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APPENDIX J IMMUNOLOGICAL CONSEQUENCES OF ANTIMICROBIALS IN ANIMAL FEEDS N. Franklin Adkinson, Jr.1 This paper addresses the issue of whether antibiotic residues consumed in edible animal tissues sensitize and/or elicit allergic reactions in humans. Although many antibiotics are potentially sensitizing in susceptible individuals, the focus of this paper is upon the penicillins and tetracyclines. Of these, the penicillins have far greater allergenic potential. The allergenicity of penicillins has been studied extensively (Levine, 1966; Stewart, 1973~. Because the penicillin group of drugs is considered the prototype for allergic reactions to drugs (Parker, 1975), much of the following commentary is derived from knowledge of hypersensitivity to penicillin. The principles in- volved, however, should apply to less allergenic antibiotics in- cluding the tetracyclines and aminoglycosides. There are three basic questions concerning this issue: 1. Is there a potential for allergic reactions in humans either directly or indirectly attributable to antibiotics in food- stuffs? 2. Are there documented cases of such allergic reactions to antibiotic residues, and, if so, what is the magnitude of the pro- blem? 3. What studies could be conducted to document further the extent of the problem, both actual and potential? PREVALENCE OF ALLERGIC SENSITIVITY TO PENICILLINS AND TETRACYCLINES Penicillins display remarkably little toxicity even in high doses. Most adverse reactions are attributed to "allergy." Allergic reactions to penicillin range from anaphylactic shock, which can be life-threatening and even fatal,-to mild evanescent skin rashes of little clinical consequence. These allergic reac- tions have differing immunological mechanisms (Table 1~. When Division of Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine at the Good Samaritan Hospital, Baltimore, Md. 301
302 TABLE 1 Immunopathological Reactions to Penicillin Gell and Examples of Adverse Coombs Type Description Penicillin Reaction I Anaphylact ic Acut e anaphylaxi s · (IgE-mediated injury) Urticaria II C '-dependent cytolysis Hemolytic anemias Thrombocytopenia Interstitial nephritis III Immune complex damage Serum sicknes s Drug feve r Cutaneous erupt ion s IV " Delayed " or c el lular Contac t de rmat iti s hype rsens itivit aImmunopathogenesis of cutaneous eruptions is not clear.
303 penicillins are given in therapeut ic dose s, the inc idence of severe life-threaten~ng reactions is small, probably less than 1 in 50,000 courses of treatment (Ids~e et al., 1968~. However, because of the huge quantities of penicillin drugs administered yearly in the United States, there are an estimated 300 to 500 deaths frog anaphylactic reactions to therapeutic penicillin each year (Feinberg, 1961~. On the other hand, mild reactions to penicillin, principally skin eruptions resembling those of measles, are common, and, at least for one semisynthetic peni- cillin (ampicillin), may afflict 10% to 12% of treated patients (Almeyda and Levantine, 1972~. Between 1% and 10% of the general population will relate a history of some adverse experience associated with penicillin therapy. The lower prevalence figure (1%) is probably more applicable to children and young healthy adult s, while the higher prevalence figure (10%) reflects the frequency with which medical chart s are likely to be marked "allergic to penicillin" among older patients hospitalized for serious medical problems. More recent s tudies of the most serious forms of allergy to peniicillin ~ type I in Table 1: IgE-mediated, or reagenic, allergy) have shown that some patients s pontaneously lose allergic sensitivity with time (Adkinson et al., 1971; Green et al., 1977; Levine and Zolov, 1969~. This spontaneous loss of allergic sensitivity is likely to occur for other less serious types of allergic reactions as well, judging from the fact that it is often possible to treat previously allergic individuals safely (Biennan et al., 1972 ; Levine, 1972 ~ . Tetracyclines are infrequently implicated in allergic reac- tions. Allergic reactions of the type I variety (anaphylactic shock and urticaria) have occasionally been documented in the literature (Schindel, 1965) but are extraordinarily rare. Tetra- cycline-induced skin rashes, including phototoxic dermatitis, are the most common adverse reactions that are generally considered "allergic, " although there is no clear evidence of an immunologi- cal basis for these reactions (Dewdney, 197 7 ~ . CONI) IT IONS FOR SEN S ITIZAT ION Some of the factors that influence the development of aller- gic hypersensitivity to penicillin are: chemical structure and reactivity of the drug; cross-reactivity with other sensitizers; dosage, duration of therapy, number of courses of therapy; mode of administration of the drug; use of additives and solvents; and
304 patient factors, including history of drug sensitivity, atopy, age, genetic factors controlling drug metabolism or immune re- sponse, and underlying disease affecting metabolism of excretion of the drug. Three factors deserve mention in the present context: pro- tein reactivity, individual susceptibility, and dose requirements. Protein Reactivity Drugs, like all small molecular weight chemicals, cannot stimulate an immune response in animals or humans unless they possess the capacity to "haptenize," i.e., interact irreversibly with larger molecules, usually proteins, thereby forming an immunogenic multivalent drug-protein complex. The immunochemistry of such interactions between penicillin and native proteins has been studied in detail (Stewart, 1967~. The principal pathways involved are schematized in Figure 1. The major antigenic determinant for penicillin is the peni- cilloyl moiety of the complex, formed by covalent linkage of the beta lactam ring of penicillin to epsilon amino groups of lysine residues in native proteins. This antigenic complex is formed naturally and spontaneously under physiological conditions without known participation of enzymes or catalysts. This penicilloyl- protein complex stimulates the host immune system to produce antibodies and immunoreactive cells that are capable of inflicting immunopathological damage. It is now well established that pre- formed penicilloyl-protein complexes are much more efficient than the unconjugated penicillin molecule at both stimulating an immune response and eliciting an allergic reaction in a previously sensi- tized individual (Siegel, 1959; Stewart, 1967~. Immunologically, the antibiotic "residue" of prime importance is the penicilloyl- protein complex rather than the free penicillin molecules. As is discussed further below, no analyses of penicilloyl residues in foodstuffs obtained from penicillin-treated animals have ever been undertaken. The relationship of the a topic status to various types of reac- tions to penicillin is uncertain except for fatal anaphylactic reactions, which occur more frequently among atopic persons.
305 FORMATION OF PENICILLIN ANTIGEN IN VIVO O H H H 11 1 1 1 ~s~ R-C-N-C-I I (CH3)2 C-N CH-COOH o penicillin ll Isomerization H SH 1 1 Nl IC = Cl Cl(CH3)2 _ R-C~ ~C~ N-CH-COOH penicillenic acid Protein O H H H R-C-N-C-C' ~C(CH3)2 C N CH-COOH oil I E-lysyl NH H amide I linkage ( I H2)4 -- --NH-CH C 11 o panicilloyl - protein MAJOR ANTIGENIC DETFRMINANT MINOR ANTIGENIC DETERMINANTS FIGURE 1. Major pathways of penicillin-protein interactions. \
306 There have been no detailed immunochemical studies of inter- ac-tions of tetracycline with host proteins (Dewdney, 1977 ~ . The protein reactivity of tetracyclines is generally considered to be quite small. This fact alone is thought to account for the rarity of hypersensitivity reactions to this class of antibiotics. Individual Susceptibility Recent studies by my laboratory have indicated that not all individuals possess the capacity to respond immunologically to therapeutically administered penicillin, even if treated with prolonged high dose therapy (Adkinson, 1977~. This suggests that there may be genetic and/or metabolic restrictions on the ability to develop hypersensitivity reactions to penicillin. The propor- tion of the general population that may be susceptible to the development of allergy to penicillin remains to be determined. Dosage Requirements for Sensitization From immunological studies of laboratory animals and humans it is clear that the dose of any immunogenic substance required for initiating an immune response is appreciably greater than that required to elicit an allergic reaction of the type I variety. The optimal immunizing dose and the minimal dose for eliciting an acute allergic reaction may differ by several orders of magnitude. Furthermore, evidence from studies of both laboratory animals and humans suggests that low-dose immunization favors the production of IgE antibody over IgG antibody in animals that are genetically capable of mounting an IgE antibody response (Marsh, 1975~. Thus, there is reason to suspect that there may be a potential for the development of IgE-mediated hypersensitivity by chronic low dose antigenic exposure. ~ ~· ~· ~ However. for ingested antigens (as opposed to inhaled, airborne antigens) this potential risk has not been explored by studies in either laboratory animals or humans. Thus, there are no data to indicate whether penicillin administered to humans chronically at residue-level doses can elicit a penicillin- specific immune response in a susceptible individual. Likewise, data concerning the threshold sensitizing dose for orally adminis- tered penicilloyl-protein complexes are not available either for laborato ry animals or humans.
307 CONDITIONS FOR PROVOCATION OF ALLERGY SYMPTOMS In an individual who has been rendered allergic to penicillin by prior therapeutic administration, what is the risk of provoking allergic symptoms by penicillin residues in ingested foodstuffs? As discussed above, the dose required to elicit an allergic reaction would be expected to be considerably below that required to initiate an immune response. The threshold dose for provoking an allergic reaction depends upon the degree of allergic sensitivity of the individual ingesting the antibiotic residues. Clinical observations were made by Walzer and Siegel in 1956 (Siegel, 1959~. They passively sensitized skin sites on normal subjects with serum drawn from patients with high reagin (IgE) titers to penicillin. All serum donors had previously experienced immediate allergic reactions following treatment with penicillin. Seventy-two hours later the recipient subjects were fed measured amounts of crystalline penicillin G. and the sensitized sites were observed for the appearance of wheel and flare signs, which are indicative of IgE-mediated skin reactions. In those studies, which were positive, the oral threshold dose of penicillin required to produce a positive skin test was 40 to 50 units. Administered intravenously, doses of 12.5 to 25 units were sufficient to produce a positive skin response. Siegel (1959) and Bierlein (1956) have provided evidence that the oral dose of penicillin required to activate a passively sensi- tized skin site in a normal recipient is from 100 to 10,000 times larger than that needed to induce a clinical reaction in the aller- gic patient from whom the reaginic serum was drawn. If one assumes a conservative ratio of 100:1, then the oral administration of as little as 0.4 units of penicillin would be sufficient to elicit allergic reactions in patients with severe IgE-mediated peni- cillin allergy. A number of reports document systemic reactions in sensitive individuals who were skin-tested with less than 1 unit of penicillin G. including one patient who developed systemic symptoms following an intradermal test with 3 x 10 units of penicillin (Bierlein, 1956~. It is therefore clear that very small doses of penicillin, administered orally or through the skin, are capable of eliciting allergic reactions in some exquisitely sensitive patients. It is doubtful that such small doses could elicit clinical symptoms in a majority of penicillin-allergic patients. Whether chronic ingestion of subthreshold doses can eventually result in symptoms is likewise unknown.
308 EVIDENCE OF ALLERGIC REACTIONS TO ANTIBIOTIC RESIDUES Milk The literature yields only a few documented cases of allergic symptoms that are clearly related to the presence of antibiotic residues in animal foodstuffs. Almost all of these reports deal with penicillin-contaminated milk. In 1959 Siegel carefully re- viewed the data on allergic reactions to penicillin in milk. He noted that in a 1956 Food and Drug Administration (FDA) nationwide survey of penicillin contamination of milk, 5.9Z of the samples were found to be contaminated with penicillin. The degree of con- tamination ranged from 0.003 to 0.55 units/ml of milk, averaging 0.032 units/ml (D. C. Grove, personal communication; Welch, 1957~. Zimmerman (1957-1958) reported that urticaria following ingestion of milk was a common occurrence among 52 penicillin-sensitive patients. Unfortunately, these patients were not studied immuno- logically, nor were the implicated milk samples analyzed for penicillin content. The best studied case of allergic reaction from penicillin in milk was reported by Borrie and Barrett (1961) in Great Britain. A 25-year-old woman suffered a moderately severe sub- acute eczematous eruption, which was traceable to penicillin- contaminated milk. Analysis revealed that some milk samples that did not contain penicillin were still capable of provoking allergic symptoms. The patient's symptoms were relieved, however, by addi- tion of penicillinase to the milk she consumed at home. Attempts at desensitization by the oral route were undertaken starting at 1 unit of penicillin per day. Desensitization had to be abandoned because of recurrent symptoms of allergy. For this patient, who possessed an intense IgE-mediated allergy to penicillin, less than 1 unit (<0.6 g) of penicillin per day was sufficient to provoke allergic symptoms. The elimination of her symptoms by the addition of penicillinase to her milk may be taken as evidence that preformed penicilloyl-milk protein complexes were not a major contributor to the elicitation of her allergic reactions. Stricter governmental enforcement of FDA regulations concern- ing penicillin-contaminated milk has reduced considerably the occult intake of penicillin by the general population over the past two decades. By the mid-1960's the prevalence of penicillin-adult ~ (Huber, 1971b). recently as 1969, Wicher et al. reported an acute allergic reac tion in a highly penicillin-sensitive patient who had ingested commercially available milk containing penicillin at approximately 10 units/ml. orated milk in the United States had dropped to 0.5% As
309 Current FDA regulations prohibit measurable penicillin resi- dues in milk offered for sale in the United States. Virtually all penicillin contamination of milk products can be traced to the therapeutic use of antibiotics in livestock and not to the use of animal feeds containing subtherapeutic doses of penicillin. Thus, the existence of allergies in humans that are attributable to penicillin-contaminated milk can be considered irrelevant to the substantive issue before the committee, namely, the health hazards of subtherapeutic doses of antibiotics. However, these cases of allergy induced by penicillin-contaminated milk provide useful in- formation regarding minimal threshold doses required for provoking allergic symptoms in highly sensitive patients. Nonmilk Foodstuffs A single case report from the Federal Republic of Germany (Tscheuschner, 1972) documents acute angioedem~ and pruritus in a penicillin-allergic patient who ingested freshly processed meat from a pig that had been given a therapeutic injection of peni- cillin 3 days prior to slaughter. Analysis of the ground pork revealed a penicillin content of between 0.3 and 0.45 units/g of meat. Since the patient noted symptoms after the first bite of the ground pork, the minimum allergenic dose for this patient was likely to have been less than 10 units of penicillin. In France, Cany (1977) reported five cases of urticarial reactions apparently induced by ingestion of food contaminated with antibiotics. Unfortunately, the antibiotic residue contained in the foodstuffs was not determined nor was the antibiotic sensi- tivity of the patients confirmed immunologically. Nevertheless, taken together, these descriptive case summaries raise the possi- bility that antibiotic-contaminated foodstuffs may be responsible for triggering allergic reactions more frequently than is generally appreciated. Additional study of antibiotic residues in meat pro- ducts produced in France would be helpful in further evaluations. The literature contains no other documented cases of allergic reactions attributable to residual antibiotics in animal tissues other than milk. LEVEL OF ANTIBIOTIC RESIDUES IN NONMILK FOODSTUFFS T _ Penicillins have a relatively short half-life and are rapidly eliminated from mammalian tissues after discontinuation of therapy.
310 Tetracyclines are excreted fairly rapidly in urine but may require 4 to 5 days to disappear from soft tissues. Moreover, they have a high affinity for bones and teeth. Messersmith et al. (1967) demonstrated that pigs fed up to five times the usual recommended concentration of penicillin in their feed (50 g of penicillin/ ton) continuously for 14 weeks had undetectable (<0.025 units penicillin/g) penicillin residues in edible tissues within 0, 5, and 7 days after withdrawal. In the same study, residues in pigs fed up to 500 g of chlortetracycline/ton continuously for 14 weeks were less than l ppm in all tissues in all sampling periods. In 1970 Huber (1971b) studied the prevalence of antibacterial drug residues in more than 5,000 animals at the time of slaughter. Tissues, urine, and/or feces were collected from swine, sheep, cattle, and poultry. Antibiotic residues ranged from a low of 9% in beef cattle to a high of 27% in swine. Tetracycline residues were found more frequently than were penicillin residues. This and similar surveys (Dean et al., 1964) indicate that exposure to antibiotic residues in foodstuffs by the general public has been appreciable. In view of the elimination studies by Messersmith et al. (1967) and others (Huber, 1971a), the widespread antibiotic resi- dues in edible meats as late as 1970 suggest that antibiotics were used frequently in therapeutic doses and/or that required periods for withdrawal from antibiotic-enriched feeds were being widely ignored. More recent surveys have reported that penicillin residues were found infrequently in edible meats except when the animals had received injections of penicillins (Food and Drug Administration, 1978~. No tetracycline residues were detected among thousands of meat samples analyzed in 1976 (Food and Drug Administration, 1978~. In the United States the impact of these tissue residues on human allergy may be mitigated somewhat by the fact that most edible meats are cooked prior to consumption. Chlortetracycline is changed by cooking into isochlortetracycline, a compound without known biological activity (Shirk et al., 1956-1957~. Similarly, the antibacterial activity of penicillin (and presumably its aller- genic potential) is significantly reduced by heating (Shahani et al., 1956~. RISK ASSESSMENT In view of the paucity of clinical, experimental, and epidem- iological data, precise estimates of the risk of acquiring or mani- festing allergic disease as a result of antibiotic residues in human
311 foodstuffs are impossible to derive. Nevertheless, several ob- servations can be made in an attempt to set the potential human health risks in perspective. First, it seems highly unlikely that a sizable proportion of those individuals ingesting foodstuffs containing trace quantities of antibiotic residues will become sensitized to a clinically significant degree. This assertion is based on three facts: · There is no evidence that such primary sensitization occurred, even after ingestion of penicillin-contaminated milk. Of course this does not prove that sensitization does not or cannot occur, but merely that clinically apparent cases are very rare or nonexistent. · In this age of antibiotics, exposure to penicillin (and other antibiotics) in therapeutic doses is very common, and the prevalence of prior therapeutic exposure to antibiotics among the adult population is appreciable. Thus, an individual is at many orders of magnitude greater risk of becoming sensitized to penicillin after treatment with a prescribed course of antibio- tic than after ingestion of antibiotic residues in food. This supposition reflects the frequency of antibiotic prescription. ~ Moreover, a greater rate of sensitization is to be ex- pected from high (therapeutic) doses of antibiotics than from the low-level exposures from foodstuffs. However, we know virtually nothing about the immunogenicity of chronic low-dose administration of penicillins and tetracyclines in human popu- lations. Clearly, such studies would be useful in defining further the risk potential for antibiotic sensitization by low level exposure. Of greater potential concern for human health is the potential provocation of an allergic reaction in a previously sensitized individual by ingestion of antibiotic residues. Here again the literature contains only a sparse number of references to allergic reactions that are traceable to antibiotic residues in foods. Almost all of the cases reported have to do with penicillin-contaminated milk, a moot issue from a regulatory point of view, although there is certainly reason to continue monitor- ing compliance to existing regulations. The case reports dealing with sensitivity reactions to peni- cillin-contaminated milk have led us to appreciate that very small
312 quantities of antibiotics are required to elicit clinically significant allergic reactions in very sensitive individuals. Apparently, some exquisitely sensitive individuals can experi- ence adverse reactions to levels of penicillin that are unde- tectable with standard assay methods. Judging from the rarity of such cases, however, it is not unreasonable to conclude that either most penicillin-allergic patients are not adversely affected by penicillin residues in contaminated milk and/or milk supplies are not frequently contaminated with penicillin residues. The second conclusion is demons/ratably true. The first conclusion is also likely to be correct since there has been little evidence that widespread contamination has resulted in a flurry of allergic problems, even during the early 1950's when the prevalence of contamination of milk by penicillin was 7% to 15% in the United States. Using the conservative estimate that the incidence of peni- cilloyl IgE antibody in the general population is 1 in 50,000 and the assumption that 1% of penicillin-sensitive patients may have ingested penicillin-contaminated milk over 1 year in the early 1950's, one could expect an appreciable number of milk- induced allergic reactions if the contaminated milk supplies were capable of eliciting allergic reactions in an appreciable number of sensitive individuals. This analytical approach leads one to the tentative conclu- sion that antibiotic-contaminated foodstuffs can provoke allergic reactions in highly sensitive individuals, but these reactions appear to occur only rarely. Thus, the admittedly sparse data indicate that there appears to be no reason to implicate antibiotic residues in animal foods as a significant source of allergic disease, either potential or actual, for the public at large. CONCLUSIONS AND RECOMMENDATIONS Based upon the above analysis' the following conclusions appear warranted. (1) There is little reason to believe that foodstuffs ob- tained from animals fattened with antibiotic-supplemented feeds impose a significant risk to human health by con- tributing to antibiotic-induced allergic reactions.
313 (2) Data are currently lacking with regard to the clini- cal consequences of oral administration of antibiotic residues to patients with various degrees of provable allergic sensitivity and the capacity of antibiotic residues to engender a specific Immune response in a genetically susceptible individual who ingests them chronically in low doses. The following investigations could be undertaken to provide more definitive information on this question: ~ A study of the content of penicilloyl-protein complex in edible tissues from animals who have been fed subtherapeutic amounts of penicillin in their feed. Since the penicilloyl-pro- tein complex may have a much longer half-life than does the free penicillin molecule and since penicilloyl protein conjugates are much more immunogenic than free penicillin, such a study would provide needed information on the presence or absence of a poten- tially Important Immunogenic residue, which until now has been ignored. Epidemiological studies of the incidence of penicillin antibodies among populations frequently ingesting foods with peni- cillin residues versus similar populations not regularly consuming such antibiotic residues. Careful attention would have to be given to matching the exposure to therapeutically administered penicillin in both groups. Ideally, this study might be best conducted among individuals who can provide documentation that they have never re- ceived penicillin therapeutically.
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