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INTRODUCTION
Anti-microbial drugs are often used in food producing animals to treat, prevent and control disease as well as improve growth and feed efficiency. Animals are known to be reservoirs of bacteria that cause disease in humans. Many such zoonotic pathogens may be transmitted to humans through cross contamination along the food chain e.g. Campylobacter from chicken. When an animal is treated with an anti-microbial drug, selective pressure is applied to all bacteria associated with that animal. Bacteria that are sensitive to that anti-microbial are killed. Bacteria that have the ability to resist the anti-microbial drug can persist and replace the sensitive bacteria. In addition, bacteria can become resistant when resistant genes are passed from a resistant bacterium to a sensitive bacterium. Thus anti-microbial drugs may increase the prevalence of resistant strains that are a potential health risk to humans.
In many countries therefore, before any animal anti-microbial drug can be approved, the manufacturer must demonstrate safety for consumers and the animals in which it will be used. Also, to assure consumers of the safety of anti- microbial drugs, food standards agencies may use risk analysis methodology to determine food safety standards regarding anti-microbial residues levels in food products of animal origin.
Thus, risk analysis is a methodology underlying the development of food safety standards. Risk analysis follows the same procedures for both chemical and microbiological hazards but only differs in risk assessment techniques. It is composed of three separate but integrated elements,
1. Risk assessment
2. Risk management and
3. Risk communication.
RISK ASSESSMENT
Risk assessment is a method of systematically organising scientific and technical information, and its associated uncertainties, to answer specific questions about health risks. It requires evaluation of relevant qualitative and quantitative data and selection of models to draw inferences from that information.
Hazard identification, in which a determination is made as to whether human exposure to the anti- microbial agent in question has the potential to increase the incidence of bacterial resistant strains in humans. The purpose of the hazard identification step is to determine whether the agent in question poses a resistant effect in exposed humans. The major types of evidence can be derived from:
(1) human studies of the association between resistant effect and exposure to the agent
(2) Long-term animal studies under controlled laboratory conditions.
Exposure assessment identifies the exposed population, describes its composition and size, and presents the type, magnitude, frequency, and duration of exposure
Dose-response assessment defines the relationship between the dose of an agent and the likelihood of a resistant effect. A quantitative relationship is derived between the dose, or more generally the human exposure and the probability of induction of a resistant effect.
Risk characterisation combines exposure and dose-response assessments to produce a quantitative risk estimate. Strengths and weaknesses, major assumptions, judgements, and estimates of uncertainties are discussed and evaluated.
Dose-response extrapolation model
In order to be compared to human exposure levels, animal data need to be extrapolated to doses much lower than those studied. Because risk at low exposure levels cannot be measured directly either by animal experiments or by epidemiological studies, a number of mathematical models have been developed for use in extrapolating from high to low doses. Different extrapolation models or procedures, while they may reasonably fit the observed data may lead to large differences in the projected risk at low doses. This extrapolation procedure is uncertain both qualitatively and quantitatively. The nature of the hazard may change with dose or may disappear entirely hence the uncertainties of quantitative risk assessment.
Uncertainty in risk estimates
Although scientists can estimate risks caused by chemicals in animals experimentally, converting these estimates to those expected in people under a wide range of conditions is difficult, and can be misleading.
By their nature, risk estimates cannot be completely accurate. The main problem is that scientists don't have enough information on actual exposure and on the effects of the chemical on humans.
Dose-response relationships often rely on assumptions about the effects of chemicals on human cells for converting results of animal experiments at high doses to human exposures at low doses.
Exposure assessment often relies on computer extrapolation models.
The extrapolation of results of animal studies to the human situation may produce two types of uncertainties: (a) uncertainties with respect to the relevance of the experimental findings to the humans. (b) Uncertainties with respect to specific human sensitivity for effects of a chemical that cannot be studied in experimental animals.
When information is missing or uncertain, risk analysts generally make assumptions that tend to prevent them from understanding the potential risk.
RISK MANAGEMENT
Risk management is defined within Codex as the process of weighing policy alternatives in the light of the results of risk assessment and, if required selecting and implementing appropriate control options, including regulatory measures. Risk assessment information is used in the risk management process in deciding what measures to take to protect public health. At international level (within Codex), examples of risk management actions may include development of a new food safety standard (Maximum Residue Level, MRL), changing the GAP (Good Agricultural Practice) in order to reduce the MRL or issuing new guidelines and recommendations regarding use of the anti-microbial drug. At national level, examples of risk management options may include withdrawal of certain uses of the anti-microbial drug to limit human exposure, new regulatory measures regarding its use or taking precautionary measures like a temporary ban until there is more concrete scientific evidence about its potential heath effects and control measures.
Essentially, risk assessment provides INFORMATION on the health risk, and risk management is the ACTION taken based on that information.
Relationship between Risk assessment and Risk management
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RISK COMMUNICATION
Risk communication is an interactive process of exchange of information and opinion on risk among risk assessors, risk managers, and other interested parties. Risk analysis links risk assessment with both risk communication and risk management. Sometimes risk communication receives attention as the starting point for risk analysis. In certain situations dialogue with stakeholders including industry, academia, and the general public may be essential at the beginning of risk analysis (Coleman et al 1999). Once the risk associated with an identified hazard is determined, it must be communicated to all stakeholders including consumers and regulatory agencies.
Microbiological risk assessment: Listeria monocytogenes
New challenges to the safety of the food supply require new strategies for evaluating and managing food safety risks. Changes in pathogens, food preparation, distribution, and consumption, and population immunity have the potential to adversely affect human health.
Risk assessment offers a framework for predicting the impact of changes and trends on the provision of safe food. Risk assessment models facilitate the evaluation of active or passive changes in how foods are produced, processed, distributed, and consumed. Aspects of the food processing and distribution system can increase or decrease a potential health hazard. Predicting the impact of a trend in one part of the food continuum requires an understanding of the whole system. While a full understanding of pathogen contamination, infection, and survival is difficult, a systematic approach to assessing the impact of the pathogen on health may improve the quality of public health decisions.
Microbiological risk assessment consists of four steps:
Hazard identification, exposure assessment, dose-response assessment, and risk characterisation. The knowledge in each step is combined to analyse the cause, effect, prevalence and concentration of the pathogen as well as the probability and magnitude of resulting health effects.
A crucial difference between chemical and microbiological risk assessment is that for the latter, exposure models must account for pathogen growth and deactivation, a process known as predictive microbiology.
L. monocytogenes is a microbial pathogen, which has been found in low concentrations in soil, water, vegetation, slaughterhouse waste, animal feed, and the gastrointestinal tract of different animals, including man. The bacterium is resistant to various environmental conditions such as high salinity or acidity. It is able to survive longer under adverse conditions than most other non-spore forming bacteria of importance in foodborne disease. L. monocytogenes occurs widely in food processing environment and can survive for long periods in processing plants, in households, or in the environment, particularly at refrigeration or frozen storage temperatures. Although frequently present in raw foods of both plant and animal origin, it is also present in cooked foods due to post-processing contamination. L. monocytogenes has often been isolated from food processing environments, particularly those that are cool and wet. L. monocytogenes has been isolated in such foods as raw and pasteurised fluid milk, cheeses (particularly soft ripened varieties), ice cream, raw vegetables, fermented raw-meat and cooked sausages, raw and cooked poultry, raw meats, and raw and smoked seafood.
Even when L. monocytogenes is initially present at a low level in a contaminated food, its ability to grow during refrigerated storage means that its levels are likely to increase during storage of food that can support the growth of the micro-organism. However, the ability of the organism to survive and grow in adverse environments and the severity of the illness it causes makes L. monocytogenes a dangerous foodborne pathogen.
L. monocytogenes causes illness by penetrating the lining of the gastrointestinal tract. Once it has invaded the tissue, the organism can protect itself against phagocytosis, grow, and migrate throughout the host. A spectrum of illness severity is observed resulting from exposure to Listeria, ranging from asymptomatic carriers through non-invasive gastrointestinal disease to systemic or invasive conditions. A partial list of systemic illness and disease caused by L. monocytogenes includes bacterial meningitis, Central nervous system, encephalitis, meningo-encephalitis, miscarriages, pre-mature and stillbirth. Milder symptoms associated with listeriosis include diarrhoea, fever and headache, often the result of high doses of L. monocytogenes in otherwise healthy individuals.
Most cases of listeriosis occur sporadically. Mild cases may go unnoticed or unreported and in these cases the cause of the illness is usually not determined. However, there have been some sporadic cases and several large outbreaks where the vehicle of infection was determined or suspected to be food. Not everyone exposed to foodborne L. monocytogenes develops listeriosis. Persons who become ill must be susceptible and receive a sufficient dose of the virulent organism. Most human cases of listeriosis occur in persons that have suppressed immunity. Those most at risk of infection are pregnant women, the elderly, and the immunocompromised. Healthy adults have a relative low risk of illness from L. monocytogenes. Listeriosis in children, adolescents, and young adults is rare but does occur superimposed upon other disorders.
Quantitative risk assessment can be used to estimate the probability of adverse health consequences from microbial pathogens in foods. It has developed recently from techniques used to assess the risk associated with chemical agents. While the basic procedure remains the same, it is more complicated because of the numerous variabilities and uncertainties associated with microbiological agents in food.
Hazard identification
In hazard identification, an association between disease and the presence of a pathogen in a food is documented. The information may describe conditions under which the pathogen survives, grows, causes infection, and dies. Epidemiological and surveillance data challenge testing and scientific studies of pathogenicity also contribute information. Data collected during hazard identification are later used in exposure assessment, where the impact of processing, distribution, preparation, and consumption of the food are incorporated.
Epidemiological and surveillance data is often expensive to obtain and only available in developed countries. Scientific data to link food borne diseases with causative agents is absent in most developing countries. Hazards identified and foods implicated depend on food production systems, dietary, handling and food preparation customs of local communities. Such data is often not available in developing countries making hazard identification extremely difficult.
Exposure Assessment
Exposure assessments utilise information and data gathered during hazard identification to describe the pathways through which a pathogen population is introduced, distributed, and challenged in the production, distribution, and consumption of food. This step differs from hazard identification in that it describes a particular food-processing pathway. Depending on the scope of the risk assessment, exposure assessment can begin with pathogen prevalence in raw materials (e.g., a "farm-to-fork" risk assessment), or it can begin with the description of the pathogen population at subsequent steps (e.g., as input to a food-processing step). In any case, the intent of risk assessment is to track the pathogen population and estimate the likelihood of its being ingested by the consumer. By completing the pathway to the consumer, we incorporate the important issues of dose-response assessment.
Dose response assessment
As with chemical risk assessment this step provides an estimate of the number of bacteria necessary to cause disease in various populations.
Dose-response assessment is used to translate the final exposure to a pathogen population into a health response in the population of consumers. This step is very difficult because of the shortage of data on pathogen-specific responses and because those responses depend on the immune status of the host (consumer). The differences in response among various susceptible populations are important features in this step.
Information is obtained on the overall number of listeriosis cases and outbreaks, the overall relative rates of illness, and the differences in the severity of manifestation of the disease. Such information is usually obtained from epidemiological data gathered in surveillance, outbreaks and sporadic case studies. Information on which to base dose-response estimates is usually insufficient and difficult to obtain. And if it is available, it is usually inaccurate for various reasons. L. monocytogenes contaminated food exhibits a range of organism virulence. For example, Listeria mocytogenes rarely affects all those who ingest the contaminated food. Human sub populations exhibit varying degrees of susceptibility to listeriosis. The variability in susceptibility would influence the number of organisms required to produce illness and the type of illness produced.
There is also variability in the relationship between the physical/ chemical nature of a Listeria-contaminated food and the fate of the organism following ingestion. Some food e.g. fatty foods tend to protect the organism during its passage through the gut while others don't. Thus, estimates of the number of micro-organisms responsible for an outbreak are sometimes inaccurate because the laboratory determination of numbers of organisms in implicated food (the dose) may not reflect the numbers actually consumed as a result of increase or decrease of numbers from the time of ingestion to the time of the analysis. The minimum dose required to cause illness is difficult to determine.
Risk assessments for Listeria and other micro-organisms usually rely on dose-response data generated from human feeding studies, which are done using healthy male volunteers. Such data tends to underestimate the risk of certain segments of the population. Another means of obtaining dose-response data is from outbreaks. Data from both outbreak and feeding studies show that the doses required to cause illness differ greatly among types, genera, species and strains of Listeria (CAST 1994). In the absence of accurate dose-response data, data is usually extrapolated from related pathogens whose data is already available or data is generated statistically using hypothetical dose-response curves.
Exposure characterisation
This step determines the probability of contact with or consumption of a pathogen. Determining the quantity consumed is another area of uncertainty with micro-organisms. When addressing exposure to chemicals, assumptions can be made regarding use rates and persistence in foods. Micro-organisms, however, occur in foods through various routes, which relate to the ecological niche of the organism, and/or to the production, processing and storage practices used. Foods involved in an outbreak are analysed for specific pathogens. Ecological studies are done to determine where specific organisms originate. The second element to exposure characterisation is the concentration (quantity) of the organism in a food. When dealing with chemicals, it is easy to determine the concentration because it rarely changes. However, with Listeria and other bacterial pathogens, populations are in a dynamic state. Thus, exposure estimates must be based on predictions, which account for potential to multiply or die in the food. Another factor that must be accounted for in exposure characterisation is that micro-organisms are seldom homogeneously distributed in foods. Thus, analysing foods for pathogens to estimate potential exposure will never yield results, which are absolute. Storage and preparation steps usually increase or decrease the level of pathogens in the foods eaten. Since sampling is never done at the point of consumption, there will always be inherent errors in exposure estimates.
Risk characterisation
Risk characterisation involves integrating the information gathered in the previous steps to estimate the risk to a population, or in some cases, to a particular type of consumer.
Deterministic - threshold models
Dose-response models can be used to define the risk of infection. These models assume a minimum, threshold dose before the response occurs. In a given population the variation in the minimal dose can be described by a distribution. For instance, the Log-Normal model assumes that the minimal dose is normally distributed (Haas 1983), whereas the Log-Logistic model assumes that it follows a logistic distribution.
Both these distributions are symmetrical about the mean, but the log-logistic distribution allows for more variance away from the mean.
However, the absence of human data, the incomplete epidemiological information available, the difficulties in extrapolating from animal data to humans, and a lack of mechanistic models are all limiting factors which contribute to the uncertainty in the description of the dose-response relationship.
Factors complicating Listeria monocytogenes risk assessment
As already mentioned, there are many factors which complicate the assessment of risk presented by Listeria monocytogenes. The most significant is that Listeria monocytogenes may originally be present is very small numbers that are difficult to detect and harmless at those levels but its potential to survive and multiply in extremely low temperatures makes its population very dynamic making it difficult to quantify the associated risk. Other factors that may influence levels of Listeria in food are:
Physical treatments such as hot holding which may kill some of the organisms; refrigeration or holding food at 4 to 5 degrees centigrade will allow slow growth and multiplication.of the organism.
The response of a human population to exposures to a foodborne pathogen is highly variable, reflecting the fact that the incidence of disease is dependent on a variety of factors such as the virulence characteristics of the pathogen, the numbers of cells ingested, the general health and immune status of the hosts, and the attributes of the food that alter microbial or host status. Thus, the likelihood that any individual will become ill due to an exposure to Listeria is dependent on the integration of host, pathogen, and food matrix effects.
Because of the difficulties associated with quantitative risk assessment, industry and governments continue to rely on experts' judgement that have previous knowledge on the intrinsic properties of foods and the potential for contamination or abuse to provide a qualitative estimate of hazards of public health significance associated with a food or processing operation. Thus, qualitative risk assessment still remains a more realistic methodology to conduct microbiological risk assessment.
REFERENCES
1. Anderson, S. A., Yeaton, W., & Crawford L. M. (2001). Risk assessment of the impact on human health of resistant Campylobacter jejuni from fluoroquinolone use in beef cattle. Food control journal, 12 (1), 13-23.
2. Bernard, D. T., & Scott, V. N. (1995). Risk assessment and food-borne micro- organisms: the difficulties of biological diversity. Food control journal, 6 (6), 329-333.
3. Coleman, M. E., & Marks, H. M. (1999). Qualitative and quantitative risk assessment. Food control journal, 10 (4-5), 289-297.
4. Haas, C. N. (1983). Estimation of risk due to low doses of micro-organisms: a comparison of alternative methodologies. Am. J. Epidemiol. 118, 573-582.
5. Hathaway, S. C. (1983). Risk assessment procedures used by the Codex Alimentarius Commission. Report of the 20th Session: FAO/WHO, Rome.
6. FAO and WHO, 1995. Application of Risk Analysis to Food Standards Issues. Report of the joint FAO/WHO expert consultation. Geneva, Switzerland, 13-17 March 1985. WHO, Geneva.
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