Chloramphenicol revisited -- zero tolerance both problematic, ‘ever-moving'

Zero Tolerance Both Problematic, ‘Ever-Moving' are not as effective. In the Netherlands, a number of registered pharmaceuti- cal products incorporate chlorampheni- col, mainly in formulations used to treat eye infections. Chloramphenicol is also used intravenously against in- fections like meningitis.
With regards to the presence of chlo- ramphenicol in the aquatic environ- ment, these human uses beg the ques- tion of whether surface waters could be a source for food product contami- nation. Several pharmaceutical com- pounds have already been detected in the aquatic environment in Germany. Focusing on the presence of antibi- otics in sewage treatment plant efflu- ents and surface water, a German re- search group led by R. Hirsch pub- lished in 1999 an analysis of water sam- ples for 18 antibiotic substances from As test equipment like this high-performance liquid chromatography system continues the classes of macrolid antibiotics, sul- to advance, it will be able to detect ever-smaller concentrations of test compounds. fonamides, penicillins, and tetracy- Some in the seafood industry question the rationale of such "limitless" testing. clines. Remarkably, chloramphenicol J. C. Hanekamp, Ph.D. munity indicates that chlorampheni- was detected in the effluent of a sewage CEO, The Heidelberg Appeal col risks are regarded as real by Euro- plant in southern Germany at a maxi- Nederland Foundation pean regulators, in addition to being a mal concentration of 0.56 μg/l and in P. O. Box 75311 solid and functional trade-protecting surface water at a maximum concen- 1070 AM Amsterdam instrument. Moreover, zero-tolerance tration of 0.06 μg/l. The Netherlands policies expound a clear notion of in- fringement, which is solely related to illegal veterinary use.
Human uses of
In my recent work on this issue, it By 1993, the Joint FAO/WHO has become clear that with regards to
beg the question
Expert Committee on Food Additives chloramphenicol, international trade of whether surface
concluded a risk assessment concern- is dealing with a multisource issue not waters could be
ing the most significant risk of human recognized or understood by govern- chloramphenicol exposure, aplastic ane- ments. This is because Council Regu- a source for food
mia, as follows: lation EEC No. 2377/90 only deals with "The Committee noted the extreme- one source: actual veterinary use. Any ly low overall incidence of aplastic ane- detection of chloramphenicol is re- Alliance. Do not reproduce without permission.
mia and the lack of association between garded as a violation of law, as the de- Medicinal products are eventually tection is only framed in terms of ille- the ophthalmic use of CAP (chloram- excreted – metabolized or unmetabo- gitimate veterinary application. lized – by their consumers. The de- phenicol) and aplastic anemia. It con- tected presence of chloramphenicol cluded that human exposure to CAP Clinical Use
was probably the result of human use residues in food of the same order as Of Chloramphenicol,
and possibly some sporadic veterinary exposure resulting from systemic up- use. However, a large number of ground take after ophthalmic use would not Chloramphenicol is still used in water samples were taken from agri- cause any demonstrable alteration in human medicine. It has a wide spec- cultural areas in Germany, and contam- the incidence of the disorder." trum of activity against Gram-positive ination with antibiotics was detected However, the continued adherence and Gram-negative bacteria. Chloram- at only two sites. Furthermore, manure to zero tolerance of chloramphenicol phenicol therapy is usually restricted is not usually disposed of together Copyright 2003, Global
residue in food by the European Com- to serious infections when other drugs with municipal wastewater. 60 GLOBAL AQUACULTURE ADVOCATE OCTOBER 2003
This indicated that flux from vet- the soil, as stated in the Hazardous Sub- that at the very low end of the scale, erinary applications to the aquatic en- stances Data Bank, an online database food matrix artifacts to which ELISA vironment are of negligible importance produced by the National Library of responds cannot be differentiated from in Germany, which leaves us with the a real presence of chloramphenicol.
human applications of chlorampheni- The question of whether nature it- The reality of false positives is a well- col or its natural production by the self could be a source of chlorampheni- known problem in the analytical sci- col in food products, apart from the hu- To give some idea of human chlo- man clinical use, needs to be answered.
Illustrative of this are the results ramphenicol consumption, S. F. Webb To that end, the Instituto Technológi- obtained in a recent collaborative trial estimated the national human con- sumption of chloramphenicol in the United Kingdom at 377 kg/year in 2001. However, the International Pro- Figure 1.
gramme on Chemical Safety's Chem- Development ical INCHEM website reported that of the detection sales of chloramphenicol are 11-440 limits of chlo- times greater in Hong Kong than sev- ramphenicol eral western countries and Australia.
in milk powder. Environmental contamination of sur- face water as a result of human use is therefore expected to be much higher in Asia than Germany and other Euro- When considering other compounds of Annex IV of Council Regulation EEC No. 2377/90, metronidazole is co Agroalimentario (AINIA) – an ac- by U. Schröder in Germany in which also of interest, as it is used clinically credited nonprofit institution in Spain shrimp with predefined amounts of like chloramphenicol, but in much created by, among others, companies chloramphenicol added were tested higher quantities. Among other appli- in the food-manufacturing sector – sam- with blank "unspiked" shrimp. In sum- cations, metronidazole is prescribed pled ready-to-sell food products ac- mary, 50% of the participating labora- in cases of protozoal infections. In the quired from retailers for the presence tories designated blank shrimp as pos- U.K., S. F. Webb estimated that about of chloramphenicol. Using a commer- itive for chloramphenicol using vari- 15.5 mt/year are clinically used. The cial enzyme-linked immunosorbent ous analytical techniques – worrying worst-case predicted environmental assay (ELISA) kit, the group detected results, given the present political per- concentration of metronidazole was chloramphenicol in numerous prod- turbations. Alternatively, they could estimated at 2.85 μg/l. ucts at very low levels. reflect a natural background level of When considering the environmen- These results were at best ambigu- chloramphenicol, as indicated by the tal persistence of metronidazole (over ous, however, as in only one case was AINIA results. However, any given a year), the reasonable assumption chloramphenicol confirmed by high- sample would have been judged posi- would be to find metronidazole in sur- performance liquid chromatography- tive by these laboratories for chloram- face waters. As with chloramphenicol, mass spectrometry. But the confirmed phenicol and removed from the market.
routine clinical use of metronidazole sample does represent an interesting – could find its way into the food chain via the aquatic environment, and re- The detection of analytes has im- sult in another misguided food scare.
The question of
proved dramatically during the past whether nature
decades, including methods used for the detection of chloramphenicol (Fig- itself could be a
Of the approximately 12,000 an- ure 1). For instance, the sensitivity of source of chloram-
tibiotics known, it is the estimated that liquid chromatographic mass spectro- some 160 are, or have been, used as hu- phenicol in food
metric method equipment has im- man medication. Streptomycetes, which products needs
proved tenfold in the last six years, account for well over half of these and its fundamental limit has not yet to be answered.
commercially and therapeutically sig- been reached. One can expect that de- nificant antibiotics, are among the most tection of chloramphenicol in parts abundant and ubiquitous soil bacteria.
albeit unexplainable – caveat for the per trillion will become feasible in the Of all the actinomycete isolations from possibility of a natural bacteriological next decade.
soil, about 90% are Streptomycetes. It source of chloramphenicol in the food Currently there is some confusion is therefore no surprise that it is possi- chain, which merits further research about the minimum required perform- ble to isolate chloramphenicol from in this area.
ance limits (MPRL) for chemical resi- Streptomyces venezuelae present in A problem with the AINIA data is dues. MRPLs are no more and no less GLOBAL AQUACULTURE ADVOCATE OCTOBER 2003
to the international market. Zero tol- erance is an ever-moving target that Diagram of a chloramphenicol requires total compliance of trade part- ners with no regulatory contribution In order to circumvent regulatory than the concentration levels that reg- of exposure to such dosages is negli- zero-tolerance instincts, first relevance ulatory laboratories in the European gible. Any reference to risk as a result levels need to be formulated, taking the Community should be able to detect of low-level exposure to chlorampheni- multisource issue into account. Sec- and confirm. The MRPLs should not col is at odds with scientific fact. ond, to eliminate differences between be mistaken for tolerance limits or any Clearly, zero risk is not realistic, exporting and importing countries, similar terminology. and this is even more pertinent when consensus has to be reached on the European Union regulatory labora- considering the multisource aspect of standardization and use of analytical tories are obligated to try and find resi- chloramphenicol, which has never been equipment. To achieve these goals, the dues of banned substances like chlo- addressed when reviewing the chlo- European Community must liberate it- ramphenicol at the lowest technically ramphenicol issue. The precautionary self from the zero-tolerance approach, possible concentrations. As a result, and zero-tolerance solution to illicit use is and the exporting countries must in- depending on the skills and equipment utterly ineffectual, as no distinction can vest in new analytical technology.
of laboratories, a concentration lower be made at the low levels dealt with here Within the greater World Trade Orga- than MRPL can lead to a positive or between environmental contamination, nization framework, these must also "noncompliant sample" result. potential natural presence, and fraud. become goals for both industry and The E.U. policy of zero tolerance Considering the vast area of organ- can also lead to economic inequality.
ic geochemistry and secondary metab- Products designated as safe by an ex- olisms of numerous organisms, the an- porting country may be designated non- alytical field is bound to turn up nu- The simple inference
compliant if the importing country merous surprises in the future, as lim- espoused by
uses a more sophisticated method of its of detection continue to decrease.
analysis that results in lower detection More and more chemicals – from in- distinguishable sources – will turn up EEC No. 2377/90 –
in our food, whereby regulators will that chloramphenicol
add to the confusion of risk. Compli- detected in food
The simple inference espoused by ance with zero-tolerance regulation will Council Regulation EEC No. 2377/90 eventually be unattainable. It will be- products is solely
– that chloramphenicol detected in food come a legal artifact of the analytical the result of illicit
products is solely the result of illicit use in food produc-
use in food production – is false. Even This brings us to another flaw of if chloramphenicol is sometimes used precaution, namely that by the regula- tion – is false.
illicitly in food production, the risk of tory choice for zero tolerance, the risk contracting aplastic anemia as a result of noncompliance is transferred fully 62 GLOBAL AQUACULTURE ADVOCATE OCTOBER 2003

Source: http://pdf.gaalliance.org/pdf/GAA-Hanekamp-Oct03.pdf