAshould work with the states to evaluate commercially available screeningtests and encouragethat those found effective for sulfa, tetracycline, and other drugs, be included in the Milk Ordinance as a supplement to the disk assay,which is primarily effective only for penicillins. If FDAdetermines that it needsadditional legislative authority to approve screeningtests apart from new drug applications, then it should seek such authority from the Congress. Third, m should prioritize and expedite its current efforts to develop and evaluate new screeningand confirmatory test methods for animal drug residues in milk, possibly according to the health risks they per- ceive to be associatedwith the individual drugs involved. Fourth, FDAshould work closely with the states to confirm, possibly on a random basis, the types and amounts of drug residues found in state screeningsamples.If this information and confirmatory testing indicates that potential problems exist, FDAshould work with the states to further expand testing. Last, if the additional information developed from increasedscreening and confirmatory testing indicates that widespread problems exist from the misuse of drugs approved and/or unapproved for use in dairy cows, m should reassessthe appropriateness of its policies on extra-label drug use and its use of concern levels as a trigger for regulatory action. w Our work was conducted from April to September 1990 at FDAheadquar- ters and field locations in the Washington, D.C., metropolitan area. (Fur- ther details on our objectives, scope,and methodology are provided in app. III.) Page 13 GAO/RCED-91-26Drug Residuesin Milk It-B11106 We discussedthe information in this report with officials in FLX’SCenter for Food Safety and Applied Nutrition, Center for Veterinary Medicine, and Office of Regulatory Affairs. Where appropriate, somechanges have been made basedon the discussionto further clarify the informa- tion presented. However, as requested by your office, we did not obtain official agency comments on a draft of this report. As arranged with your office, unless you publicly announceits contents earlier, we will make no further distribution of this report until 30 days after the date of this letter. At that time we will send copiesto the Sec- retary, HHS;the Commissioner,m; interested congressionalcommittees; and other interested parties upon request. This review was conducted under the direction of John W. Harman, Director, Food and Agriculture Issues,who may be reached at (202) 276 6138. Other major contributors are listed in appendix IV. Sincerely yours, /J J. Dexter Peach Assistant Comptroller General Page14 GAOjIKXXMl-28DrugResiduesin Milk Page 16 GAO/BcEIM)l-26 Drug lteddriea in MilL contents Letter 1 Appendix I Federal Regulation of Tolerance Setting Process Monitoring Milk Safety 18 18 24 Drug Residuesin the Milk Supply Appendix II 26 Results and 1988 Survey 1988 Follow-Up Survey 26 26 Limitations of FDA’s 1990 Survey 28 Efforts to Determine the Presenceof Antibiotic Drug Residuesin the Nation’s Milk Supply Appendix III 39 Objectives, Scope,and Methodology Appendix IV 40 Major Contributors to This Report Tables Table II. 1: FDA ScreeningResults for Drug Family 31 Residuesin the 1990 Milk Survey Using the Charm II Test Table 11.2:Initial FDA ScreeningResults for Sulfa Drug 32 Residuesin the 1990 Milk Survey Using HPLC Table 11,3:Tolerances/Levels of Concern for Selected 36 Antibiotic Drug Residuesin Milk and the Level of Detection for the Methods FDA Used in Its 1990 Survey (In Parts-Per-Billion) Page 16 GAO/RCED-Sl-28m Realdueain Milk Contenta -. Abbreviations ADI acceptabledaily intake CDC Centers for DiseaseControl CFSAN Center for Food Safety and Applied Nutrition, FDA CSPI Center for Sciencein the Public Interest CVM Center for Veterinary Medicine, FDA FDA Food and Drug Administration Federal Food, Drug, and CosmeticAct GAO General Accounting Office GAP Government Accountability Project HHS U.S. Department of Health and Human Services HPLC high pressure liquid chromatography ppb parts-per-billion wm parts-per-million SMZ sulfamethazine Page17 GAO/RCED-91-26Drug Residuesin Ml& Appendix I * Federal Regulationof Drug Residuesin the Milk Supply Under the Federal Food, Drug, and CosmeticAct (FFDCA), as amended (21 U.S.C.301 et seq.),the Food and Drug Administration @DA)is responsible for ensuring the safety and purity of the nation’s milk supply. In addition, FDA is required to determine whether new animal drugs for use in food-producing animals,1such as antibiotics for use in milk-producing dairy cows (dairy cows), are safe and effective for those animals and whether the edible products derived from treated animals, such as milk, will be safe for human consumption. Under FFDCA and FDA policy, food items containing unapproved animal drug residues that may be harmful to humans are consideredto be adulterated and subject to regulatory action. Generally, a new animal drug may be legally marketed in the United Tolerance Setting States only if FDA has determined that it is safe and effective and has Process established tolerances for its intended uses.A tolerance is a’legally binding limit that defines the amount of residuesof a new animal drug in edible tissue (or other edible products such as milk) from treated ani- mals that is demonstrated to be safe in the human diet. FM usestoxicology and residue data to assesspossible health risks of an animal drug residue in milk and determine the tolerance level that will protect the public health within a practical certainty. The risk of a drug residue dependson both the toxicity of animal drug residues(i.e., their potential to causeadversehealth effects in humans) and potential human exposure to residues in the diet. Sponsorsof new animal drugs must submit data to FDA that substanti- ates the safety and effectiveness of the proposed drug. The data must be specific for each use and speciesof animal for which the drug is intended and, for food-producing animals, must include evidence showing the safety of residues of the drug (including metabolites2) and acceptablemethods for recovering and measuring such residues from edible products. ‘Under FFDCA,new drugs are drugsthat are not generallyrecognizedby qualified experts assafe and effective for their labeleduses. ‘Drug compoundsadministeredto food-producinganimalscan form or breakdown into new sub- stances(metabolitesand degradationproductsof the compound)by the animal’sbiologicalsystems, which can posetoxicologicalconcernsof their own. Therefore,the t&al residueof a drug proposed for usein food-producinganimalsconsistsof the parent drug and its metabolitesand any other sub stanceformedin or on food becauseof the useof the parent compound. Page 16 GAO/RCED-91-26Drug Residuesin Milk Federal Regulation of DNg ltmidues in the =IJnPPlY FM’S risk assessmentprocessfor animal drug residues in milk has six steps: 1. Identifying the nature and amount of residues from the parent drug and its metabolites and the depletion of the residues after treatment. 2. Comparing the metabolism of the drug in the animal speciesproposed for the toxicity testing with the metabolism of the drug in the animal targeted for treatment (to determine which residues must be tested for toxicity and which laboratory animal speciesto use for toxicity studies). 3. Determining the toxic effects of residues,if any, from sponsor-sub- mitted studies and the safe concentration of all residues from the pro- posed drug. 4. Identifying which residue to measure as an indicator of the safe con- centration of all residues and establishing a tolerance for that residue (referred to as the “marker residue”). 6. Evaluating the analytical method proposed by the sponsor to measure the marker residue reliably in milk at the tolerance level (referred to as the “regulatory method”). 6. Establishing the withdrawal period for the administered drug to ensure the depletion of residues at or below the safe concentration level as indicated by the marker residue (when the marker residue is at or below its tolerance level) so the milk can be safely consumed.(FDA does not establish a tolerance when residues above the safe concentration are unlikely to occur at zero withdrawal.) For non-carcinogenicdrugs, FDAestablishesthe safe concentration for the drug residues basedon the acceptabledaily intake (ADI) for the drug. Adjustments are made for differences between test animals and humans in food consumption versus body weight, a safety factor, and the esti- mated amount of milk consumedby an individual per day. The ADI is the estimated daily intake of a drug residue which, during a lifetime of exposure (70 years), is not expected to causeappreciable health risks on the basis of all known facts at the time. The ADI is basedon the highest drug dosagedemonstrated to have no observableeffect in the most sen- sitive test animal speciesused in the toxicity studies divided by a safety factor. Page 19 GAO/RCED91-28Drug Residuesin Milk Appendix I Federal Ragulatlon of Drug Iteaiduea in the -SuPPlY The safety factor is intended to provide a margin of safety and account for the inherent uncertainty in projecting the results of animal toxi- cology tests to humans. FDA usessafety factors of 100 to 1,000 depending on the nature of the effects observed at the higher dosage levels in the test animals and the length of the study. FDAthen calculates the safe concentration using the ADI, the weight of the averageadult (60 Kg), and the maximum amount of milk that FDA estimates an individual can consumeper day-l .6 liters. FDA'S calcula- tions assumethat all dairy cows are treated with the drug and thus an individual will consume1.6 liters of milk containing the drug residues per day, assumptions which FM officials believe overstate a person’s likely exposure to actual drug residues in the milk supply. For drug residues that are carcinogens,FDAdetermines the dosethat will satisfy the “no residue” requirement of FFDCA to establish the safe con- centration level. Under FFDCA,FDAcannot approve a new animal drug if the drug induces cancer in humans or animals unless (1) the drug will not adversely affect the animals for which it is intended and (2) no res- idue of the drug is found by methods approved by FDAregulation, in any edible portion of the animals after slaughter or in any food derived from the living animals. FDA has operationally defined “no residue” to mean no significant risk of cancer- correspondingto a risk to test animals of no more than 1 in 1 million over a lifetime of drug exposure. FIX calcu- lates the concentration of drug residue yielding no significant risk of cancer level from the tumor data using a statistical extrapolation procedure. Unlike the risk assessmentprocessused for other health effects of drugs, FDA doesnot use an acceptabledaily intake in assessingcarcino- genic effects. The ADIis a level of drug intake which is safe within a practical certainty. Scientists have been unable to determine whether a safe, threshold level exists for carcinogensbecausethe mechanismsthat produce cancer are not completely understood. Therefore, lacking infor- mation establishing the mechanismof carcinogenesisfor a particular drug residue, FDAusesdose-responsemodels which assumethat some risk of contracting cancer exists for even minute exposuresto carcino- genic drug residues.Dose-responseassessmentdefines the relationship between estimated dietary exposure to a carcinogenand the probability of carcinogeniceffects. There is no tolerance established for sulfamethazine (SMZ)in milk becauseFDA has not approved its use in milk-producing dairy cows. If a Page20 GAO/RCELk91-26Drug Residuesin Milk c Federal ItqulatIon of Dmg Reaiduealn the hfuk SUPPlY veterinarian or farmer usesSMZin dairy cows, illegal drug residuesin milk can result. Recently, ells estimated that treatment of just a single cow with SMZ can contaminate the milk, when pooled, of 70,000 cows. Concern Levels When tolerances do not exist or cannot be calculated becausethe neces- sary toxicology and residue data are not available, m may set “concern levels” for drug residues.For milk, these levels correspondto the lowest level of the drug residue that can be quantified by an analytical method or one-third of the lowest published tolerance for the drug residue in edible tissue. Concern levels are not official tolerances and do not represent FDA approval of the drug use. Rather, these values represent an informal level of action/concern that FDAusesas a target for developing analyt- ical methods to monitor unapproved usesand to help set priorities for possible regulatory action against those who illegally use the drug. In the past, FDAhas approved certain animal drugs and established a zero tolerance for their residues,basedon the specified analytical method available at that time. The sensitivity level of the available method then, in essence,becamethe “action level” for these residues. For example, m initially set a zero tolerance for erythromycin, an antibiotic used to treat infections in dairy cows. However, the lowest level quantifiable in milk using the analytical method acceptedwhen the zero tolerance was established was 50 parts-per-billion. Consequently, for regulatory purposes,F~DAhas “operationally” defined this tolerance at 60 ppb. m’s Center for Veterinary Medicine (CVM) has determined that safe levels cannot be established for the drugs chloramphenicol and SMZ, becauseof human food safety concerns.FI~Apolicy states that neither of these drugs should be used in dairy cows becausethere is concern about any detectable level of the drugs in milk. However, SMZ,which is avail- able over-the-counter, is approved for cattle, dairy cows that are not producing milk, swine, chickens, and turkeys in order to treat respira- tory diseasesand, in someinstances,to promote weight gain. Sulfamethazine Level of SMZresidues in milk and other food products have becomea concernto Concern U m becausethe drug has been shown to be carcinogenicin laboratory animals. Two animal studies conducted by FDA'SNational Center for Toxicological Researchhave demonstrated that moderate-to-high doses Page 21 GAO/RCEl%91-26Drug Residuesin Milk Appendix 1 FedetralRegulation of Drug lb&ha in the mk SUPPlr of SMZproduced thyroid tumors in laboratory rats and mice. m is con- sidering whether to permit continued use of SMZ as currently approved. Controversy exists within m as to whether a safe level can be set for SMZ becausethe data necessaryto make such a determination are incom- plete. However, CVM has calculated a concern level for total residues of SMZ in milk to be 12 ppb(for the parent compound and its metabolites combined), on the basis of a preliminary risk assessmentusing available toxicology data. CVM estimates that total SMZ residues of 12 ppbover a lifetime of exposure may present no more than an insignificant risk of cancer in humans. However, existing safety data do not allow a marker residue to be established. CVM estimates that if the parent drug SMZwas used as the marker residue, then the concern level would be in the 1 to 6 ppb range. CVM believes that the low levels of SMZ projected to be safe in milk will preclude practical use of the drug in dairy cows. Approved and Residuesof drugs, including antibiotics, can occur in milk as the result Unapproved Drug Use in of legal or illegal use of drugs. FDAhas approved 63 drugs for use in or on dairy cows, including 20 antibiotic drugs. FRAhas established toler- Dairy Cows ancesin milk for 21 of the 63 drugs approved for use in dairy cows3 In addition, about 26 drugs, including 12 antibiotics, not approved for use in dairy cows are believed to be used in the dairy industry. Generally, an illegal use occurs when a drug residue is found that exceedsits tolerance level, when misuse of a drug approved for use in dairy cows results in residues in milk for which no tolerance has been established, or when residues of a drug not approved for use in dairy cows results in residues in milk. Under FFDCA, the actual or intended use of a new animal drug in a food- producing animal in a manner inconsistent with the approved labeling causesthe drug to be adulterated. FDA may consider taking regulatory action against the veterinarian, producer, or other persons involved, whenever such actual or intended unapproved use is found. 3F’DAhas not establishedtolerancesfor many drugs approvedfor usein or on dairy cowsbecause somedrugs were approvedyears agoon the basisof data that indicatedthat no safety problemwould result from useof the drug, or becauseFDAdeterminedthat residuesof the drug aboveits safe concentrationlevel would be unlikely to occur at zerowithdrawal. Also, tolerancesin milk exist for four drugs,for which the approval of their usesin dairy cowshas apparently beenwithdrawn. FDA attorneysadvisedus that failure to removethe tolerancesof thesefour drugs from the regulations was inadvertent, and that FDAdoesnot establishtolerancesfor residuesin milk of drugsthat are not approvedfor usein dairy cows. Page 22 GAO/lKXD-91-26 Drug Residueain MUk Appendix I FederalBegulationofDrueBesiduesinthe =suPPlY FDA’sCenter for Veterinary Medicine has established guidelines for vet- erinarians to treat food-producing animals with drugs not approved for them, and/or not approved for the particular manner in which used, if the animal’s health is otherwise immediately threatened or suffering and/or death would result from not treating the affected animal. In establishing this policy, known as the extra-label drug use policy, FDA said that it would ordinarily refrain from initiating regulatory action against licensed veterinarians for using or prescribing in their practice any drugs they could legally obtain, provided l a careful medical diagnosis was made by an attending veterinarian within the context of a valid veterinarian-client-patient relationship; . a determination was made that: (a) there is no approved drug specifi- cally labeled to treat the condition diagnosedor (b) drug therapy at the dosagerecommendedby the labeling has been found clinically ineffec- tive in the animals treated; . procedures are instituted to assurethat the identity of the treated ani- mals is carefully maintained; and . the time period for drug withdrawal prior to marketing meat, milk, or eggsis significantly extended; steps are taken to assurethat the assignedtime frames are met; and no illegal residues occur. FDA’sextra-label use policy doesnot permit non-veterinarians, such as dairymen, to treat food-producing animals with drugs not approved for them and/or in an unapproved manner. FDA’spolicy states that lay per- sons cannot be expected to have sufficient knowledge and under- standing concerning animal diseases,pharmacology, toxicology, drug interactions, and other scientific considerations to use drugs in treating food-producing animals in any manner other than as labeled on an approved drug. FIN has declared that chloramphenicol and diethylstilbestrol may not be used in treating food-producing animals under the extra-label use policy. In addition, dimetridazole, ipronidazole, or other nitroimidazoles may not be used under the extra-label use policy in unapproved species.Fur- thermore, FDAhas required manufacturers of all SMZ products to add a warning to product labels that SMZ is not to be used in female dairy cattle 20 months of age or older. Page23 GAO/RCED-Vl-26DrugResiduesinMilk Federal ltagulation of Drug R.&dues in the Milk SUPPlY FDAadministers the Federal/State Milk Sanitation Program through Monitoring Milk Interstate Milk Shippers Agreements to ensure the safety and whole- Safety somenessof fresh milk and cream in the United States. Under this pro- gram, the producers of Grade A pasteurized milk are required to pass inspections and be rated by cooperating state agencies. FDA’smilk safety program is a collaborative federal/state effort that dates back to the mid-1920s. The program was established after the pro- mulgation of the Standard Milk Ordinance by the Public Health Service to assist states and municipalities in initiating and maintaining effective programs for the prevention of milk-borne diseases. To provide for uniform interpretation of this ordinance, an accompa- nying codewas published in 1927 which set forth administrative and technical details to achieve satisfactory compliance. This milk regula- tion, now titled the Grade A Pasteurized Milk Ordinance (the Milk Ordi- nance), has undergone numerous revisions since that time and is the basic standard used today in the voluntary cooperative interstate milk safety program in which all 60 states and the District of Columbia par- ticipate. The Milk Ordinance is recognizedby public health agencies,the milk industry, and many others as a national standard for milk sanitation. Under the cooperative federal/state milk safety program, FDAdoesnot routinely analyze milk samples for animal drug residues.Instead, FDA relies on the states to do routine testing of the milk supply. Milk proces- sors also routinely test raw milk. FDAdoesnot routinely review state or processortest results, but has conducted sampling and testing for pesti- cide chemicals,microbiological contaminants, and certain drug residues basedon inspection findings or reports of potential problems. Within the FDA,the administration of the agency’smilk safety program is basically divided between the Center for Food Safety and Applied Nutrition (cm) and CVM, with FDA’sfield offices performing inspec- tions and sample collections and providing analytical support, CFSAN’S Milk Safety Branch is responsible for monitoring the overall conduct of the milk safety program carried out by the states. CVM is responsible for providing technical expertise in the development of testing and analyt- ical methodology related to animal drugs. In addition, CVM is responsible for evaluating the safety and effectiveness of new animal drugs and, with respect to new animal drugs for dairy cows, evaluating the condi- tions for use that would preclude the presenceof potentially hazardous residues in milk. Page 24 GAO/WED-91-26Drug Residuesin Milk Appe,ndix II Resultsand Limitations of FDA’s Efforts to Determinethe Presenceof Antibiotic Drug Residuesin the Nation’s Milk Supply FW conducted several efforts to determine the presenceof antibiotic drug residues in the nation’s milk supply between 1988 and 1990, including: l In March 1988, FDAconducted a survey of 10 cities to determine the presenceof sulfamethazine, a suspectedcarcinogen(cancer-causing agent), in milk. . Following the 1988 survey, FDA used data from a questionnaire sent to state regulatory agenciesby the National Conferenceon Interstate Milk Shipments to determine whether the presenceof SMZ in milk declined between May 1988 and September 1988, following FDA'S efforts intended to eliminate SMZ use in milk-producing dairy cows (dairy cows). l In late 1989 and early 1990, FDAconducted a survey of 14 cities to deter- mine the presenceof selectedantibiotic drug residues in the milk supply after two independent surveys reported finding numerous contaminated milk samples. Although similar in purpose, each of FDA’Sefforts were different in design and produced different results. In addition, limitations in FDA'S efforts, both individually and collectively, may preclude any compari- sonsof the results of the efforts and any conclusionsabout the safety of the overall milk supply. 1988 Survey researchersdetected the residues of a variety of animal drugs in milk. Among the drug residues reportedly detected was SMZ, one of about 46 antibiotic drugs in the class of drugs known as sulfonamides (sulfa). SMZ use in animals has been controversial becauseit is a suspectedcarcin- ogen. In addition, SMZ residues in milk may pose a risk for individuals allergic to sulfa-based drugs. Although SMZ was not approved for use in milk-producing dairy cows and FDAhad not established tolerances for SMZ residues in milk, FDA established an unofficial concern level for SMZ at 10 ppb in milk. Subse- quent to reports that independent surveys had detected SMZ in milk, FDA, in March 1988, conducted its own milk survey related to the presenceof SMZ. Methodology * FDAregional office personnel collected five retail shelf milk samples (representing five different dairy processors)from each of 10 cities Page 26 GAO/RCED-91-26Drug Residuesin Mtlk AppendixII Redta and Llnd~tions of FM% Effort43to Detennlne the Reeence of Antibiotic Drug Residueain the Nation’s Milk Supply (Atlanta, Boston, Chicago,Dallas, Denver, KansasCity, Newark, Phila- delphia, San Francisco, and Seattle). FDAscientists initially used a test method, known as high pressure liquid chromatography (HPLC), to screena total of 49 samples(one location provided only four samples) for SMZ.FDAscientists used a second,more specific method, known as mass spectrometry, to confirm the presenceof SMZin the samplesthat yielded positive results over 10 ppb under the HPLCmethod. Results The March 1988 survey found varying levels of SMZin 73 percent of the samplestested. Specifically, 36 of the 49 samplestested showed levels of SMZpresent in the milk ranging from 0.8 ppb to 40.3 ppb. Five samples tested above 10 ppb,the unofficial concern level for SMZthat FDAwas ‘using at that time, and 10 of the samplestested above 6 ppb. Limitations The 1988 FDAsurvey was limited for several reasons.First, the survey focused only on one animal drug-SMZ. The survey did not determine whether any other unapproved drug residues were present in the milk samples although FDAofficials believe that about 26 unapproved drugs, someof which may posetoxicological concernsto humans, might be used in the dairy industry. The survey also did not determine whether any approved drugs were present at levels above their tolerances. Second,FDAdid not design the survey to provide any statistically valid estimates from the survey results to the nation’s milk supply. Thus, no conclusionscan be reached on the basis of this limited survey regarding the safety of the nation’s milk supply. The March 1988 survey results raised FDA’Sconcern about the possible 1988 Follow-Up misuse of SMZby the dairy industry becauseSMZwas not approved for Survey use in dairy cows. In response,J?DAtook several steps to eliminate SMz residues in the milk supply, including an educational campaign aimed at dairy farmers. FDAcoordinated this educational effort with the National Conferenceon Interstate Milk Shipments (the National Conference)-a voluntary organization comprised of federal and state health and agri- cultural officials and the dairy industry-that together with FDA,over- seesa cooperative, federal/state program (the Interstate Milk Shippers Program) to ensure the sanitary quality of milk and milk products shipped interstate. To assessthe effectiveness of the educational program and follow-up on the 1988 FDAsurvey, the National Conferencesent a questionnaire on Page 26 GAO/RCED-91-26Drug Residuesin Milk Resulti and undtations of FM% Rfforta to De&erndnethe Rwence ofAntibiotlcDrng Residuesin the Natlon’r MUJcSupply October 8,1988, to all state regulatory agencylaboratories to obtain information regarding the number of raw milk samplestested for SMZ from May 1988 to September 1988 and the results of those tests. FDA’S Milk Safety Branch analyzed the results. Results FDA’sanalysis of state data showed that 4,887 samplesof raw milk were tested from May to September 1988 and that 6 percent of the reported samplestested (247 out of 4,887) contained SMZ.Further, FDAreported that only 1 percent of the reported test samples(64 out of 4,887) con- tained SMZresidues above 10 ppb.According to FDA,the results of the follow-up questionnaire indicated a significant reduction in the presence of SMZ residues in milk. On the basis of these results, FDAdeclared that the SMZ problem had been resolved. Limitations Although FDAconcludedthat the results from the follow-up survey showed a dramatic decreasein the level of SMZresidues in the nation’s milk supply compared with the 1988 FDAsurvey results, limitations in the follow-up survey preclude direct comparison with FDA’S1988 survey or any conclusionsregarding the safety of the nation’s milk supply. The follow-up survey cannot be relied upon to be representative of the nation’s milk supply. First, the states responding to the survey who tested milk samplesproduce only about 66 percent of the nation’s milk supply. More importantly, FDAcould not provide documentation showing how the responding states sampled milk products. If the testing states did not use statistical methods to select the samples,then the resulting state and national data are highly suspect.FDAalso did not know whether similar analytical methods and calibration standards were employed by the states in testing for SMZresidues,or whether all the methods used were capable of detecting SMZat the 10 ppbhealth concern level FDAhad established at that time. In particular, somestates may have used a method that is unable to detect many drug residues, including SMZ,at their levels of concern. Under the Pasteurized Milk Ordinance,the Bacillus Stearothermophilus disk assay is the only official method recognizedto detect antibiotic drug residues in milk for regulatory purposes.However, FDAscientists have found that this method is primarily useful only in detecting peni- cillin antibiotics and cannot detect low levels of many other antibiotics. For example, the method can only detect levels of SMZat and above 16 Page 27 GAO/RCED-Sl-26DcuglteeidueninMllk Appendix II Result8 and Lllnltations of FM’s lwforta to Detennlne the Presenceof Antibiotic Drug Residuesin the Nation's Milk Supply parts-per-million (ppm) or higher- 1,600 times the 10 ppb concern level set by FM for SMZin milk. Although FDAofficials believe that states had other testing methods available in addition to the disk assay method to detect SMZresidues, it is unknown what specific methods the states used. If somestates used only the disk assay method, then their results might have understated the number of samplescontaining SMZresidues above FDA’Slevel of con- cern. Also, similar to the earlier 1988 survey, the 1988 follow-up effort only obtained data on the presenceof sMz-no data on the possible pres- enceof other unapproved or approved drugs was gathered. We cannot say with certainty that the results developed by FDAin its follow-up survey are flawed. However, given a sample representing only 66 percent of the nation’s milk supply, no assurancesthat state samples were statistically drawn, and questions about state testing compara- bility, the results would likely be correct only by coincidence. Subsequentto FDAconcluding, on the basis of the 1988 follow-up survey, 1990Survey that the SMZproblem had been solved, the Wall Street Journal (the Journal) reported the results of two surveys of animal drug residues in milk on December29,1989. One survey was sponsoredby the Journal and the other by the Center for Sciencein the Public Interest (CSPI), a consumer food safety and nutrition organization. The Journal reported that its survey found that 38 percent of 60 retail milk samples contained residues of antibiotics, possibly including SMZ and other unapproved drugs. The CSPIsurvey found that 20 percent of 20 retail milk samplescollected in the Washington, DC., area contained sulfa drugs, again possibly including SMZand other unapproved drugs. Both surveys used an analytical method called Charm II. The Charm II test is considered a screeningtest becauseit can report- edly detect the presenceof sevenclassesof antibiotic drug residues in milk (e.g., aminoglycosides,beta-lactams (penicillins), chloramphenicol, macrolides, novobiocin, sulfonamides, and tetracyclines). However, except for chloramphenicol and novobiocin, which are individual chem- ical entities, the Charm II test can only indicate that a member of a par- ticular chemical family of antibiotics may be present in milk samples tested, it cannot identify the specific antibiotic drug residue(s) respon- sible for the positive result. The identification of the specific antibiotic drug(s) must be determined by an independent confirmatory method of Page 28 GAO/RCEDBl-26 Drug Residuesiu Milk Appendix ll Remlta and Limitationa of FDA’s Efforta to Deterndne the Presenceof Antibiotic Drug Residuesin the Nation’s Milk Supply analysis, according to FDAofficials. For example, the Charm II test can indicate that a member of the sulfonamide classof antibiotics may be present in a milk sample tested, but cannot identify which specific sul- fonamide drug(s), such as sulfamethazine or sulfadimethoxine, caused the positive response. Methodology rm~designedits 1990 survey to test the reliability of the independent surveys and to confirm or discount claims that animal drug residues are present in milk. To do this, FDAfield office personnel obtained two con- tainers of milk with the samelot number and date from 6 stores in each of 14 cities. The 14 cities included all those in the Journal’s survey, as well as those included in FDA’sprevious survey efforts (Atlanta, Balti- more, Boston, Chicago,Dallas, Denver, KansasCity, Los Angeles, Miami, Minneapolis, New York, Philadelphia, San Francisco, and Seattle). The milk samplescollected were then analyzed for the presenceof antibiotic drug residues.According to FDAofficials, the survey was a “snapshot” of the presenceof certain drug residues in milk. The containers collected at each location were shipped over night; one . container was sent to FDA'SBeltsville laboratory and one container was sent to FDA'SPhiladelphia District laboratory. Beltsville and Philadelphia ultimately received 70 milk sampleseach-l container each from the five stores selectedin each of the 14 cities. The Philadelphia laboratory used the sameCharm II test method used in the Journal and CSPIsurveys to screenits 70 milk samplesfor drug residues.Subsamplesof all sam- ples found positive by the Charm II test in Philadelphia were sent to FDA'SDenver laboratory for further testing using modified HPLC,thin layer chromatography, gas chromatography, and microbiological test methodologies.Denver also performed mass spectrometry confirmatory testing for samples showing positive screeningresults for chloramphen- icol, sulfadiazine, and sulfamethazine. FDAofficials believe that the mass spectrometry method, which is more difficult and costly to perform than other methods, represents state-of- the-art procedures in analytical chemistry and is the most reliable method available for identifying specific compounds.FDA considersall other test methods, including HPLC,to be screeningtests because although they may be able to tentatively identify which one of a number of drugs may be present in milk, they cannot positively identify the drug found. Page 29 GAO/RCED-91-26Drug Residuesin Milk ltaaulta and rdndtationa of FlM% Effort49to De&ma&e the Presenceof Antibiotic Drug Residuesin the Nation’e MU Supply The Beltsville laboratory used multi-residue HPW screeningmethods to test all of its 70 samples for the presenceof 10 sulfa and 3 tetracycline antibiotic drugs. The Beltsville laboratory also used mass spectrometry to confirm and “fingerprint” the results of their HPW testing, but only had confirmatory tests for chlortetracycline, oxytetracycline, sulfadia- zine, sulfamethazine, and tetracycline. Also, with the exception of three sulfamethazine samples,Beltsville limited its confirmatory testing to samplesthat its HPLCtesting indicated had residues equal to or in excess of established concern levels. Overall, FDAcould only perform confirmatory testing for six of the antibiotics selectedfor the 1990 survey, and, according to the Director of FIN’SCenter for Veterinary Medicine, the survey cost $360,000. Results In total, the screeningtest results from FDA’sthree participating labora- tories initially indicated that 91 percent of the milk samplestested (64 out of 70) contained low levels of antibiotic drug residues and that many samplescontained multiple drug residues.FDAperformed mass spec- trometry testing on three of the samplesfor which screeningtests indi- cated low levels of sulfamethazine and confirmed its presencebelow 6 ppb. FLWdid not find any antibiotic drug residues at or above concern levels, or at or above the level of detection sensitivity of the methods used on the remaining samplesselectedfor mass spectrometry testing. However, FDA’sattempt to confirm the presenceof sulfachloropyridazine was inconclusive becauseof problems with the confirmatory method. FDAonly had confirmatory methods for six of the other drugs selectedfor the 1990 survey, and three of these methods could not detect their respective drugs at established concern levels. Philadelphia/Charm II The Philadelphia laboratory’s results using the Charm II test were sim- Results ilar to the results from the Journal and CSPIsurveys in that many of the samplestested indicated the presenceof antibiotic drugs. The Philadel- phia laboratory results indicated that 61 percent (36 out of 70) of the samplescontained antibiotic drug residues,mostly tetracyclines, and somesamplescontained multiple residues. Table II. 1 provides a sum- mary of FDACharm II results. Page 30 GAO/IUXD-91-26 Drug Residuesin Milk . AppendlxII RemlltaandLlml~tlona of FM% Efrortato Ik3tellulnethe- ofAnubloticDrug ResldaeaIn the Nation’sMilk Supply Table 11.1:FM Screonlng Rerulto for Drug Frmlly Rorlduer In the 1990 Milk Percent of Suwoy Uolng the Charm II Tw Number of Positive Safnosll; Poeltlve SaFot;; Drug Family (out of 70) Aminoglycosides (gentamicin) 4 --- 6 Bets-lactams (penicillin) 1 1 Chloramohenicol 1 1 Macrolides (erythromycin) 1 1 Novobiocin 5 -- 7 Sulfonamides 15 21 Tetracvclines 34 49 Source: Prepared by GAO from FDA data. DenverLaboratory Results Subsamplesof the 36 samples found positive using the Charm II test were sent to m’s Denver laboratory for further screeningand confir- matory testing. Basedon this screeningand/or confirmatory testing, the Denver laboratory reported that it could not corroborate any of the Phil- adelphia laboratory’s positive Charm II results. However, the test method Denver used for five samples which Charm II indicated the pres- enceof novobiocin was not as sensitive to the drug as the Charm II test is claimed to be. The Denver method was also incapable of detecting novobiocin residues at the health concern level established by FDA. Ekltsville Laboratory Sulfa Drug The Beltsville laboratory’s HPU=test results indicated that 86 percent Resulti (60 out of 70) of the milk samplestested contained sulfa drug residues; 46 percent (32 out 70) of the samplescontained multiple sulfa residues. Specifically, Beltsville initially found that 16 percent (11 out of 70) con- tained sulfa residues greater than or equal to 10 ppb, the FDA-designated concern level for these drugs at that time; 83 percent (68 out of 70) con- tained sulfa residues at levels less than 6 ppb;and 1 percent (1 out of 70) contained residues between 6 and 10 ppb. Table 11.2provides a summary of initial results from the Beltsville laboratory using HPLC. Page31 GAO/RCEDBl-26 DrugResiduesin Milk Resulta and Limitation of FDA’s Eff-ortu to Detmudne the Presence of Antibiotic Jhug IUeiduen in the Nation% Milk Supply Table 11.2:lnltlal FDA Screening Retrultr for Sulfa Drug Realdues in the 1990 Milk Percent of Survey Ming HPLC Number of Poritlve Sapot;; Poaitlve Saro$l; Drug (out of 701 Sulfachloropyridazine 3 4 Sulfadiazine 32 46 Sulfadimethoxine 3 4 Sulfamerazine 47 67 Sulfamethazine 10 14 Sulfamethizole 1 1 Source: Prepared by GAO from FDA data. Beltsville’s HPU results also indicated that 10 of the 11 samplesthat tested positive for sulfa residues at or above 10 ppbcontained sulfadia- zine at levels ranging from 10 to 316 ppband that 1 sample contained sulfachloropyridazine at 16 ppb. However, the Beltsville laboratory did not confirm the presenceof sulfa- diazine at or above 10 ppb in any of the samples found positive by their HPLCmethod. Through additional testing using a revised HPU procedure, thin layer chromatography, and mass spectrometry, Beltsville subse- quently found that the compound theobromine interfered with the ini- tial HPLCscreeningtests and led to false positive results. Theobromine is a caffeine-related substancefound in chocolate.FDAbelieves that the substancemay have found its way into the milk sampled as a trace res- idue of chocolate milk processedby the samedairy plants. (Beltsville did not reanalyze sampleswith low levels of sulfadiazine (less than 10 ppb) using the revised HPLCprocedure becausethese levels were under the designated level of concern.) Beltsville attempted to confirm the presenceof sulfachloropyridazine above 10 ppb in the remaining sample, but its analysis was inconclusive becauseof problems with the confir- matory method. Although low levels of sulfa drugs (i.e., less than 5 ppb)were detected in many of the milk samplesusing the HPLCmethod, FDA advised that these results must be interpreted cautiously becausemany low level positive results could be due to interference near the ability of this method to detect low levels of sulfa drugs in milk. Also, Beltsville generally did not attempt to confirm HPLCresults indicating sulfa residues below the con- cern level of 10 ppb.However, three sampleswith the highest indicated concentrations of SMZ(all less than 6 ppb) were analyzed using the mass Page 32 GAO/RCED-91-26Drug Residuesin Milk Appendix II Reeulta and Lhitatlone of FM’II Rfforta to Detmntne the Prewnce of Antibiotic bye Reelduesin the Nation’s Milk Supply spectrometry method and the presenceof SMZ~in these sampleswas confirmed. Beltmille Laboratory The Beltsville laboratory HPLCtest results indicated that one sample Tetracycline Results tested contained oxytetracycline at 99 ppb.Beltsville was unable to con- firm the presenceof this drug using its mass spectrometry method. However, the confirmatory method could only detect oxytetracycline at 100 ppb or more. The health concern level FDAset for this drug was 30 ppb. Limitations As in its previous efforts, the 1990 FDAsurvey of antibiotic drug resi- dues in milk was not statistically designedto be representative of the nation’s milk supply. According to rn~ officials, the survey was a snap- shot and the results could be completely different if the samesurvey was conducted again. In addition, the 1990 survey was limited for sev- eral reasons. Limit.& Number of Confiiatiry FDAmay have been unable to confirm someof the positive screeningtest MethodsAvailable results in its 1990 survey becauseit did not have methods to identify and confirm the presenceof all drugs detected by the screening methods. Thus, unconfirmed results may have been due, in part, to the presenceof a drug residue not detectable by FDA’S confirmatory method. For example, about 32 antibiotic drugs, approved and/or unapproved for use in dairy cows, may have been in use by the dairy industry at the time of the 1990 survey. However, other than the Charm II test, FDAonly had screeningtests of its own for 17 antibiotic drugs included in its 1990 survey and mass spectrometry methods to confirm the presenceof only six of these drugs in the milk samplestested. Regarding sulfa antibi- otics, the Charm II test FDA’s Philadelphia laboratory used reportedly could, in its screeningmode, detect 15 drugs in the sulfa class family. Only 10 sulfa drugs were included in the 1990 survey, and FDAhad con- firmatory (mass spectrometry) methods for only 2 of these. In addition, the Beltsville laboratory found evidenceof a substancepre- sent in milk samplescollected from Philadelphia that did not correspond to any of the 10 sulfa drugs that its HPLC methods could identify. According to the Chief, Method Validations and Analytical Branch, ‘During the 1990survey, CVM revisedits preliminary risk assessment for SMZand concludedthat it could not set a safelevel of SMZin milk becauseof data gaps,but estimateda safeconcentrationof total residuesof SMZ(including metabolites)in milk to be 12 ppb, with a likely markerresiduein the l-6 ppb range. Page 33 GAO/RCED-91-26Drug Residuesin Milk . Redta and Lbdt.atione of me Effort# to DetermIne the Rwence of Antibiotic Drug Reaidnw in the Nation’6 Milk Supply Center for Veterinary Medicine, the presenceof the identified substance could possibly be due to the processingand packaging of the retail milk samplesused in the survey, the result of animal husbandry practices, or the presenceof another sulfa or someother drug. DiscountedResults Questioned FW discounted Charm II test results from its Philadelphia laboratory that indicated the presenceof novobiocin in Ssamples, or 7 percent of the 70 samplestested, basedon the results of a microbiological screening test method used by its Denver laboratory that was less sensitive to the drug than the reported detection capability of Charm II. The microbio- logical method was also unable to detect novobiocin residues at the tol- erance level established by rn~. Specifically, using the Charm II test with a reported detection sensitivity of 60 ppb,the Philadelphia laboratory found five samplesthat contained novobiocin. Denver, using a “green book” microbiological screeningtest with a detection sensitivity of 200 ppb,did not corroborate these results. However, the tolerance level established by FQAfor novobiocin was 100 ppb. According to FDAofficials, there were no other screeningtests avail- able for novobiocin. Also, according to the Chief, Method Validations and Analytical Branch, Center for Veterinary Medicine, the Beltsville laboratory did not test milk samples for this drug becauseFW lacked a confirmatory method for novobiocin. Consequently, although the Charm II results indicating the presenceof novobiocin were discounted, FIN did not know whether novobiocin was present in the samplestested above the established tolerance level, but below the detection level of the green book method used. Limitations in Existing Someof the other analytical methods FDAused in the 1990 survey were confirmatory Methods also unable to detect and confirm the presenceor absenceof various drug residues at their concern levels. For example, three of the six drugs in the 1990 survey for which FW had confirmatory methods were tetra- cycline antibiotics. Thesethree drugs were/are approved to treat dairy cows, but only one, chlortetracycline, had an m-established tolerance for its residue in milk. For survey purposes,F+DA established unofficial concern levels for the residues of these three drugs in milk. However, the confirmatory methods FDAused in the 1990 survey were incapable of detecting the presenceof these drugs at their concern levels. For example, the concern level for oxytetracycline was 30 ppb, but FRA’S mass spectrometry confirmatory test could only confirm it at 100 ppb or more. Consequently, although the Beltsville laboratory found one sample that contained oxytetracycline at 99 ppb using the HPU=method, Page 34 GAO/ICED-@l-36Drug Reoidueain Milk Beltsville was unable to confirm the HPLCresult with the mass spectrom- etry method. Thus, although m reported that it could not confirm the presenceof any tetracycline drugs, the drugs may still have been present at levels exceedingthe concern level for human consumption, but below the con- firmatory test level of detection for these drugs. Table II.3 shows a com- parison between the tolerance/concern levels for the antibiotic drug residues in milk tested and the level of detection of testing methods m used in the 1990 survey. Page36 ‘,, Appendix II Reeulte ad Llmltations of FM’8 Rfforta to Detmmlue the Presenceof Antibiotic Drug Reeidueain the NatIon’s Milk Supply Table 11.3:Tolerances/Levels of Concern for Selected Antibiotic Drug Residues in Milk and the Level of Detection for the Methods FDA Used In Its 1990 Survey (In Parts-Per-Billion) Tolerance/ Philadelphia Beltsville Denver Drug Concern Level’ Charm Ilb BHPLCC BMSd DQBMW DHPLC’ DTLV DMSh Penicillin o/10 4.8’ . . 10 l l l Tetracycline -/80 200’ 50 100 50-175 40 9 l Chlortetracycline __ o/30 200’ 30 100 50-175 40 l l Oxytetracycline -130 200’ 40 100 50-l 75 40 l l Chloramphenicol -IO 100 . . . . . 1 .._._ _..- _.-._-...-.-__--__ Streptomvcin O/125 1OOi . . . . . . Gentamicin -130 50’ . . 20-70 l l l Erythromycin o/50 100’ . . 25 l . l Novobiocin 1oo/- 50 . . 200 l l l ..~.._ Sulfanilamide _. “~“. .._......_ --... --____~ -110 10’ 5 l . . . . Sulfadiazine -/IO 10’ 0.9 10 . . 100 10 Sulfathiazole . ..-.--.-..-- -/IO 10’ 1 l . . 50 ’ Sulfamerazine ._. i--_-. ._.---- -/IO IO’ 0.5 l . . 10 l Sulfapyridine -/IO 10’ 0.9 l . . . . Sulfamethizole _ .._ _ -110 IO’ 2 l . . . . Sulfamethazine -110 IO’ 2 2 . . 5 5 Sulfachloropyridazine -110 IO’ 1 l . . . . Sulfadimethoxine lO/lO 10’ 0.7 l . . 5 l Sulfaquinoxaline -/IO 10’ 1 l . . IO 9 Qalue indicates tolerance and/or level of concern for drug residues in milk at the time of the FDA 1990 survey. bCharm II = Values are for the screening mode of the Charm II test used by FDA’s Philadelphia District Laboratory. %HPLC = High pressure liquid chromatography method that the FDA Beltsville Laboratory used %MS = The mass spectrometry method that the Beltsville Laboratory used to confirm test results. ‘DGBMB = FDA Antibiotic Residues in Milk, Dairy Products and Animal Tissues: Methods, Reports, and Protocols, Revised Oct. 1968. Reprinted Dec. 1974. (Called the Green Book microbiology methods.) ‘DHPLC = Modified HPLC method that the FDA Denver Laboratory used. eDTLC = The thin layer chromatography method that the Denver laboratory used. hDMS = The gas chromatography/mass spectrometry method that the Denver Laboratory used. ‘The Charm II test generally detects the presence of antibiotic drug families-not individual drugs. The values given represent the levels of detection for the family of drugs for the individual drug listed. ‘Different Charm II detection levels are given for gentamicin and streptomycin although both are mem- bers of the aminoglycoside family, because the manufacturer claims that the test is more sensitive to gentamicin. Source: Prepared by GAO using FDA data. Page 36 GAO/RCED91-26Drug Residueein Milk lballt4 and Llmlmlone of ma J?iffort$to Determine the Preeenceof Autibiotk Drug Reeidur, in the Nation% Milk Supply In establishing concern levels for the 1990 survey, FDAcould only con- sider parent drug compoundsbecausethey lacked data on the metabo- lites of the parent drug compoundsin milk. Accordingly, FDAdid not analyze the milk samplesfor metabolites of the antibiotic drugs they tested for-only the parent drug compound. Unexplained Discrepanciesin Several unexplained discrepanciesin test results exist from the different ResultsExist methods that m used in its 1990 survey that may render the survey results inconclusive. For example, as indicated earlier in table II. 1, most of the Charm II positive results were for tetracycline. However, the Denver laboratory was unable to corroborate these results using green book microbiological methods, even though these methods were report- edly more sensitive to tetracycline than Charm II. According to FDA, there are no data available to explain this difference. Similarly, the Belt- sville laboratory was unable to detect three specific tetracyclines in most of the samplesthat Charm II found positive for tetracycline drugs, even though the HPL~method Beltsville used was reportedly more sensi- tive to these drugs than Charm II. Validity of Test Methods Questionsexist about whether the methods FDAused in its 1990 survey had been adequately validated. The HPLCand mass spectrometry methods FDAused in the 1990 survey did not undergo multilaboratory evaluation as specified in the Center for Veterinary Medicine formal methods trial procedures.For example, the Center considersthe HPLC method only a research method becauseit has not gone through the usual validation procedures normally followed in FDA.FDAofficials said that the methods were validated at FDA'Sown laboratories and peer reviewed by two university scientists expert in toxicological analysis. Although the reviewers concludedthat the manner in which FDAused its methods in the survey was credible and adequate,they could not fully “credentialize” the procedures becauseof the lack of data on the repro- ducibility of the methods. Furthermore, the scientists questioned the number of false positives produced by the Beltsville HPLCscreening procedures. In addition, two scientists from the Centers for DiseaseControl (CDC) evaluated FDA'Sanalytical methods used in the 1990 survey and found them adequate. However, the cut scientists suggestedthat additional method development work is neededto determine the performance of the methods using retail versus raw milk and to lower the level of detec- tion for the methods below the concern levels for the tetracycline drugs tested. Page 37 GAO/RCED-91-26Drug Residuesin Milk * -- APpsndk n Reeulw and Llmt~tlonm of FMb Efforta to DetonnlnetlKlPreeeneeofAnnbiotleDrug Reeidue#lntlIe~wr~supply For example, the analytical methods FDAused to detect the presenceof the three tetracyclines were developedusing raw milk. However, FDA collected milk samplesoff the shelf. The extent to which retail versus raw milk may affect test results is unknown. Handling of Milk Samples Questionsexist about FW’Squality assuranceof the handling of the milk c!dkted samplescollected. About 46 percent of the milk samplesanalyzed in the 1990 survey were beyond their shelf-life “pull-by dates.” According to FW, milk conditions such as spoiled milk, can causethe Charm II test to indicate false positive results, especially for tetracyclines. Consequently, the selection and handling of milk samples are critical to achieving accu- rate results. According to FDAofficials, becauseof time constraints the 1990 survey was not structured and no criteria were set for what the pull-by dates for milk samples should have been. However, none of the samples ana- lyzed by FDAwere spoiled, according to the Chief, Method Validations and Analytical Branch, Center for Veterinary Medicine. Page 80 GAO/I&ED-@l-26Lhqij Residuesin Milk *a Appendix iI ObJ- 'WS, Scope,and Methodobgy As requested by the Chairman, Human Resourcesand Intergovern- mental Relations Subcommittee,HouseCommittee on Government Oper- ations, we reviewed the adequacy of survey efforts conducted by FDAin 1988 and 1990 to determine the presenceof animal drug residues in milk and whether the information developedprovided sufficient basis for m’s public statements attesting to the safety of the milk supply. To obtain information on FDA’ssurvey efforts, we interviewed officials and obtained documents from FDA’sCenter for Veterinary Medicine, Center for Food Safety and Applied Nutrition, Office of Regulatory Affairs, and the FDAlaboratories at Heltsville, Denver, and Philadelphia. We also reviewed documents the Subcommitteeobtained from FDA related to its surveys of animal drug residues in milk and pertinent reports FDAissued as a result of its surveys. In addition, we reviewed FDA,state, and industry testimony regarding their efforts to detect drug residues in milk, given before the Subcommitteeon February 6, 1990. We also met with the Center for Sciencein the Public Interest, to deter- mine its views of FDA'Ssurveys of animal drug residues in milk. Our review, which was done from April to September 1990, was con- ducted in accordancewith generally acceptedgovernment auditing stan- dards. We conducted our review primarily at FDA'SCVMheadquarters in Rockville, Maryland. The information in this report was discussedwith officials in FDA'S Center for Food Safety and Applied Nutrition, Center for Veterinary Medicine, and Office of Regulatory Affairs. Where appropriate, changes have been made basedon the discussionto further clarify the informa- tion presented. However, as your office requested,we did not obtain official agency comments on a draft of this report. Page 39 GAO/RCED91-26Drug Residuesin Milk Appendix IV Major Contributors to This Report Edward M. Zadjura, Assistant Director Resources, Michael J. Rahl, Assignment Manager Community, and Max L. Aguilar, Evaluator-in-Charge Economic William M. Layden, Senior Evaluator Scott W. Weaver,Staff Evaluator Development Division, - Statistician Mitchell B. Kamman. Washington, DC. (160704) Page 40 GAO/BCED-91-28m Residuea in Milk Ordering Ittformatiott ‘I’ttv first. five c0pir-s of each GAO report. are free. Additiottal copies are $2 each. Orders should be sent to the followittg address, accom- ptttitvl by a. check or money order made out. to the Superitttendettt of I)ocutttt~tit.s, when necessary. Orders for 100 or ttlort* copies to be tttailt~d LO a sittglv address are discounted 25 percent,. Ii.% (;t~titval Accoutitittg Off& P.O. 130x 6016 GaiUtc~rstmrg, MI) 20877 ()rdc~rs may also be placed by calling (202) 275-624 1. r .-_.._ .-... .-.- -_.- .___- -_-... “--...“.._ ._._.-.-_..--...l __.__-_ --.-_---__--- -.-. ----- -_.
Food Safety and Quality: FDA Surveys Not Adequate to Demonstrate Safety of Milk Supply
Published by the Government Accountability Office on 1990-11-01.
Below is a raw (and likely hideous) rendition of the original report. (PDF)