RISK ANALYSIS

4. RISK ANALYSIS

4.1. Principles

Risk analysis is a process composed of hazard identification, risk assess- ment, risk management, and risk communication (Figure 1). It encompasses assessing and managing the risk together with the appropriate communication between risk assessors, stakeholders, and risk managers. Typically, a policy framework is established by risk managers to describe the types of risk that need to be addressed. A strategy for assessing the risk is formulated in consul- tation with technical experts and risk assessors. The policy framework also provides an explanation of the type of risk management options that can be considered under the legislative and regulatory framework of the country. Finally, the policy framework should explain the risk decision-making process, including methods for evaluating and quantifying risks and the level of risk deemed to be acceptable (European Commission, 2000; Vose et al., 2001). The risk assessment is a step-by-step approach with regular exchange with risk managers. A preliminary qualitative assessment is recommended by the OIE

Risk Management Brief description of the situation, product or commodity involved

Values expected to be placed at risk (e.g. human health)

Assessment of effectiveness of

A. Risk Evaluation

Potential consequences Consumer perception of the risks

measures taken Distribution of risks and benefits Review risk management and/or assessment as necessary

D Value judgements and . Monitoring and review

1. Identification of a food safety problem

3. Ranking of the hazard for risk assessment and 2. Establishment of a risk profile policy choice for the risk

assessment process conducting a risk assessment 4. Establishment of risk assessment policy for

risk management priority

5. Commitment of resources

Hazard identification

Risk Communication

7. Consideration of risk assessment result 6. Commissioning of risk assessment

Hazard characterisation Exposure assessment Risk characterisation

C. Implementation of management decision

Risk Assessment

B. Risk management option assessment

Risk perception Value judgement Precautionary principle

Identification of available management options Benefits costs Selection of preferred management option, including

Other technical factors consideration of an appropriate safety standard

Final management decision Regulatory or other control measures

Figure 1. Risk evaluation (DG Health and Consumer Protection, 2000).

ad hoc group (Vose et al., 2001) to advise risk managers on the feasibility of quantitatively assessing the risk and on the identified risk management strate- gies. The report is made public. On the basis of this report, managers will determine whether the risk is sufficiently severe to warrant further action. If the risk is considered sufficiently important and if it is feasible, risk man- agers may then instruct risk assessors to fully assess the risk (qualitatively and/or quantitatively) and the reduced level of risk that would exist after each identified risk reduction option. Through several iterations, the risk assess- ment and the risk reduction options are refined. The aspect of risk communi- cation is particularly helpful in ensuring transparency of the risk analysis as a whole and the efficient collection of data. On the basis of the result of the risk assessment, risk managers determine the appropriate actions to take in order to manage the risk in the most efficient manner and make public their decision. Risk managers have to implement their decision and organise the follow-up of these regulatory and other measures in order to evaluate the impact of these decisions. The data collected by the follow-up must be assessed in order to allow possible amendments of the risk analysis policy, the assessment strategy, the outcome of the scientific assessment and the regulatory and other actions that have been taken.

Several reports about antimicrobial resistance in bacteria from animal ori- gin have been established in different member states and at the level of the European Commission. In the case of several antimicrobials used as feed addi- tives, the risk decision of the risk manager (DG Health and Consumer Protection) was based on a review of the opinion of the scientific committee on animal nutrition, member states reports and now, the opinion of the European Food Safety Authority (EFSA).

As the antimicrobial resistance risk is combined with a microbiological risk, the progress of risk assessment is linked with the development of knowl- edge and tools for qualitative, semi-quantitative, and quantitative risk assess- ment. The risk assessment process is subdivided into four components: risk release, exposure, consequence, and estimation (Figure 1). The risk release is the description of the biological pathways necessary for the use of an antimi- crobial in animals to generate resistant strains or resistant determinants into a particular environment, and estimating the probability of that complete process occurring either qualitatively or quantitatively. The fact that data on new compounds (veterinary drugs, additives) has to be provided by the phar- maceutical industry to describe the impact of treatment on the intestinal flora and environment will contribute to our knowledge. Moreover, the knowledge of the epidemiology of some zoonotic bacteria is continuously improved and used to reduce their release by different ways according to the principles of the zoonoses directive (Wegener et al., 2003). The development of the monitoring and surveillance programmes for several antimicrobial resistant

Antibiotic Use in Animals 659

660 Pascal Sanders bacteria, combined with epidemiological studies in herds and food industry,

contributes to the description of the biological pathways necessary for expo- sure of animals and humans to the hazards released from a given source and allows estimation of the probability of the exposure occurring either qualita- tively or quantitatively. These are the objectives of exposure assessment. Several epidemiological studies have been recently published (Helms et al., 2002, 2003) to describe the relationship between specified exposures to a biological agent and the consequences of this exposure. For some zoonotic infections, the presence of antibiotic resistance increases the risk of failure of an antibiotic treatment as well as the morbidity and mortality, notably for people with other diseases (Helms et al., 2003).

4.2. Feed additives

4.2.1. Benefits

Antibiotic usage in animals are analysed as a risk–benefit for animals, producers, and consumers. By common understanding, modern animal agri- culture is practiced with the intent of returning a profit to the livestock pro- ducer. Two economic considerations influence the selection of programmes used by any livestock producer (Gustafson and Bowen, 1997). The first is that many diseases commonly affect groups of animals rather than individuals. It is more economical to prevent a disease than to rely on a treatment. This type of use can prevent death losses as well as the loss of performance that often accompanies both clinical and subclinical infections. These prevention efforts can include a variety of practices, such as immunisation, adequate nutrition, appropriate husbandry practices, and effective sanitation and isolation. In many cases, it will also be appropriate and beneficial to use prophylactic antibiotics during crucial periods of the animal life.

The second economic benefit gained from the use of antibiotics in animal agriculture is derived from the enhancement of some production parameters. They represent an extremely important tool in the efficient production of pork, beef, poultry meat, and other animal products. When used at low (subthera- peutic) levels in feeds, antibiotics improve growth rate and efficiency of feed utilisation, reduce mortality, and morbidity, and improve reproductive perfor- mance (Cromwell, 2002). Using feed additives for the past 50 years improved the consumer access to food from animal origin with a regular price decrease. In the same period, animal genetics, animal husbandry, and feed technology have continuously improved and modified the management of herds. In Europe, the risk associated with the selection of resistant zoonotic bacteria was evaluated in the late 1960s (Swann, 1969) and contributed to the ban of usage

Antibiotic Use in Animals 661 of broad-spectrum antibiotic as additives at subtherapeutic levels in feed.

According to the European directive, only narrow-spectrum drugs active against Gram-positive bacteria are approved as potential growth promoters. Most of them are not used or have a limited usage in human medicine at the first time of approval.

4.2.2. Risk

The work done in Europe by several teams gave good evidence that approved drugs could select for resistant bacteria. For example, the presence of vancomycin-resistant enterococci selected by avoparcin use was demonstrated in the intestinal flora of treated animals, in people in contact with the animals, in the environment, and on the food produced by the animals (Aarestrup, 1999; Klein et al., 1998; Willems et al., 2000). The spread of genetic elements carry- ing resistance genes from animals to consumers was described (Jensen et al., 1998). The final steps in risk analysis which are the passage of the resistant genes to bacteria responsible for human infection have not been assessed. But, using a theoretical approach, it was demonstrated that the animal usage of antibiotics reduced the time needed for emergence of resistant pathogens in human medicine (Lipsitch et al., 2002; Smith et al., 2002).

The available data demonstrate the selection of resistant bacteria in the animal intestinal flora of treated animals and the spread of these bacteria from animals to humans by contact or by food. The data are, however, insufficient to reasonably assess the potential risk issue at the human level. Indeed, preva- lence of resistant enterococci is low in Europe and the worst scenario, which is the emergence of a totally resistant Staphyloccocus aureus after transfer and combination of genetic elements, has not occurred. Moreover, pathogenic E. faecium for humans differ from those of animal origin and harbour specific virulence genes (Willems et al., 2000). The risk manager has considered that the risk is potentially of such severity that one cannot wait for sufficient data before taking action. According to the OIE ad hoc group recommendations and the precautionary principle, it is reasonable for risk managers to take a temporary risk avoidance action that minimises any exposure to the risk. The five points to consider before taking this action have been reached. First, a risk assessment was done on the basis of available data. The risk avoidance action which was a suspension of market authorisation, provided a reduction of antimicrobial resistance in targeted bacteria. This effect was previously observed in Denmark (Monnet, 2000). The action did not limit trade but showed a negative impact of the production cost in comparison with countries outside Europe. The benefit of use of feed antimicrobial additives was detri- mental for the quality perception by the consumer. Even if the risk for human health was not accurately evaluated, the market authorisation suspension was

662 Pascal Sanders

a benefit in term of safety perception by the consumer. The decision was taken in conjunction with a commitment to acquire the necessary data to help assess the severity of the risk. The process remained transparent by the publication of opinions on the web.

4.3. Veterinary drugs

4.3.1. Benefits

Antibiotics are also used to prevent and treat diseases in animals. In the case of bacterial infection, the efficacy of an antimicrobial treatment has to be demonstrated by pre-clinical studies and clinical studies. In experimental infections, antimicrobials reduce mortality and morbidity. The clinical cure of animals is the result of antibiotic activity and immune response. The clinical efficacy shown by clinical signs does not necessarily reflect a bacteriological cure defined as the eradication of bacteria from the site of infection. Few vet- erinary drugs are evaluated on the basis of their clinical and bacteriological efficacy (e.g., intramammary treatment of cow mastitis). For most of them, evaluation is based on clinical criteria such as the improvement of clinical signs (e.g., temperature, cough, or diarrhoea), mortality, and relapse a few weeks after the end of the treatment. Zootechnical parameters, such as feed efficacy and growth rate, are also compared. For ethical reasons, the pre-clini- cal and clinical trials are performed in comparison with previously approved drugs. Data provided by these trials cannot assess whether the ultimate goal, which is a total bacterial cure, is achieved.

4.3.2. Risks

If bacterial eradication does not occur, fewer bacteria are present at the site of infection and the ratio between resistant and susceptible bacteria can be changed allowing a more resistant population to grow and become predomi- nant. The consequences are negative for animal health. The risk for the animal owner is the further development of disease with a higher cost of treatment. The second risk is the transfer of antibiotic-resistant pathogenic bacteria to people in contact with animals (animal owners and relatives, technical staff, veterinary practitioner). The third risk, linked with the exposure of intestinal or commensal flora to antibiotics is the selection in treated animals of antibiotic- resistant zoonotic bacteria (Salmonella spp., Campylobacter spp., verotoxi- genic E. coli, Yersinia spp., etc.). These bacteria could infect people in contact with the animals and could reach consumers via the food chain. The fourth risk is the diffusion of these bacteria in the environment and their spread in soil and

Antibiotic Use in Animals 663 water. The fifth and sixth risks are those related to the selection of antibiotic-

resistant genes in bacteria from the intestinal and commensal flora of animals, with the risk of transfer of these genes to pathogenic bacteria (Blake et al., 2003). All these bacteriological risks are the subject of many discussions and some epidemiological studies of salmonella infection demonstrate their occur- rence (Helms et al., 2002). For some zoonotic infections, the presence of antibiotic resistance increases the risk of failure of the antibiotic treatment as well as morbidity and mortality, notably for people with other diseases (Helms et al., 2003).

The risk evaluation related to antimicrobial treatment is complex due to the combination of different events and the ecology principles driving this risk (Vose et al., 2001). It should be stated that the development of a risk assess- ment framework is on-going in Europe, with the development of knowledge and research in different member states. Most of this research on risk assess- ment is focused on susceptible bacteria (Rocourt et al., 2003; Rosenquist, 2003; Wegener et al., 2003) more than resistant bacteria.

For veterinary medicines, the risk evaluation is very developed and was recently strengthened. The use of antimicrobials by veterinarians contributes to the health of animals. The selection of resistant bacteria depends largely on the conditions of this use. Bad conditions of use, such as the inappropriate choice of antibiotics, dosage, or duration of treatment, will favour the selection and preservation of resistant bacteria. The difficulty is to encourage good prac- tices of use (adequate prescription) which have a limited effect on the selection of resistant bacteria but have a beneficial clinical effect, and to distinguish these from bad practices, that is, useless or inadequate prescription.

4.4. Communication

Communication is a critical step in the risk evaluation process (Figure 1). Communication about antimicrobial resistance selected by non-human use needs to be developed. First, the misperception about modern animal hus- bandry by the general population is well known. Few people in European cities have a personal experience of animal husbandry. This is due to the decreased importance of agriculture in Europe. Moreover, with the development of the bio-security concept in animal production, a large part of animal production is now secured against pathogens by use of a closed environment with limited access. This hides major industrial production, such as poultry and pigs from the general population. Moreover, the development of misperceptions about animal production by consumers has created a need for some people to return to “natural” food. This need has contributed to the development of the concept of organic food which limits the usage of drugs and pesticides and was reinforced

664 Pascal Sanders by the communication around this product even if the advantages are not scien-

tifically demonstrated (Anonymous, 2003). This need was also supported by the development of environmental concerns by European consumers.

Moreover, perceptions about antimicrobial resistance due to animal production have been affected by previous experiences such as hormone administration to calves, and BSE and Listeria outbreaks. The efforts by ani- mal producers, veterinarians, food industry, and administrations to manage these different hazards in the past by implementation of regulations and devel- opment of hazard analysis and critical control point (HACCP) principles are not appreciated by consumers because their effect is countered by each new outbreak highlighted by the media, even if the global frequency of outbreaks has been reduced (Fife-Schaw and Rowe, 1996; Kirk et al., 2002).

To develop communication around antimicrobial resistance in bacteria of animal origin, it is necessary to develop the understanding of physicians about drug usage in veterinary medicine and the control of zoonotic agents in the food chain. Animal producers, in collaboration with veterinarians, have to develop their means of communication on the modern animal husbandry and food industry. The development of quality assurance in animal production con- tributes to the reinforcement of consumer confidence. By developing quality and traceability-based contracts with producers, food producers, and distribu- tors contribute to the development of safety, but they have to regularly verify the compliance with the contract by the way of analytical self-controls. The source of emergent antimicrobial resistant bacteria was thus investigated and identified during an outbreak (Desenclos et al., 2002; Helms et al., 2002). Through the rapid alert surveillance system for food, the production originating from a source (herd, food workshop) was traced and where possible, recalled from the market. Quality assurance provides a powerful tool to control outbreaks and limit health impact but needs a good knowledge of crisis communication by the food-chain manager to manage any new event and limit its economic impact.