Risk analysis and Codex Procedure for MRL of veterinary drugs

Draft documents prepared by France for the CCRVDF

IFAH Comments

"Risk Analysis and Establishment of Maximal Residue Limits for Veterinary Medicinal Products in Foods by the Codex Alimentarius"

• Change title to Veterinary Drugs, as this is the official designation in the CAC procedural manual for therapeutic, prophylactic or production drugs.
• Under paragraph 2. Introduction and under paragraph 4.2.1 Risk evaluation, a reference is made to risk/benefit. Codex does not and should not make determinations on the benefit of a veterinary drug only it’s safety as residues in food. Codex cannot make subjective determinations as to whether a product presents a benefit to a member country, as this is purely the member countries' sovereign right to determine. Codex is not an international registration body but rather a food standard setting organization. Risk/benefit can only be fully implemented by the veterinarian working with the professional livestock manager.
• Under paragraph 4.1.1, Hazard Identification, the last sentence refers to "…the full range of residues". MRLs for antimicrobials are based on the microbiologically-active residue - not on the "full range of residues". There are likely other situations where that last sentence is not true. The first bullet point includes the term "relay bioavailability". The idea that one can feed incurred residues and then detect any meaningful levels in the blood is not within the realm of scientific capability.
• Under paragraph 4.1.2, Hazard characterization, it is stated that if an ADI cannot be established an MRL could still be recommended with an approach that is "pragmatic and prudent". We don’t know what this means but it sounds arbitrary. JECFA must base a decision to set an MRL on some scientific or technical basis. This should be explained.
• In the third paragraph of 4.1.2 we suggest replacing the first two sentences with: "If epidemiological studies could be carried out in humans then it would be possible to directly characterize an adverse effect caused in humans following the ingestion of toxic drug residues. Unfortunately, the difficulty of implementing such a study makes these studies unlikely to be able to identify the adverse effects of low residue levels with the required efficiency."
• In the sixth paragraph of 4.1.2 laboratory animal are "auto-exposed" to the metabolites, as was mentioned in the last paragraph above 4.1.2. It is not assumed that "the toxicity of each metabolite is equal to that of the parent substance."
• Under 4.1.2 bullet point after the seventh paragraph it is not true that a "dose-response relationship must be established".
• Under 4.1.2 we suggest that the paragraph following the 2 bulleted points be deleted. It brings up the issue of quantifying the risk. Although JECFA/Codex has used the terminology for years, there is no real "risk assessment" here. A risk assessment should attempt to estimate the probability of the hazard. The hazard here is an adverse effect in a human due to exposure to drug residue through meat. They use an MRL to try to manage the risk but never establish the level of risk. I don't think they should bring it up; moving in this direction would require a change in the whole approach. They then say "The JECFA procedure is therefore more pragmatic" so let's just describe the JECFA procedure and let it go at that.
• Under 4.1.2 in the paragraph that begins with "This safety factor value of 100…", the last sentence should read: "A NOEL is therefore calculated for each toxicological study and the NOEL with the lowest value will be used to calculate the ADI for the studied substance."
• We have no idea what the last paragraph of 4.1.2 is trying to describe. This needs to be clarified.
• The second paragraph under 4.1.3, Exposure assessment, should read something like: "Estimating consumer exposure is based on the daily consumption of foods combined with the amount of veterinary drug residues in the food."
• Under 4.1.3 the second and fourth bullet points say the same thing. The third one could be expanded beyond young animals to any animals slaughtered at a time longer than the established withdrawal time.
• Under paragraph 4.1.4, Risk characterization, it should be explained that JECFA applies a further level of precaution in establishing MRL’s in compliance with an ADI. The establishment of such a "global ADI" assumes that all countries import all species and commodities where an MRL has been established. This is clearly not a realistic scenario. Countries importing no or very little of certain meat products, such as organ meats or offals are still expected to comply with MRL’s that are set under a total exposure scenario. This adds further to the extreme conservatism of the MRL setting process.
• The second bullet point in 4.1.4 in the second paragraph seems to suggest the possibility of establishing a worst-case residue species. That is great if it is possible, but we think it is a futile suggestion.
• We disagree with the statements made in the seventh bullet point under 4.1.4. This is already considered in the residue evaluation and the proposed withdrawal time. The "10%" estimate appears to be have arbitrarily determined.
• We also disagree with the last paragraph under 4.1.4. This opens the door for CCRVDF to second-guess the scientific decisions made by JECFA. We think this could lead to greater delays in the process if the Committee began to question every data set or estimate that JECFA may have employed during their evaluation.
• Under paragraph 4.2.1, Risk evaluation, the term "socially acceptable risks" is used in two instances. We do not understand what is meant by this term since the JECFA evaluation is based a scientific determination of the risk to public health applying safety factors and conservative assumptions as levels of precaution. Introducing the term "socially acceptable" has a number of meanings in different countries. JECFA should not be making judgements on what is socially acceptable rather on what has been proven safe by all available data. Member countries make these societal judgements not Codex.
• Paragraph 4.2.2, Assessment of management options, is suggesting that the Committee consider factors that are clearly beyond the scope of OLF's identified at the 12^th meeting of CCRVDF. Thus, IFAH recommends that the second and third sentences of that paragraph read as follows:

• The first paragraph in 4.2.2 suggests CCRVDF get involved in the allocation of the ADI among the various food tissues and milk. This is unacceptable. Industry should be able to allocate these values as long as human health is protected by not exceeding the ADI.
• We have serious problems with paragraph 5, Conclusions. It introduces concepts in that were never brought up in the body of the report. Is "a priori limiting" really "more important than estimating a risk to public health"? If so, then this would suggest that we shouldn’t permit these drugs to be used in the first place. It appears to be another way of stating the precautionary principle rather than basing the decisions on sound science and risk assessment. The last sentence is not clear and does not seem to follow anything in the paragraph.

Annex I -"Establishment by CCRVDF of a Risk Assessment Policy For

THE SETTING of Maximal Residue Limits For VETERINARY MEDICINAL Products in Foods."

• Paragraph 2.2.1, Information requested to JECFA, recommends that experimental protocols be specified to assess allergic potential of a substance. It should be stated for what type of compounds this should be developed. Is this to apply to all veterinary drugs? Is this a new requirement suggested for JECFA?
• Paragraph 2.3.1, Information requested by JECFA, suggests that JECFA do a study on the probability of ingestion of injection site residues. Why should JECFA be asked to do this? The CCRVDF is currently considering a paper on injection sites and a previous review of this issue commissioned by COMISA has already estimated the likelihood of exposure.
• Paragraph 2.3.1, Information requested by JECFA, requests that JECFA suggest to CCRVDF a strategy on exposure to residues of endogenous substances. We are at a loss to understand what this means. JECFA is well equipped to review these substances having considerable experience with the beef hormones and rBst. We would delete this suggestion entirely as it focuses unnecessary importance to endogenous substances.
• Paragraph 2.3.3, Estimation of the drug residue level in animal derived food ingested by the consumer, recommends a specific study of consumer exposure to residues in milk to assess health effects on children. This is totally unnecessary. In a discussion of exposure assessment the papers describe in detail the conservatisms inherent in the evaluation noting gross overestimates of consumption, including milk, which are clearly protective of children. We recommend this suggestion be deleted as unnecessary and also very expensive to conduct.
• Paragraph 2.4.2.3, Allocation of the ADI between foods, we don’t understand in the first sentence what is meant by " should be done pragmatically in order to improve the conditions of use of this substance in veterinary medicine." Why should JECFA be attempting to improve the conditions of use of veterinary drugs? It is their function to determine the safety of the residues. Conditions of use should be left up to the registration authority.
• In Paragraph 2.4.2.4, Harmonization of MRL values between various animal species, the second paragraph implies that JECFA should factor in consumer perception regarding MRLs that may be different between species. JECFA should be operating strictly on a scientific basis and should not be arbitrarily adjusting their recommendations to satisfy perceptions that an MRL in one species may be less safe than an MRL in another species because it is different.
• As an overall comment on this section, it appears that many of the difficulties discussed with the allocation of ADIs across foods and species could be alleviated if JECFA and CCRVDF considered the adoption of a risk assessment policy that is more in line with the policies of the JMPR and CCPR. The JMPR tends to recommend MRLs based on good agricultural practices with only a general reference to the ADI. The JECFA in demanding that all MRLs comply precisely with the upper limit of the ADI, unnecessarily hampers their ability to establish MRLs for all species and may limit future applications of new uses of a compound. The most compelling reason to reconsider the policy is that compliance with an ADI at the global level is for all practical purposes an artificial exercise since not all countries import all food commodities that may contain a residue.

Annex II – "Risk Management and Codex Procedure FOR ESTABLISHING MRLS of Veterinary Medicinal Products."

• Recommendation no. 2, suggests that CCRVDF consider utilizing technical dossiers submitted by national or regional authorities. IFAH does not agree with this suggestion and believes JECFA should evaluate the drug substance based on standards and policies established by the committee.
• Recommendation no. 4, again alludes to a risk/benefit ratio in order to facilitate adoption of ADIs and MRLs. The implication is that the Committee should take into account consumer perceptions as to the value of a veterinary drug to society. We completely reject this notion as it is outside the scope of Codex and the CCRVDF to place a value on a particular substance. The job of Codex is to establish safe food standards to assure consumer perception and facilitate fair trade. It is not to make value judgments that would then guide a decision whether or not to establish an ADI or an MRL for a particular compound. It is up to the national authority to utilize risk/benefit to determine whether or not to register that substance in their country.

May 2001