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Assessment of user safety, exposure and risk to veterinary medicinal products in the European Union
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Regulatory Toxicology and Pharmacology 50 (2008) 114–128 www.elsevier.com/locate/yrtph
Assessment of user safety, exposure and risk to veterinary medicinal products in the European Union K.N. Woodward
*
Schering-Plough Animal Health, Breakspear Road South, Harefield, Uxbridge, Middlesex UB9 6LS, UK Received 15 August 2007 Available online 23 October 2007
Abstract Safety is an important part of veterinary drug assessment while user safety is a critical part of the overall safety assessment. In the European Union (EU), user safety is addressed through preclinical studies and by relationships with exposure but a key part of the process is the user safety assessment. EU user safety guidelines are available and these make certain recommendations but in places they lack detail and clarity. This paper seeks to examine the relevant factors that lie behind user risk assessments for veterinary medicinal products in general while focusing on EU requirements, the determination of risk management and risk communication strategies and how this relates to user safety assessment and pharmacovigilance responsibilities. 2007 Elsevier Inc. All rights reserved. Keywords: User safety; Exposure assessment; Risk assessment; Veterinary drugs; Risk communication; Pharmacovigilance
1. Introduction In the development, launch and marketing of medicinal products, safety is clearly of paramount importance. For human medicinal products, this quite rightly gives a priority to patient safety which can be balanced against any risks to arrive at an acceptable strategy for use and indeed, for authorization or approval. Clearly, patient safety is also important for veterinary medicinal products, particularly as animals may have significant emotional or financial values, or indeed both. However, those who use, apply or are otherwise exposed to veterinary medicinal products must also be protected from any potential harmful effects, particularly as veterinary medicines may not always be given under the same clinical conditions normally associated with the administration of human medicines, for example, on the farm. Many veterinary pharmaceutical products contain the same active ingredients as their human counterparts, and potentially toxic substances such as the anti-neo*
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plastic drugs are being increasingly used in veterinary medicine. Moreover, some veterinary medicinal products are administered in such a way that user exposure is more likely, or more extensive than with human counterparts. Examples include vaccination of poultry and dipping of sheep for ectoparasitic conditions. At this point, it is appropriate to emphasize that in the EU, the term ‘‘veterinary medicinal product’’ includes not only pharmaceuticals but also ectoparasiticides (which in the EU are by definition and mode of use pharmaceuticals) and vaccines and other biologics intended for use in both companion and food-producing animals. In fact the formal definition as set out in EU legislation includes substances or combinations of substances intended to treat or prevent diseases or those administered to restore, correct or modify physiological function. This latter category captures products such as those intended to modify or synchronize estrous. Moreover, the definition extends to medicated feeds and premixes formulations and some veterinary homeopathic formulations. However, it excludes some formulations intended as coccidiostats or histomonostats which are covered by separate EU legislation (Anon, 2001).
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In the European Union (EU) user safety assessment is an important and integral part of the overall process of safety evaluation of applications for MAs for veterinary medicinal products submitted to European regulatory authorities. To reflect this, ‘‘safety’’ as a component of MA dossiers includes not only the usual pre-clinical studies, but also a requirement for a safety expert report and a user safety risk assessment (Woodward, 2004a). In fact, the typical MA application dossier for a veterinary medicinal product will cover safety in four areas—user, consumer, patient and environmental. Those relevant to user safety are discussed below. 1.1. Part IIIA (safety) of the EU dossier For both companion and food-producing animals this will contain the normal range of laboratory pharmacology and toxicology studies, normally on the active ingredient itself, administered in a suitable vehicle. The nature of the pharmacology studies will usually be dictated by the type of drug subject to the MA application. In addition to the results of pharmacokinetic studies, there will also be studies designed to demonstrate or even to quantify the desired pharmacodynamic properties of the drug (for example, antimicrobial, anesthetic, analgesic, anti-inflammatory or hormonal effects). The toxicology studies usually comprise, but are not limited to, acute toxicity, repeat dose toxicity, studies on reproductive performance and developmental effects and genotoxicity studies. Carcinogenicity studies may be required for drugs which elicit a positive response in the genotoxicity studies or for those which give rise to suspicion, for example, seemingly precancerous lesions in repeat dose studies. Studies of local effects, including skin and eye irritation and dermal sensitization, are also normally required and nasal pungency and other sensory forms of irritation may also need to be addressed, where necessary by risk assessment approaches (Nielsen et al., 2007). Under some circumstances, more specialized studies may also be required for example neurotoxicity and neurobehavioral studies for organophosphorus compounds and pyrethroids. For antimicrobial drugs intended for use in food animals, studies to investigate potential effects of microbiologically active residues on the human gut flora are also essential. 1.2. Safety expert report All three of the expert reports (safety, quality and clinical efficacy) required for submission in MA application dossiers are intended to be primarily critical appraisals of the data generated for the respective parts of the dossier. The safety expert should examine the relevant pharmacology and toxicology data, and where necessary, the microbiological data and comment on its relevance for the envisaged use of the product in question, its quality and compliance with regulatory guidelines (e.g. OECD guidelines on types of study and OECD and other guidelines
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on good laboratory practice), mechanistic studies included or required, relevance to human hazard and risk assessment and the need for repeating existing studies or the conduct of further studies. Where possible, the expert should also identify suitable no-observed effect levels (NOELs) and, for food animals, calculate appropriate acceptable daily intake (ADI) values, which may be based on pharmacodynamic, microbiological or toxicological end-points. The expert should also consider potential harmful effects of other constituents of the dossier. Indeed, for products intended for use in food animals, the expert will need to consider whether any pharmacologically active ingredients, which covers both the active and excipients, including those used in veterinary biologics, are subject to a requirement for maximum residue limits (MRLs) or other considerations under Regulation No. (EEC) 2377/90 prior to an MA being granted. The potential hazards to humans arising from organisms used in veterinary vaccines, and notably live zoonotic organisms, also need to be considered and addressed in the safety expert report. 1.3. The user safety assessment This has many of the attributes of an expert report, and notably, of a safety expert report. In fact, there is no reason why this cannot be part of the safety expert report except that many would regard it (and the safety expert report) as a stand alone document. The purpose of the user safety assessment is to bring together the safety data submitted in the dossier and the opinions and conclusions in the safety expert report, with an assessment of the scope for potential human (user) exposure to the veterinary medicinal product under consideration and an assessment of the possible outcomes of such exposures. In other words, the user safety assessment should be designed to consider the hazards associated with product and the potential risks involved with its use. In this document, the hazards are not limited to the biological; physico-chemical hazards, and notably flammability and possibly explosivity, and their associated risks, should also be addressed. Arising from this is the need to identify risk reduction and risk management measures and means of conveying information about potential hazards and risks, to users. All of these areas pose potential problems of understanding and interpretation for the authors of user safety assessment reports and indeed for recommendations for studies to further investigate user safety issues and assuage concerns, especially regulatory concerns. To address these issues, the European Medicines Agency (EMEA) and the Committee for Medicinal Products for Veterinary Use (CVMP), the major pan-European regulatory committee in the EU, have elaborated guidelines on user safety assessment for both veterinary pharmaceutical and biologic products (European Medicines Agency, 2006, 2003). These guidelines provide a brief outline of the major topics which should be addressed in assessing user safety and consequently, in what should appear in a
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user safety assessment. However, they provide no detail and instead, focus on a series of broad headings with theoretical considerations rather than practical applications (Woodward, 2007). However, they do adequately define user as any person that may come into contact with the veterinary medicinal product or its components before, during or after its administration. This extends therefore to veterinarians and other veterinary health-care workers, to farmers, members of the animal owning public, animal beauticians, bystanders and animal breeders (European Medicines Agency, 2003). This contribution seeks to examine the practical aspects of user safety assessment.
Hazard Identification and Assessment Identification of biological and physical hazards associated with a veterinary medicinal product; characterisation of dose responses
Exposure Assessment Estimation of the degree of exposure based on the type of product, and its intended use with predicted exposure levels where possible
2. Overall assessment The purpose of user safety assessment is to consider hazards posed by a specific veterinary medicinal product, to determine potential routes of exposure and the likely extent of any exposure, and thus to determine possible risks. Once these objectives have been achieved, the next steps are to examine how the risks might be minimized and to communicate information about those risks to the user. Although it is tempting to assume that the major hazards will be biological (toxicity), physical ones (e.g. flammability or explosivity) should not be overlooked. The process of user safety assessment is summarized in Fig. 1. 3. Hazard identification and assessment The active ingredients used in veterinary medicinal products are subject to a considerable degree of testing, particularly if the active component is also used in human medicinal products. This will include tests in laboratory species and in the target animal patients. All of these can be used, and indeed are used, in the hazard identification and assessment process. These studies will include: • Pharmacological studies to identify and quantify pharmacokinetic behavior and pharmacodynamic properties in both laboratory species and target animals. • Toxicological studies. • Microbiological (safety) studies (other than those intended to reveal pharmacodynamic activity) e.g. studies to identify potential effects on the human gastrointestinal flora for residues of antimicrobial drugs. • Target animal safety studies designed to identify potential adverse effects in the intended patient or patients. Medicines intended for use in food-producing animals may have a more comprehensive data set available than those intended for companion animal use because of the need to identify potential consumer hazards and risks arising from the presence of drug residues in food. In addition to pharmacological and toxicological studies, these will also include the microbiological safety studies referred to above (Cerniglia and Kotarski, 1999, 2005; Woodward, 1998). Safety data
Risk Assessment Likelihood that a biological hazard (or physical hazard) will occur under predicted exposure scenarios
Risk Management Identification and introduction of appropriate measures to control or reduce exposure and mitigate associated risks
Risk Communication Provide information to the user to advise on potential hazards and risks, and measures to be taken to avoid or reduce risks e.g. in product literature and on the product label Fig. 1. Summary of user safety assessment (based on Fairhurst, 2000; Tennant, 2001).
may also be available from the use of the drug in human patients, including data from pharmacovigilance activities. For the majority of drugs used in veterinary medicines, the results of toxicity studies set out in Table 1 will normally be available, at least for applications for MAs in the EU, based on the requirements of EU legislation (Woodward, 1997, 2000 and 2004b). These and other studies allow the construction of pharmacological and toxicological profiles and the identification of no-observed effect levels (NOELs) and dose–response relationships. However, it is obvious that many veterinary medicinal products are formulated with other excipients such as solvents and the potential adverse effects of these, and the combination with the other constituents must also be con-
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Table 1 Toxicity studies normally required to support marketing authorisation applications for veterinary medicinal products in the EU Study
Comments
Single dose toxicity
For older drugs, LD50 studies are usually available, for more recent drugs, studies to investigate acute effects (rather than lethality as a major end-point) are generally available (Rhodes, 2000)
Repeat dose studies
To identify organ-specific toxicity; usually two species and 90-day duration
Effects on reproduction
Effects on reproductive performance and fertility. Embry- and fetotoxicity, teratogenicity (preferably in two species, including one non-rodent)
Genotoxicity
Studies for potential to induce mutations and clastogenic effects
Carcinogenicity
Usually only required if confirmed as genotoxic or if related to known carcinogens (Galer and Monro, 1998)
Studies of specific effects
May include mechanistic studies or studies of specific toxic effects such as immunotoxicity or hepatotoxicity—usually dependent on findings from other studies. Neurotoxicity studies in the hen required for organophosphorus compounds
sidered. Data for these materials are frequently available in the open literature. However, for products where exposure is highly likely in the absence of any protective measures, and usually for liquid formulations, some limited testing of the formulation is often required. This testing would include tests for skin and eye irritation, for dermal sensitization, and for acute oral and dermal toxicity. For formulations that might be inhaled, inhalation toxicity studies may be required under some circumstances, for example, where exposure by inhalation is likely to be significant (e.g. anesthetic gases). Some veterinary drugs may induce hypersensitivity reactions (other than dermal sensitization) and this possibility should be considered (Dayan, 1993; Woodward, 1991) but investigators should not lose sight of the fact that many topically applied drugs used in human medicine are dermal sensitizers (Anon, 2002; Menezes de Pa´dua et al., 2007; Pe´tavy-Catala et al., 2001; Rodrı´gues-Morales et al., 2001) and some of these are used in veterinary medicine and there is evidence that some have resulted in occupational dermatitis (Rudzki and Rebandel, 2001). The majority of vaccines and other biological products generally contain relatively innocuous components both in terms of the antigens and the solvents, adjuvants and other constituents. However, because of the hazards associated with high-pressure self-injection of oil-based vaccines, due consideration must be given to potential adverse effects (bin Zakaria et al., 1996; Burke and Brady, 1996; Couzens and Burke, 1995; Gwynne Jones, 1996; Jones, 1996; Neal and Burke, 1991; O’Neill et al., 2005; O’Sullivan et al., 1997; Patterson et al., 1988; Richardson et al., 2005; Windsor et al., 2005; Woodward, 2005a). Moreover, some adjuvants may give rise to inflammatory reactions at self-injection sites (Spickler and Roth, 2003). Products containing organic solvents, some gaseous products and aerosol formulations may be flammable and could even pose risks of explosions under some conditions. Gaseous products and substances with high vapor pressures need particular attention because of the possibility of systemic exposure and the subsequent expression of pharmacological or toxicological effects in exposed individuals.
4. Exposure assessment The potential for user exposure depends to a large extent on the pharmaceutical form of the product in question. Some products or types of product may have very low potential for user exposure while others may offer considerable potential for exposure. To illustrate this, a number of examples are considered below: • Low potential for exposure: Tablets and capsules (except in cases of intentional or accidental consumption), anthelmintic boluses and other sustained release devices. • Moderate potential for exposure: Topical creams, gels and liquids applied manually. Products for conventional injection. • High potential for exposure: Pour-on liquid products for large animals, high volume injectable products (e.g. poultry or fish vaccines), ectoparasiticidal products administered by dipping or spraying. Medicated feeds. Furthermore, some activities associated with the use of a product may enhance the chances of exposure. For example, the need to dilute a concentrate, to mix a medicated feed onfarm, to fill a syringe or to connect a gaseous anesthetic to its delivery apparatus. However, more mundane activities including opening the product pack can lead to potential for user exposure. Self-injection is not the only hazard associated with injectable products. Physical injuries arise from simple needle stick injuries regardless of the presence or absence of any drug. In fact needle stick injuries are common among veterinarians and aquaculture workers (Leira and Baalsrud, 1997; Wilkins and Bowman, 1997) as they are in human health-care workers (Bliski, 2005; Smith and Leggat, 2005) and these may lead to adverse effects (Hill et al., 1998). Other factors which must be taken into account include the extent of exposure, the frequency, the duration of exposure on each occurrence and the interval between exposures. Thus, veterinarians, veterinary workers or farm workers repeatedly exposed to a particular product occupationally may sustain greater degrees of exposures than companion animal owners who may be exposed on single occasions or at worst, intermittently.
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If exposure is likely to occur, the degree of exposure and systemic absorption then needs to be assessed. In the absence of data, it is often difficult to make these assessments and the EU Guideline is not helpful in this respect. In fact it refers the reader to another EU document, the Technical Guidance Document on Risk Assessment (European Commission Joint Research Centre, 2003) developed to provide information for risk assessment on new and existing substances and for biocides. While there is no absolute objection in translating methodologies between classes of chemicals, for example, between biocides and veterinary drugs, and while this document provides more in depth advice on issues which should be taken into account as part of exposure assessment it is restricted by generalities and limitations. For example, under dermal exposure, which it recognizes as the ‘‘most frequently used indicator’’ it concludes that at present, ‘‘there is no consensus view as to how dermal exposure is best assessed, although model prediction make some suggestions’’. This is not particularly helpful to those engaged in user safety assessments. In practice, there is frequently a need to make some basic assumptions. 4.1. Dermal exposure In the absence of data to the contrary, the only pragmatic approach for liquid formulations is to assume that the entire contents of a container is spilt onto skin or onto clothing which has direct contact with skin. This has some utility for smaller containers (500 ml or below) but is generally unreasonable for larger containers where there must be some realistic assumption that mitigating action would be taken to prevent further personal contamination. There are models to predict dermal exposure although these are not readily available (Georgopoulos and Lioy, 1994; Oppl et al., 2003; Marquart et al., 2003; Schneider et al., 1999; Van Hemmen et al., 2003; Van-Wendel-de-Joode et al., 2003). These include factors for determining exposure such as volatility of the liquid, viscosity, area of skin likely to be exposed, chances of spillage occurring, and number of events likely, all of course relating to the type of product or industrial use envisaged. Historical data, such as that derived from questionnaires requesting data from exposed employees about splashing rates and cleaning habits may also be considered and together, the data can be used to make estimates of degree and extent of dermal exposure (Cattani et al., 2001; European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), 1993; Van-Wendel-de-Joode et al., 2003). Should dermal contamination be predicted, then knowledge of pharmacokinetics of the drug (rate and extent of absorption) in laboratory animals or target species, or preferably and if available in humans, can be used to estimate the absorbed dose. Alternatively, or in support of, models which make use of physico-chemical properties (polarity of substance, octanol–water partition coefficients) to predict skin permeability may also be employed (Potts and Guy,
1992; Wilschut et al., 1995). Other factors such as loss of drug from desquamated skin prior to absorption can also be used, where the drug type is suited to this phenomenon (Reddy et al., 2000). Many of these and related issues have been reviewed by the International Programme on Chemical Safety (International Programme on Chemical Safety, 2006). A special case exists for products such as ectoparasiticides applied externally to companion animals. Here stroking could lead to dermal contamination and potential hand to mouth oral exposure, which might pose a health risk, especially to children, and adverse effects have been reported in companion animal owners (Ames et al., 1989). Estimation of potential exposure by this route may be made by using absorbent pads or gloves to stroke treated animals followed by solvent extraction so that the amount of drug can then be quantified using physico-chemical methods (US EPA, 1996). Predictive modeling for dermal and inhalation exposure to pesticides has been used for registration purposes in the past (Luo et al., 2007; Søeborg et al., 2007; Van Hemmen, 1993). In the EU, the development of the EASE (estimation and assessment of substance exposure) model has permitted the routine use of this approach as the model is available for download at the European Chemicals Bureau website (http://ecb.jrc.cec.eu.int/). The model uses physico-chemical properties, toxicological data and containment measures (full containment, ventilation, spray application) to predict dermal and inhalation exposure for chemicals (Northage, 2005; Tickner et al., 2005) that has been developed and validated for a number of exposure scenarios (Cherie and Hughson, 2005; Creely et al., 2005). It has potential utility for use in veterinary medicinal product user exposure assessment, including exposure by the dermal route, and has been used by this author for the estimation of dermal and inhalation exposures to veterinary medicinal products. Another model, the European Predictive Operator Exposure Model (EURO POEM), developed for use with plant protection products, may also have some utility although this appears less developed than EASE (Machera et al., 2001 & 2003; Van Hemmen, 2001). A model for predicting dermal exposure to topically applied ectoparasiticides when handling treated sheep or wool from treated animals has been developed and is convenient for adaptation for similar circumstances with other types of product in other animals (Villie`re, 2001). This model has recently been updated and refined (Australian Pesticides and Veterinary Medicines Authority, 2006). The passage of solvents through living donor skin has been shown to be a useful model of skin permeation (Ursin et al., 1995) and there is no reason why such a model could not be used for the study of dissolved or suspended components of veterinary medicines other than the restricted availability of skin samples. In addition, the recommendations of the European Commission Guidance Document on Dermal Absorption developed for plant protection
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exposure assessment has some considerable value (European Commission, 2004). Finally, it should be noted that WHO, through the International Programme on Chemical Safety, has examined dermal absorption in some depth and has drawn conclusions and made recommendations that can be used in occupational risk assessment (International Programme on Chemical Safety, 2006). 4.2. Accidental self-injection Self-injection of a veterinary medicinal product is a potentially hazardous experience, and notably when the product in question is a potent toxicologically or pharmacologically active material, such as prostaglandins, injectable anesthetics and euthanasia agents. There have been incidents with the catatonia-inducing immobilizing drug etorphine, including at least one fatality, following accidental self-injection (Anon, 1976; Firn, 1973; Goodrich, 1977; Vaudrey, 1974) and reports of cardiac abnormalities in workers following self-injection of the macrolide antimicrobial drug tilmicosin and two fatalities have been reported (Crown and Smith, 1999; Kuffner and Dart, 1996; Veerhuizen et al., 2006; Von Essen et al., 2003). However, such reports are rare, and with the examples mentioned here depended on unusual circumstances (the exceptional potency of etorphine and extreme sensitivity in humans, and probable intravenous self-injection of tilmicosin, a cardiac toxicant). In the majority of cases, injuries sustained during injection of animals are of the needle stick variety with a wet needle i.e. contaminated with the liquid product. In these circumstances it is reasonable to assume that the maximum delivered dose is no more than 0.1 ml. It is more difficult to estimate how much of a dose is likely to be delivered following actual self-injection (rather than needle stick injury) with the use of a conventional syringe. The best approach is to assume that a fraction of the syringe contents, 10–50% depending on the size of the intended dose and thus syringe contents and the viscosity and hence syringability of the preparation in question. With automated, high-pressure equipment, usually used to mass vaccinate poultry, the entire dose may be delivered but here the hazards are those of high-pressure injection injuries and the associated dissipation of kinetic energy rather than those of toxicological or pharmacological concern (see earlier and Woodward, 2005a) although an autoimmune response may be induced by hydrocarbon adjuvants (Kuroda et al., 2004). Self-injection of Johne’s disease (paratuberculosis; Mycobacterium paratuberculosis) vaccine, a product containing Freund’s complete adjuvant has resulted in injection site injuries (Patterson et al., 1988; Richardson et al., 2005; Windsor et al., 2005). These were similar in nature to those seen with Freund’s adjuvant itself and with other Freund’s adjuvanted preparations (Shah et al., 2001). Needle stick injuries are relatively common and may also be sustained from incorrectly disposed of veterinary needles (bin Zakaria et al., 1996; Poole et al., 1998; Sillis, 2003).
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4.3. Inhalation exposures Prior to applying for a MA it is difficult to obtain data on occupational inhalation exposure to dusty medicated feeds and gaseous products or volatile liquids. Unfortunately, this issue of exposure to respirable materials needs to be addressed so that user safety can be discussed in the application dossier. This leaves the applicant or the author of the user safety expert report with a number of options: • To argue that inhalation is unlikely or not a problem, based on scientific arguments (low volatility, use of exhaust systems or scavenging equipment, use of dust suppressants in dusty feed mixes). • Suggest that the product is used in the outdoor environment and that any vapors will therefore dissipate and not present a health risk. • Argue that as the product has been shown to be of low toxicity by the inhalation route (and by other routes of administration) that inhalation exposure by the user is of low or no relevance to human user risk assessment. Halothane is an anesthetic agent used in both human and veterinary medicine. Around 1 in 30,000 patients given the drug develop severe hepatic damage due to reactive metabolites combining with liver proteins to elicit an autoimmune response (Bird and Williams, 1992; Neuberger and Williams, 1988). In human medicine, occupational exposure to halothane has long be recognized as a potential health problem and efforts have been made to reduce associated risks (Byhahn et al., 2001; Davenport et al., 1980; Henderson and Matthews, 2000; Sitarek et al., 2000; Woodward, 2005a). This has led to concerns over the safety of veterinary anesthetic use and has resulted in recommendations for ventilation and scavenging systems in veterinary surgical areas (Burkhart and Stobbe, 1990; Dreesen et al., 1981; Gardner et al., 1991; Green, 1981; Hoerauf et al., 1998; Korczynski, 1999; Meyer, 1999; Milligan et al., 1980; Moore et al., 1993; Potts and Craft, 1988; Schuchman et al., 1975; Stimpfel and Gershey, 1991; Ward and Byland, 1982a,b; Wingfield et al., 1981) thus reflecting the undoubted importance of this area of hazard and risk assessment. Should the measures set out above fail to provide convincing arguments of occupational safety, then the applicant may decide, or the author of the user safety assessment recommend that studies be undertaken to measure atmospheric concentrations of the drug during simulated in-use conditions. The design of such studies is beyond the scope of this article and indeed, this should remain the province of individuals and organizations with the necessary expertise and experience in carrying out this type of work, which in any case will almost certainly be individual in nature depending on the type of product being considered and the envisaged use. However, a number of points are worth considering.
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Of these, the main one is that any simulated exposures should be as realistic as possible and should model the actual conditions under which the product is likely to be used. It may be necessary, for example, to carry out onfarm use of a product, and to measure atmospheric concentrations and personal exposures in these simulated use conditions. It will be essential not only to measure general atmospheric concentrations in the workplace environment but also those in the vicinity of the actual operation (mixing, preparing medicated feed, providing the medicated feed to animals, use of a volatile material in the veterinary clinic). This can be done with personal samplers for example placed at lapel height on the users, which are useful to determine potential exposures in the breathing zone (Lacey et al., 2006; Peretz et al., 2005; Tatum et al., 2001; Thorpe, 2007). The types of samplers used will depend on the nature of the medicinal product (gaseous or dust), while the numbers of samples taken will largely depend on the usual nature of the workplace environment (large pig unit versus clinic) and on statistical considerations; other factors like temperature, the degree of ventilation or exhaust and particle size and sample stability will also need to be considered (Brown, 1988; Harper and Guild, 1996; Harper and Muller, 2002; Thorpe, 2007). For sampling dusty materials, particle size considerations also need to be taken into account (Combes and Warren, 2005; Harper et al., 2002; Schneider et al., 2002) along with air movement conditions (Witschger et al., 2004), the re-suspension of dust from workplace clothing (Cohen et al., 1984) and the entrapment of dust in areas on the sampler other than the filters, which can introduce measurement bias (Puskar et al., 1991). It is also necessary to identify the components of dust collected, or more specifically the pharmaceutical content from inert materials such as feed, and to determine the range of particle sizes as only those with a respirable size will have any potential toxicological hazards and risks associated with them (Hearl, 1997; Notø et al., 1996; Soutar et al., 1997). An alternative approach to experimental procedures and simulated exposures is to use modeling and again the EASE example described earlier has considerable utility for predicting inhalation exposures (Cherie and Hughson, 2005; Creely et al., 2005). It can be combined with the results of other measurements or models, for example, those dealing with pulmonary particle deposition (Choi and Kim, 2007; Jaques and Kim; 2000; Lo¨ndahl et al., 2007). 4.4. Oral exposure Oral exposure to veterinary medicines is generally likely to be low except in the cases of self-medication with veterinary products or intentional abuse. The possibility of children consuming veterinary formulations, especially of products intended for companion animal treatment in the domestic environment cannot be excluded but this is seem-
ingly rare although children are generally more sensitive to chemical toxicity than adults (Dourson et al., 2002), and so where relevant, this possibility must be addressed. However, the main route of oral exposure for most veterinary medicinal products is likely to be hand to mouth transfer following dermal contamination with liquid, cream, powder or dusty formulations, particularly when eating or smoking and to a lesser extent, when drinking. It is extremely difficult to predict the expected doses arising from this route of exposure, and the only practicable solution is to suggest fractions of the intended therapeutic dose, based on likelihood of contamination and degree of contamination, which in turn will be based on the physical properties of the product and the intended therapeutic uses and doses. Oral exposure may also occur as a result of inhalation exposure, and here, the larger non-respirable particles may be assumed to contribute to the oral dose; the total exposure can be presumed to be the sum of the inhaled fraction and the non-respirable fraction. This area is often more conveniently addressed under risk management measures (see later). It is essential to be clear at this point that particle size in this context refers to a very specific feature, the aerodynamic diameter, and not to size alone. Aerodynamic diameter is a function of physical diameter and density (Hext, 2000) as shown below: Aerodynamic diameter = physical diameter · (density)1/2 Hence, a particle of 2 lm physical diameter and density of 4 g cm 3 would behave aerodynamically in workplace air in the same manner as a particle of 4 lm physical diameter and density of 1 g cm 3. Hence, when considering respirable particles, the aerodynamic diameter is the important measurement of concern. 4.5. Biological monitoring Where necessary, biological monitoring may be conducted as confirmation and quantification of exposure as part of any experimental study of exposure, and the data generated used in the user safety assessment, or it can be conducted post-authorization and the information gained used in a future or revised user safety assessment. Biological monitoring implies knowledge of the pharmacokinetic behavior of the drug in humans although this may be inferred from animal data, and particularly from data on formation of metabolites and appropriate biomarkers, and rate and extent of absorption and body clearance (Droz et al., 1989; Duggan et al., 2003; Fairhurst, 2000; Henderson et al., 1989; International Programme on Chemical Safety, 2001; Leung and Paustenbach, 1988; Olajos and Salem, 2000; Waterfield and Timbrell, 2000). This may involve the development of biological indices of exposure, possibly using physiologically based pharmacokinetic modeling (Fiserova-Bergerova, 1987,1990; Hays et al., 2007; Kirman et al., 2003; Leung, 1992; Rigas et al., 2001; Thomas et al., 1996; Truchon et al., 2006). However, as the majority of exposures to veterinary medicinal
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products is usually expected to be low or moderate, such measures will only be required on exceptional occasions, and then only for the more toxic substances. 5. Risk assessment In the context of user safety assessment this implies an appraisal of whether there is any likelihood that the hazards identified may be expressed in users of the veterinary medicinal product. Unfortunately, there is rarely sufficient data available for this (British Medical Association (BMA) 1987) because there usually have been no exposures and no measurements of ensuing adverse effects. This means that the process is really one of risk estimation or, to put the problem another way—knowing the biological properties of the molecule, and particularly the NOELs from animal studies or indeed from human use, is it likely that these will be seen in the user of a specific veterinary medicinal product at the levels identified in toxicology or pharmacology studies? In general, the risks should be characterized for the unprotected worker as risk management strategies can be considered in the next part of the process. To make this assessment, the dose likely to be received by the unprotected worker, on the basis of the exposure assessment, should be compared to NOEL from animal studies; if NOEL values are not available, as is sometimes the case, then the lowest observed effect level (LOEL) may be used as an alternative. In doing these comparisons, the likely routes of exposure should be considered and contrasted with the results of the studies using the same route(s) of exposure. Where possible, the duration of the animal experiments should represent the likely duration of exposure. For example, single and intermittent exposures will be best represented by acute toxicity studies. Prolonged exposure may be better modeled by repeat dose studies. If the major route of exposure is inhalation, then inhalation studies will represent the most relevant exposure route in the animal models. However, if the major route of exposure is local e.g. dermal exposure, then skin irritation and dermal sensitization studies may be the most relevant although dermal absorption and potential systemic effects may be important. To assess this possibility, percutaneous absorption data from animal models, from human experience or from in vitro models becomes critical. If absorption is likely to occur, then the degree of absorption needs to be evaluated against the effects noted in dermal toxicity studies. Nevertheless, the potential for local dermal effects should not be overlooked. For example, the antimicrobial drug olaquindox has been reported to cause allergic and photoallergic effects, notably in exposed pig farmers while the macrolide antibiotic spiramycin has resulted in contact dermatitis and bronchial asthma (Bedello et al., 1985; Belhadjali et al., 2002; Davis and Pepys, 1975; Francalanci et al., 1986; Hjorth and Weismann, 1973; Paggiaro et al., 1979; Sanchez-Perez et al., 2002; Woodward, 2005a). The majority of veterinarians and veterinary staff, and certainly members of the pet owning public or farmers, will
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not be exposed to the majority of veterinary medicinal products on a daily basis; the majority of potential exposures will be intermittent and even rare. This needs to be accounted for in the assessment process. In assessing risks, the terms qualitative risk and quantitative risk are sometimes used. These are not particularly helpful terms in user risk assessment. First, the term risk implies probability which in turn implies some degree of quantitative assessment. Second, these are not true risk assessments in that neither the sponsor nor the author of the user safety assessment is trying to define the probability of any particular hazard being expressed. Instead, the applicant and the author, and indeed the regulator is trying to assess how near to a biologically significant dose, identified usually from animal studies, is the user likely to be exposed under normal conditions of use. Freak accidents, extreme misuse or abuse, and absurd user conditions are not normally taken into account. The assessment should be made on the basis of a realistic user exposure scenario bearing in mind the intended mode of employment of the product. For products where oral exposure might occur, the expert could well compare the degree of exposure not only with the NOEL or LOEL, but also with the acceptable daily intake (ADI) value. For drugs used in food animals, the ADI is usually calculated by dividing the NOEL by a suitable safety or uncertainty factor. This is usually 100 although it could be higher, usually in the face of a defective data package or lower, and particularly if the pivotal data for hazard assessment were based on human observations or studies (e.g. determination of a pharmacological dose for use in human medicine). If the product is used only in companion animals, there is no reason why the author of the user safety assessment cannot calculate an ADI value based on the toxicology data available, which in most circumstances is likely to be adequate (see earlier) following the normal approach for this procedure (Herrman and Younes, 1999; Joint FAO/WHO Expert Committee on Food Additives (JECFA), 1957 and 1987; Woodward, 2004b). The degree of exposure, seen as the received dose, can then be compared with the NOEL (or LOEL or ADI value) to determine the margin of exposure (MOE). In considering the MOE a number of factors need to be taken into account including the likely degree of systemic absorption, the nature of the adverse effect and its severity, the numbers of persons likely to be exposed (e.g. small numbers of veterinarians versus larger numbers of companion animal owners), the differences between routes of exposure between the animal models and potentially exposed humans, the likely frequency of exposure and the duration of those exposures and any dose–response relationship, where relevant. If the margin of exposure is very low i.e. the exposure is unlikely to result in adverse effects, then no risk management measures may be required. On the other hand, if the MOE is found to be high, then suitable risk management measures will be needed to protect human health.
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There may be occasions when occupational exposure limits (OELs) for the drug in question have been established by regulatory authorities. These are exemplified by the threshold limit values (TLVs) for substances present in workplace atmospheres first developed by the American Conference of Governmental Industrial Hygienists (ACGIH) in the US in the 1950s (ACGIH, 1950; Paull, 1984). These, or the underlying principles, have subsequently been used by other countries, including the UK and indeed, form the basis for EU-wide OELs (Fairhurst, 2000; Illing, 1991a,b; Zielhuis et al., 1991). Unfortunately, few OELs have been established for products likely to be used as veterinary medicinal products. This in itself need not be a deterrent as OELs can be derived if necessary de novo for airborne materials using the toxicology and pharmacology data generated for the product, assumptions on degree of absorption, and suitable safety factors to allow for interspecies and intraspecies variability and other variables (Fairhurst, 1995,2000; IPCS, 1994; Zielhuis and van der Kreek, 1979) and some of these have focused on pharmaceuticals, admittedly in industrial and manufacturing environments (McHattie et al., 1988; Naumann et al., 1996). In exceptional circumstances, use can be made of physiologically based pharmacokinetic (PBPK) models. These models can reduce the need for specific data on exposure scenarios and have proved to be useful tools in risk assessment (Chiu et al., 2007). However, they do rely on adequate packages of pharmacokinetic data which may not always be available for many veterinary drugs. 6. Risk management Risk management (or risk reduction) sets out the measures necessary to reduce exposure and hence to mitigate any risks and such measures must first and foremost be practicable. This means to a large extent that any precautions, specialist equipment or protective clothing must be readily available and have an expectation for being used and, if this is unlikely to happen, or specialist equipment is unlikely to be available, then there is little reason for making the necessary recommendations. Hence, there is limited or no value in making recommendations for specialist equipment for products intended for use at home by the pet owning public whereas the same recommendations may be wholly appropriate for use on farms or in veterinary clinics. One of the major tools available to control exposure is to restrict distribution of the product, for example, to prescription only although this may still mean that it may be prescribed by a veterinarian for administration at home. However, many other potentially hazardous products, by their very nature, will only be used on-farm or in the clinic by trained veterinary professionals. Examples include anesthetics and euthanasia agents. Closed delivery systems may be used or recommended for some potentially hazardous products while dusty materials such as medicated feeds may have dust-suppressants added to reduce inhalation
exposures. Inert mineral oils, vegetable oils and propylene glycol have been used for this purpose. Packaging and containers may be modified to reduce potential exposure, including accidental exposures such as spillages on to skin and methods of treatment may be modified to reduce exposure e.g. pour-on formulations rather than spraying, where appropriate and practicable, products may be supplied as ready-to-use formulations to reduce exposure to potentially hazardous materials, particularly during dilution procedures. In some circumstances, it may be appropriate to consider smaller rather than larger pack sizes to reduce the amount of material made available for use and left over afterwards. For some products, it may be appropriate to recommend personal protective equipment (PPE). This could include masks, goggles, protective clothing such as impermeable aprons or gloves and breathing apparatus or dust masks. However, as already suggested, such recommendations should only be made where there is confidence that the measures will be observed in practice. They are perhaps more likely to be observed by those trained in or comfortable with their use and inevitably this will mean agricultural or veterinary professionals such as farmers, farm workers, veterinarians and veterinary nurses. The measures should be practicable. It is of limited use recommending heavy protective clothing such as impermeable aprons and gloves, rubber boots, goggles and breathing apparatus for those involved in heavy manual work such as sheep dipping, if the ensuing discomfort associated with sweating and handling sheep means that these will be abandoned in favor of ease of movement and access to cool air and subsequent exposure to potentially toxic materials such as organophosphorus sheep dips. Under these circumstances, one level of protective measures will be appropriate for measuring out the concentrated product and preparing the dip bath and another to dipping and handling the sheep. Whatever recommendations for PPE are chosen, the EU guideline itself recommends that these be ‘‘practicable e.g. PPE must be readily available to the user, and measures should not hamper the use of the product. . .’’ (European Medicines Agency, 2003). Any measures recommended should be appropriate, proportional and adequate to reduce exposures to an acceptable level and should be suitable to the intended use. For example, the materials for suggested gloves should be impermeable to the product and any solvents present. Clearly, there is little point in recommending a glove type only to find that it is permeable to a solvent present in the formulation or worse, a solvent that will ultimately damage or destroy the glove. Respirators recommended for use with dusty materials must be capable of offering the correct degree of protection for the product in question. For example, they should be chosen to protect against fine powders, coarse dusts or aerosols, as appropriate (Brown, 1995; Howie, 2005). They should also have the correct workplace protection factor (WPF) defined as the ratio of the average concentration of the dust or aerosol outside the respirator to that in the respirator, while the device is
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worn in the workplace (Crump, 2007; Nicas and Neuhaus, 2004). Unfortunately, there is extensive within-wearer variation of WPF and variation across populations of respirator users. This has led to the development of assigned protection factors (APFs) for respirators to reduce the effects of these variations and to facilitate the choice of suitable and appropriate equipment (Nicas and Neuhaus, 2004; Vaughan and Rajan-Sithamparanadarajah, 2005), and this aspect must be considered when making any specific recommendations.
To facilitate user compliance, labels for veterinary medicinal products should be as uncluttered as possible and information regarding safe use, contraindications and precautions should be clear, unambiguous and concise. If faced with vast amounts of text and advisory phrases, human nature will ensure that frequently, this will be ignored. The phrases ‘‘keep out of reach of children’’ and ‘‘shake well before use’’ may ensure a degree of peace and encourage physical fitness but may do nothing for safe and effective use of a medicinal product.
7. Risk communication
8. Discussion
The purpose of this is to disseminate information on the hazards and risks associated with a product, and the measures necessary under risk management to reduce exposure and concomitant risks. For veterinary medicinal products, this largely means the information, warnings and recommendations made on the label and in other product literature such as the package insert although it could also include posters or warning notices to be displayed in the workplace. In the EU, these are normally set out in the Summary of Product Characteristics (SPC) for subsequent inclusion in the product literature. The purposes of risk communication are essentially fourfold, to provide information on the risk or risks, to provide advice on what specific exposures to avoid, to suggest how these can be avoided and to suggest what should happen if exposure occurs. An example is given below:
This paper has focused on European requirements for veterinary medicinal products and particularly on those for user safety assessments. However, as many regulatory authorities outside of the EU also have user safety requirements, the concepts, applications and elements of risk assessment discussed here have applicability beyond that of the EU and indeed, are used in other countries and notably in the US. User safety assessment is a logical process that considers the innate hazardous properties of a substance or its formulation into a veterinary medicinal product, the potential routes of exposure for the user and the ensuing risks from the route or routes of exposure likely in practice under normal patterns of use of the product in question. The main aim of this is for the drug sponsor or the author of the user safety assessment to be able to consider and then recommend appropriate risk management measures to reduce exposure to an acceptable level bearing in mind the associated hazards and criteria derived from these such as NOEL or ADI values which have particular value in assessing the risks associated with accidental ingestion. These then appear in the product literature as part of risk communication. Inevitably, regulatory authorities may take a different view from the one proposed by the sponsor and so initial proposals and the views of the author of the user safety assessment may be subject to modification and enhancement. Equally inevitably, many of the judgments made in the assessment process are cautious or precautious in nature (Illing, 1999,2001). That is, they frequently take into account worst case scenarios and ask the question ‘‘what if?’’ In extreme, rare circumstances, risk assessment may conclude that the degree of uncertainty for a particular scenario is so great, for example because of doubts over toxicological safety or exposure assessment, or even over whether or not a particular product can ever be used in a safe manner, that authorization for use may be withheld, but even so, societal benefits e.g. from the use of a product, in this case a drug for which there is no alternative therapy may dictate authorization, but under carefully controlled conditions of use (Illing, 1999; Rogers, 2003). The safety assessment of a veterinary medicine does not stop with the issue of an MA or any other form of registration or approval. Pharmacovigilance activities can and do reveal further insights into the hazards associated with vet-
May cause skin irritation. Avoid contact with skin. Wear protective gloves when diluting product and when dosing animals. In case of contact with product wash affected parts with copious amounts of water. It could go on to state ‘‘In case of skin contamination and severe skin irritation, seek medical advice and show this label to your physician’’. The precise wording will of course be dictated by local regulatory requirements and by national cultural choices, opinions and attitudes. The benefits from all of this will eventually depend on whether or not the user reads the label and observes the recommendations. Failure to do this may have potentially trivial consequences—a mild rash, a transient ocular irritation or no effect whatsoever. However, for potentially toxic materials or for drugs with potent pharmacological activity, failure to read the product literature or a subsequent decision to ignore the advice, may have grave consequences including severe local effects (eye damage) or systemic effects, and in some cases disability or death. A regulator may conclude that if a product cannot be used safely or if evidence suggests that for a marketed product the advice is being routinely ignored, then the product should not be authorized or its MA should be suspended or withdrawn.
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erinary medicinal products (Keck and Ibrahim, 2001; Keller et al., 1998; Woodward, 2005b). The findings from pharmacovigilance programs, including those following human exposures, can further refine hazard evaluations, risk assessment and risk management and risk communication strategies culminating, for example, in modifications or additions to product labeling. One approach to enhance the user safety associated with veterinary medicinal products is the adoption of safe-handling protocols such as those recommended by the National Institute for Occupational Safety and Health (NIOSH) (see, for example, NIOSH, 2004). In fact, these are becoming common place in human medicine in the EU including the UK, especially for potentially toxic materials such as antineoplastic agents which have the potential to induce genetic damage in exposed health-care workers (Anwar et al., 1994; Burgaz et al., 2002; Fucic et al., 1998; Testa et al., 2007). The process of user safety evaluation is rarely straightforward and may be complicated by issues surrounding toxicity evaluation, particular in areas associated with the determination of relevance of findings in animal models to hazard assessment, and in estimating potential exposures. This further emphasizes the need for clear, concise and unambiguous guidelines which can guide a product sponsor, and the author of user safety assessments, to valid scientific conclusions and realistic outcomes. The overall aim should be to balance any risks associated with the use of the product, through the identification of an appropriate MOE, to ensure safe use of the drug and to confer its benefits to both the treated animal and to its owners. Comparing benefits and risks is a challenge even when balancing the therapeutic benefits to a human patient against the known risk (Breckenridge, 2003; Holden, 2003; Meyboom and Egberts, 1999; Miller, 1993) but it takes on an extra dimension when examining the benefits of a pharmaceutical or immunological product to an animal patient versus the potential risks to the user. A well thought out and professionally executed user safety assessment can facilitate this process. References ACGIH, 1950. Threshold limit values for 1950. A. M. A. Arch. Ind. Hyg. Occup. Med. 2, 98–100. Ames, R.G., Brown, S.K., Rosenberg, J., Jackson, R.J., Stratton, J.W., Quenon, S.G., 1989. Health symptoms and occupational exposure to flea control products among California pet handlers. Am. Ind. Hyg. Assoc. J. 50, 466–472. Anon, 1976. Immobilon: why the VPC suspended the licence. Vet. Rec. 99, 156. Anon, 2001. Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products. Official Journal of the European Union, L 311, 1–66 as amended by Directive 2004/28/EC of the European Parliament and the Council of 31 march 2004 amending Directive 2001/82/EC on the Community code relating to veterinary medicinal products. Official J. Eur. Union, L 136, 58–84. Anon, 2002. Cutaneous drug reaction reports. Am. J. Clin. Dermatol. 3, 223–227.
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Regulatory Toxicology and Pharmacology 50 (2008) 114–128 www.elsevier.com/locate/yrtph
Assessment of user safety, exposure and risk to veterinary medicinal products in the European Union K.N. Woodward
*
Schering-Plough Animal Health, Breakspear Road South, Harefield, Uxbridge, Middlesex UB9 6LS, UK Received 15 August 2007 Available online 23 October 2007
Abstract Safety is an important part of veterinary drug assessment while user safety is a critical part of the overall safety assessment. In the European Union (EU), user safety is addressed through preclinical studies and by relationships with exposure but a key part of the process is the user safety assessment. EU user safety guidelines are available and these make certain recommendations but in places they lack detail and clarity. This paper seeks to examine the relevant factors that lie behind user risk assessments for veterinary medicinal products in general while focusing on EU requirements, the determination of risk management and risk communication strategies and how this relates to user safety assessment and pharmacovigilance responsibilities. 2007 Elsevier Inc. All rights reserved. Keywords: User safety; Exposure assessment; Risk assessment; Veterinary drugs; Risk communication; Pharmacovigilance
1. Introduction In the development, launch and marketing of medicinal products, safety is clearly of paramount importance. For human medicinal products, this quite rightly gives a priority to patient safety which can be balanced against any risks to arrive at an acceptable strategy for use and indeed, for authorization or approval. Clearly, patient safety is also important for veterinary medicinal products, particularly as animals may have significant emotional or financial values, or indeed both. However, those who use, apply or are otherwise exposed to veterinary medicinal products must also be protected from any potential harmful effects, particularly as veterinary medicines may not always be given under the same clinical conditions normally associated with the administration of human medicines, for example, on the farm. Many veterinary pharmaceutical products contain the same active ingredients as their human counterparts, and potentially toxic substances such as the anti-neo*
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plastic drugs are being increasingly used in veterinary medicine. Moreover, some veterinary medicinal products are administered in such a way that user exposure is more likely, or more extensive than with human counterparts. Examples include vaccination of poultry and dipping of sheep for ectoparasitic conditions. At this point, it is appropriate to emphasize that in the EU, the term ‘‘veterinary medicinal product’’ includes not only pharmaceuticals but also ectoparasiticides (which in the EU are by definition and mode of use pharmaceuticals) and vaccines and other biologics intended for use in both companion and food-producing animals. In fact the formal definition as set out in EU legislation includes substances or combinations of substances intended to treat or prevent diseases or those administered to restore, correct or modify physiological function. This latter category captures products such as those intended to modify or synchronize estrous. Moreover, the definition extends to medicated feeds and premixes formulations and some veterinary homeopathic formulations. However, it excludes some formulations intended as coccidiostats or histomonostats which are covered by separate EU legislation (Anon, 2001).
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In the European Union (EU) user safety assessment is an important and integral part of the overall process of safety evaluation of applications for MAs for veterinary medicinal products submitted to European regulatory authorities. To reflect this, ‘‘safety’’ as a component of MA dossiers includes not only the usual pre-clinical studies, but also a requirement for a safety expert report and a user safety risk assessment (Woodward, 2004a). In fact, the typical MA application dossier for a veterinary medicinal product will cover safety in four areas—user, consumer, patient and environmental. Those relevant to user safety are discussed below. 1.1. Part IIIA (safety) of the EU dossier For both companion and food-producing animals this will contain the normal range of laboratory pharmacology and toxicology studies, normally on the active ingredient itself, administered in a suitable vehicle. The nature of the pharmacology studies will usually be dictated by the type of drug subject to the MA application. In addition to the results of pharmacokinetic studies, there will also be studies designed to demonstrate or even to quantify the desired pharmacodynamic properties of the drug (for example, antimicrobial, anesthetic, analgesic, anti-inflammatory or hormonal effects). The toxicology studies usually comprise, but are not limited to, acute toxicity, repeat dose toxicity, studies on reproductive performance and developmental effects and genotoxicity studies. Carcinogenicity studies may be required for drugs which elicit a positive response in the genotoxicity studies or for those which give rise to suspicion, for example, seemingly precancerous lesions in repeat dose studies. Studies of local effects, including skin and eye irritation and dermal sensitization, are also normally required and nasal pungency and other sensory forms of irritation may also need to be addressed, where necessary by risk assessment approaches (Nielsen et al., 2007). Under some circumstances, more specialized studies may also be required for example neurotoxicity and neurobehavioral studies for organophosphorus compounds and pyrethroids. For antimicrobial drugs intended for use in food animals, studies to investigate potential effects of microbiologically active residues on the human gut flora are also essential. 1.2. Safety expert report All three of the expert reports (safety, quality and clinical efficacy) required for submission in MA application dossiers are intended to be primarily critical appraisals of the data generated for the respective parts of the dossier. The safety expert should examine the relevant pharmacology and toxicology data, and where necessary, the microbiological data and comment on its relevance for the envisaged use of the product in question, its quality and compliance with regulatory guidelines (e.g. OECD guidelines on types of study and OECD and other guidelines
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on good laboratory practice), mechanistic studies included or required, relevance to human hazard and risk assessment and the need for repeating existing studies or the conduct of further studies. Where possible, the expert should also identify suitable no-observed effect levels (NOELs) and, for food animals, calculate appropriate acceptable daily intake (ADI) values, which may be based on pharmacodynamic, microbiological or toxicological end-points. The expert should also consider potential harmful effects of other constituents of the dossier. Indeed, for products intended for use in food animals, the expert will need to consider whether any pharmacologically active ingredients, which covers both the active and excipients, including those used in veterinary biologics, are subject to a requirement for maximum residue limits (MRLs) or other considerations under Regulation No. (EEC) 2377/90 prior to an MA being granted. The potential hazards to humans arising from organisms used in veterinary vaccines, and notably live zoonotic organisms, also need to be considered and addressed in the safety expert report. 1.3. The user safety assessment This has many of the attributes of an expert report, and notably, of a safety expert report. In fact, there is no reason why this cannot be part of the safety expert report except that many would regard it (and the safety expert report) as a stand alone document. The purpose of the user safety assessment is to bring together the safety data submitted in the dossier and the opinions and conclusions in the safety expert report, with an assessment of the scope for potential human (user) exposure to the veterinary medicinal product under consideration and an assessment of the possible outcomes of such exposures. In other words, the user safety assessment should be designed to consider the hazards associated with product and the potential risks involved with its use. In this document, the hazards are not limited to the biological; physico-chemical hazards, and notably flammability and possibly explosivity, and their associated risks, should also be addressed. Arising from this is the need to identify risk reduction and risk management measures and means of conveying information about potential hazards and risks, to users. All of these areas pose potential problems of understanding and interpretation for the authors of user safety assessment reports and indeed for recommendations for studies to further investigate user safety issues and assuage concerns, especially regulatory concerns. To address these issues, the European Medicines Agency (EMEA) and the Committee for Medicinal Products for Veterinary Use (CVMP), the major pan-European regulatory committee in the EU, have elaborated guidelines on user safety assessment for both veterinary pharmaceutical and biologic products (European Medicines Agency, 2006, 2003). These guidelines provide a brief outline of the major topics which should be addressed in assessing user safety and consequently, in what should appear in a
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user safety assessment. However, they provide no detail and instead, focus on a series of broad headings with theoretical considerations rather than practical applications (Woodward, 2007). However, they do adequately define user as any person that may come into contact with the veterinary medicinal product or its components before, during or after its administration. This extends therefore to veterinarians and other veterinary health-care workers, to farmers, members of the animal owning public, animal beauticians, bystanders and animal breeders (European Medicines Agency, 2003). This contribution seeks to examine the practical aspects of user safety assessment.
Hazard Identification and Assessment Identification of biological and physical hazards associated with a veterinary medicinal product; characterisation of dose responses
Exposure Assessment Estimation of the degree of exposure based on the type of product, and its intended use with predicted exposure levels where possible
2. Overall assessment The purpose of user safety assessment is to consider hazards posed by a specific veterinary medicinal product, to determine potential routes of exposure and the likely extent of any exposure, and thus to determine possible risks. Once these objectives have been achieved, the next steps are to examine how the risks might be minimized and to communicate information about those risks to the user. Although it is tempting to assume that the major hazards will be biological (toxicity), physical ones (e.g. flammability or explosivity) should not be overlooked. The process of user safety assessment is summarized in Fig. 1. 3. Hazard identification and assessment The active ingredients used in veterinary medicinal products are subject to a considerable degree of testing, particularly if the active component is also used in human medicinal products. This will include tests in laboratory species and in the target animal patients. All of these can be used, and indeed are used, in the hazard identification and assessment process. These studies will include: • Pharmacological studies to identify and quantify pharmacokinetic behavior and pharmacodynamic properties in both laboratory species and target animals. • Toxicological studies. • Microbiological (safety) studies (other than those intended to reveal pharmacodynamic activity) e.g. studies to identify potential effects on the human gastrointestinal flora for residues of antimicrobial drugs. • Target animal safety studies designed to identify potential adverse effects in the intended patient or patients. Medicines intended for use in food-producing animals may have a more comprehensive data set available than those intended for companion animal use because of the need to identify potential consumer hazards and risks arising from the presence of drug residues in food. In addition to pharmacological and toxicological studies, these will also include the microbiological safety studies referred to above (Cerniglia and Kotarski, 1999, 2005; Woodward, 1998). Safety data
Risk Assessment Likelihood that a biological hazard (or physical hazard) will occur under predicted exposure scenarios
Risk Management Identification and introduction of appropriate measures to control or reduce exposure and mitigate associated risks
Risk Communication Provide information to the user to advise on potential hazards and risks, and measures to be taken to avoid or reduce risks e.g. in product literature and on the product label Fig. 1. Summary of user safety assessment (based on Fairhurst, 2000; Tennant, 2001).
may also be available from the use of the drug in human patients, including data from pharmacovigilance activities. For the majority of drugs used in veterinary medicines, the results of toxicity studies set out in Table 1 will normally be available, at least for applications for MAs in the EU, based on the requirements of EU legislation (Woodward, 1997, 2000 and 2004b). These and other studies allow the construction of pharmacological and toxicological profiles and the identification of no-observed effect levels (NOELs) and dose–response relationships. However, it is obvious that many veterinary medicinal products are formulated with other excipients such as solvents and the potential adverse effects of these, and the combination with the other constituents must also be con-
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Table 1 Toxicity studies normally required to support marketing authorisation applications for veterinary medicinal products in the EU Study
Comments
Single dose toxicity
For older drugs, LD50 studies are usually available, for more recent drugs, studies to investigate acute effects (rather than lethality as a major end-point) are generally available (Rhodes, 2000)
Repeat dose studies
To identify organ-specific toxicity; usually two species and 90-day duration
Effects on reproduction
Effects on reproductive performance and fertility. Embry- and fetotoxicity, teratogenicity (preferably in two species, including one non-rodent)
Genotoxicity
Studies for potential to induce mutations and clastogenic effects
Carcinogenicity
Usually only required if confirmed as genotoxic or if related to known carcinogens (Galer and Monro, 1998)
Studies of specific effects
May include mechanistic studies or studies of specific toxic effects such as immunotoxicity or hepatotoxicity—usually dependent on findings from other studies. Neurotoxicity studies in the hen required for organophosphorus compounds
sidered. Data for these materials are frequently available in the open literature. However, for products where exposure is highly likely in the absence of any protective measures, and usually for liquid formulations, some limited testing of the formulation is often required. This testing would include tests for skin and eye irritation, for dermal sensitization, and for acute oral and dermal toxicity. For formulations that might be inhaled, inhalation toxicity studies may be required under some circumstances, for example, where exposure by inhalation is likely to be significant (e.g. anesthetic gases). Some veterinary drugs may induce hypersensitivity reactions (other than dermal sensitization) and this possibility should be considered (Dayan, 1993; Woodward, 1991) but investigators should not lose sight of the fact that many topically applied drugs used in human medicine are dermal sensitizers (Anon, 2002; Menezes de Pa´dua et al., 2007; Pe´tavy-Catala et al., 2001; Rodrı´gues-Morales et al., 2001) and some of these are used in veterinary medicine and there is evidence that some have resulted in occupational dermatitis (Rudzki and Rebandel, 2001). The majority of vaccines and other biological products generally contain relatively innocuous components both in terms of the antigens and the solvents, adjuvants and other constituents. However, because of the hazards associated with high-pressure self-injection of oil-based vaccines, due consideration must be given to potential adverse effects (bin Zakaria et al., 1996; Burke and Brady, 1996; Couzens and Burke, 1995; Gwynne Jones, 1996; Jones, 1996; Neal and Burke, 1991; O’Neill et al., 2005; O’Sullivan et al., 1997; Patterson et al., 1988; Richardson et al., 2005; Windsor et al., 2005; Woodward, 2005a). Moreover, some adjuvants may give rise to inflammatory reactions at self-injection sites (Spickler and Roth, 2003). Products containing organic solvents, some gaseous products and aerosol formulations may be flammable and could even pose risks of explosions under some conditions. Gaseous products and substances with high vapor pressures need particular attention because of the possibility of systemic exposure and the subsequent expression of pharmacological or toxicological effects in exposed individuals.
4. Exposure assessment The potential for user exposure depends to a large extent on the pharmaceutical form of the product in question. Some products or types of product may have very low potential for user exposure while others may offer considerable potential for exposure. To illustrate this, a number of examples are considered below: • Low potential for exposure: Tablets and capsules (except in cases of intentional or accidental consumption), anthelmintic boluses and other sustained release devices. • Moderate potential for exposure: Topical creams, gels and liquids applied manually. Products for conventional injection. • High potential for exposure: Pour-on liquid products for large animals, high volume injectable products (e.g. poultry or fish vaccines), ectoparasiticidal products administered by dipping or spraying. Medicated feeds. Furthermore, some activities associated with the use of a product may enhance the chances of exposure. For example, the need to dilute a concentrate, to mix a medicated feed onfarm, to fill a syringe or to connect a gaseous anesthetic to its delivery apparatus. However, more mundane activities including opening the product pack can lead to potential for user exposure. Self-injection is not the only hazard associated with injectable products. Physical injuries arise from simple needle stick injuries regardless of the presence or absence of any drug. In fact needle stick injuries are common among veterinarians and aquaculture workers (Leira and Baalsrud, 1997; Wilkins and Bowman, 1997) as they are in human health-care workers (Bliski, 2005; Smith and Leggat, 2005) and these may lead to adverse effects (Hill et al., 1998). Other factors which must be taken into account include the extent of exposure, the frequency, the duration of exposure on each occurrence and the interval between exposures. Thus, veterinarians, veterinary workers or farm workers repeatedly exposed to a particular product occupationally may sustain greater degrees of exposures than companion animal owners who may be exposed on single occasions or at worst, intermittently.
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If exposure is likely to occur, the degree of exposure and systemic absorption then needs to be assessed. In the absence of data, it is often difficult to make these assessments and the EU Guideline is not helpful in this respect. In fact it refers the reader to another EU document, the Technical Guidance Document on Risk Assessment (European Commission Joint Research Centre, 2003) developed to provide information for risk assessment on new and existing substances and for biocides. While there is no absolute objection in translating methodologies between classes of chemicals, for example, between biocides and veterinary drugs, and while this document provides more in depth advice on issues which should be taken into account as part of exposure assessment it is restricted by generalities and limitations. For example, under dermal exposure, which it recognizes as the ‘‘most frequently used indicator’’ it concludes that at present, ‘‘there is no consensus view as to how dermal exposure is best assessed, although model prediction make some suggestions’’. This is not particularly helpful to those engaged in user safety assessments. In practice, there is frequently a need to make some basic assumptions. 4.1. Dermal exposure In the absence of data to the contrary, the only pragmatic approach for liquid formulations is to assume that the entire contents of a container is spilt onto skin or onto clothing which has direct contact with skin. This has some utility for smaller containers (500 ml or below) but is generally unreasonable for larger containers where there must be some realistic assumption that mitigating action would be taken to prevent further personal contamination. There are models to predict dermal exposure although these are not readily available (Georgopoulos and Lioy, 1994; Oppl et al., 2003; Marquart et al., 2003; Schneider et al., 1999; Van Hemmen et al., 2003; Van-Wendel-de-Joode et al., 2003). These include factors for determining exposure such as volatility of the liquid, viscosity, area of skin likely to be exposed, chances of spillage occurring, and number of events likely, all of course relating to the type of product or industrial use envisaged. Historical data, such as that derived from questionnaires requesting data from exposed employees about splashing rates and cleaning habits may also be considered and together, the data can be used to make estimates of degree and extent of dermal exposure (Cattani et al., 2001; European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), 1993; Van-Wendel-de-Joode et al., 2003). Should dermal contamination be predicted, then knowledge of pharmacokinetics of the drug (rate and extent of absorption) in laboratory animals or target species, or preferably and if available in humans, can be used to estimate the absorbed dose. Alternatively, or in support of, models which make use of physico-chemical properties (polarity of substance, octanol–water partition coefficients) to predict skin permeability may also be employed (Potts and Guy,
1992; Wilschut et al., 1995). Other factors such as loss of drug from desquamated skin prior to absorption can also be used, where the drug type is suited to this phenomenon (Reddy et al., 2000). Many of these and related issues have been reviewed by the International Programme on Chemical Safety (International Programme on Chemical Safety, 2006). A special case exists for products such as ectoparasiticides applied externally to companion animals. Here stroking could lead to dermal contamination and potential hand to mouth oral exposure, which might pose a health risk, especially to children, and adverse effects have been reported in companion animal owners (Ames et al., 1989). Estimation of potential exposure by this route may be made by using absorbent pads or gloves to stroke treated animals followed by solvent extraction so that the amount of drug can then be quantified using physico-chemical methods (US EPA, 1996). Predictive modeling for dermal and inhalation exposure to pesticides has been used for registration purposes in the past (Luo et al., 2007; Søeborg et al., 2007; Van Hemmen, 1993). In the EU, the development of the EASE (estimation and assessment of substance exposure) model has permitted the routine use of this approach as the model is available for download at the European Chemicals Bureau website (http://ecb.jrc.cec.eu.int/). The model uses physico-chemical properties, toxicological data and containment measures (full containment, ventilation, spray application) to predict dermal and inhalation exposure for chemicals (Northage, 2005; Tickner et al., 2005) that has been developed and validated for a number of exposure scenarios (Cherie and Hughson, 2005; Creely et al., 2005). It has potential utility for use in veterinary medicinal product user exposure assessment, including exposure by the dermal route, and has been used by this author for the estimation of dermal and inhalation exposures to veterinary medicinal products. Another model, the European Predictive Operator Exposure Model (EURO POEM), developed for use with plant protection products, may also have some utility although this appears less developed than EASE (Machera et al., 2001 & 2003; Van Hemmen, 2001). A model for predicting dermal exposure to topically applied ectoparasiticides when handling treated sheep or wool from treated animals has been developed and is convenient for adaptation for similar circumstances with other types of product in other animals (Villie`re, 2001). This model has recently been updated and refined (Australian Pesticides and Veterinary Medicines Authority, 2006). The passage of solvents through living donor skin has been shown to be a useful model of skin permeation (Ursin et al., 1995) and there is no reason why such a model could not be used for the study of dissolved or suspended components of veterinary medicines other than the restricted availability of skin samples. In addition, the recommendations of the European Commission Guidance Document on Dermal Absorption developed for plant protection
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exposure assessment has some considerable value (European Commission, 2004). Finally, it should be noted that WHO, through the International Programme on Chemical Safety, has examined dermal absorption in some depth and has drawn conclusions and made recommendations that can be used in occupational risk assessment (International Programme on Chemical Safety, 2006). 4.2. Accidental self-injection Self-injection of a veterinary medicinal product is a potentially hazardous experience, and notably when the product in question is a potent toxicologically or pharmacologically active material, such as prostaglandins, injectable anesthetics and euthanasia agents. There have been incidents with the catatonia-inducing immobilizing drug etorphine, including at least one fatality, following accidental self-injection (Anon, 1976; Firn, 1973; Goodrich, 1977; Vaudrey, 1974) and reports of cardiac abnormalities in workers following self-injection of the macrolide antimicrobial drug tilmicosin and two fatalities have been reported (Crown and Smith, 1999; Kuffner and Dart, 1996; Veerhuizen et al., 2006; Von Essen et al., 2003). However, such reports are rare, and with the examples mentioned here depended on unusual circumstances (the exceptional potency of etorphine and extreme sensitivity in humans, and probable intravenous self-injection of tilmicosin, a cardiac toxicant). In the majority of cases, injuries sustained during injection of animals are of the needle stick variety with a wet needle i.e. contaminated with the liquid product. In these circumstances it is reasonable to assume that the maximum delivered dose is no more than 0.1 ml. It is more difficult to estimate how much of a dose is likely to be delivered following actual self-injection (rather than needle stick injury) with the use of a conventional syringe. The best approach is to assume that a fraction of the syringe contents, 10–50% depending on the size of the intended dose and thus syringe contents and the viscosity and hence syringability of the preparation in question. With automated, high-pressure equipment, usually used to mass vaccinate poultry, the entire dose may be delivered but here the hazards are those of high-pressure injection injuries and the associated dissipation of kinetic energy rather than those of toxicological or pharmacological concern (see earlier and Woodward, 2005a) although an autoimmune response may be induced by hydrocarbon adjuvants (Kuroda et al., 2004). Self-injection of Johne’s disease (paratuberculosis; Mycobacterium paratuberculosis) vaccine, a product containing Freund’s complete adjuvant has resulted in injection site injuries (Patterson et al., 1988; Richardson et al., 2005; Windsor et al., 2005). These were similar in nature to those seen with Freund’s adjuvant itself and with other Freund’s adjuvanted preparations (Shah et al., 2001). Needle stick injuries are relatively common and may also be sustained from incorrectly disposed of veterinary needles (bin Zakaria et al., 1996; Poole et al., 1998; Sillis, 2003).
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4.3. Inhalation exposures Prior to applying for a MA it is difficult to obtain data on occupational inhalation exposure to dusty medicated feeds and gaseous products or volatile liquids. Unfortunately, this issue of exposure to respirable materials needs to be addressed so that user safety can be discussed in the application dossier. This leaves the applicant or the author of the user safety expert report with a number of options: • To argue that inhalation is unlikely or not a problem, based on scientific arguments (low volatility, use of exhaust systems or scavenging equipment, use of dust suppressants in dusty feed mixes). • Suggest that the product is used in the outdoor environment and that any vapors will therefore dissipate and not present a health risk. • Argue that as the product has been shown to be of low toxicity by the inhalation route (and by other routes of administration) that inhalation exposure by the user is of low or no relevance to human user risk assessment. Halothane is an anesthetic agent used in both human and veterinary medicine. Around 1 in 30,000 patients given the drug develop severe hepatic damage due to reactive metabolites combining with liver proteins to elicit an autoimmune response (Bird and Williams, 1992; Neuberger and Williams, 1988). In human medicine, occupational exposure to halothane has long be recognized as a potential health problem and efforts have been made to reduce associated risks (Byhahn et al., 2001; Davenport et al., 1980; Henderson and Matthews, 2000; Sitarek et al., 2000; Woodward, 2005a). This has led to concerns over the safety of veterinary anesthetic use and has resulted in recommendations for ventilation and scavenging systems in veterinary surgical areas (Burkhart and Stobbe, 1990; Dreesen et al., 1981; Gardner et al., 1991; Green, 1981; Hoerauf et al., 1998; Korczynski, 1999; Meyer, 1999; Milligan et al., 1980; Moore et al., 1993; Potts and Craft, 1988; Schuchman et al., 1975; Stimpfel and Gershey, 1991; Ward and Byland, 1982a,b; Wingfield et al., 1981) thus reflecting the undoubted importance of this area of hazard and risk assessment. Should the measures set out above fail to provide convincing arguments of occupational safety, then the applicant may decide, or the author of the user safety assessment recommend that studies be undertaken to measure atmospheric concentrations of the drug during simulated in-use conditions. The design of such studies is beyond the scope of this article and indeed, this should remain the province of individuals and organizations with the necessary expertise and experience in carrying out this type of work, which in any case will almost certainly be individual in nature depending on the type of product being considered and the envisaged use. However, a number of points are worth considering.
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Of these, the main one is that any simulated exposures should be as realistic as possible and should model the actual conditions under which the product is likely to be used. It may be necessary, for example, to carry out onfarm use of a product, and to measure atmospheric concentrations and personal exposures in these simulated use conditions. It will be essential not only to measure general atmospheric concentrations in the workplace environment but also those in the vicinity of the actual operation (mixing, preparing medicated feed, providing the medicated feed to animals, use of a volatile material in the veterinary clinic). This can be done with personal samplers for example placed at lapel height on the users, which are useful to determine potential exposures in the breathing zone (Lacey et al., 2006; Peretz et al., 2005; Tatum et al., 2001; Thorpe, 2007). The types of samplers used will depend on the nature of the medicinal product (gaseous or dust), while the numbers of samples taken will largely depend on the usual nature of the workplace environment (large pig unit versus clinic) and on statistical considerations; other factors like temperature, the degree of ventilation or exhaust and particle size and sample stability will also need to be considered (Brown, 1988; Harper and Guild, 1996; Harper and Muller, 2002; Thorpe, 2007). For sampling dusty materials, particle size considerations also need to be taken into account (Combes and Warren, 2005; Harper et al., 2002; Schneider et al., 2002) along with air movement conditions (Witschger et al., 2004), the re-suspension of dust from workplace clothing (Cohen et al., 1984) and the entrapment of dust in areas on the sampler other than the filters, which can introduce measurement bias (Puskar et al., 1991). It is also necessary to identify the components of dust collected, or more specifically the pharmaceutical content from inert materials such as feed, and to determine the range of particle sizes as only those with a respirable size will have any potential toxicological hazards and risks associated with them (Hearl, 1997; Notø et al., 1996; Soutar et al., 1997). An alternative approach to experimental procedures and simulated exposures is to use modeling and again the EASE example described earlier has considerable utility for predicting inhalation exposures (Cherie and Hughson, 2005; Creely et al., 2005). It can be combined with the results of other measurements or models, for example, those dealing with pulmonary particle deposition (Choi and Kim, 2007; Jaques and Kim; 2000; Lo¨ndahl et al., 2007). 4.4. Oral exposure Oral exposure to veterinary medicines is generally likely to be low except in the cases of self-medication with veterinary products or intentional abuse. The possibility of children consuming veterinary formulations, especially of products intended for companion animal treatment in the domestic environment cannot be excluded but this is seem-
ingly rare although children are generally more sensitive to chemical toxicity than adults (Dourson et al., 2002), and so where relevant, this possibility must be addressed. However, the main route of oral exposure for most veterinary medicinal products is likely to be hand to mouth transfer following dermal contamination with liquid, cream, powder or dusty formulations, particularly when eating or smoking and to a lesser extent, when drinking. It is extremely difficult to predict the expected doses arising from this route of exposure, and the only practicable solution is to suggest fractions of the intended therapeutic dose, based on likelihood of contamination and degree of contamination, which in turn will be based on the physical properties of the product and the intended therapeutic uses and doses. Oral exposure may also occur as a result of inhalation exposure, and here, the larger non-respirable particles may be assumed to contribute to the oral dose; the total exposure can be presumed to be the sum of the inhaled fraction and the non-respirable fraction. This area is often more conveniently addressed under risk management measures (see later). It is essential to be clear at this point that particle size in this context refers to a very specific feature, the aerodynamic diameter, and not to size alone. Aerodynamic diameter is a function of physical diameter and density (Hext, 2000) as shown below: Aerodynamic diameter = physical diameter · (density)1/2 Hence, a particle of 2 lm physical diameter and density of 4 g cm 3 would behave aerodynamically in workplace air in the same manner as a particle of 4 lm physical diameter and density of 1 g cm 3. Hence, when considering respirable particles, the aerodynamic diameter is the important measurement of concern. 4.5. Biological monitoring Where necessary, biological monitoring may be conducted as confirmation and quantification of exposure as part of any experimental study of exposure, and the data generated used in the user safety assessment, or it can be conducted post-authorization and the information gained used in a future or revised user safety assessment. Biological monitoring implies knowledge of the pharmacokinetic behavior of the drug in humans although this may be inferred from animal data, and particularly from data on formation of metabolites and appropriate biomarkers, and rate and extent of absorption and body clearance (Droz et al., 1989; Duggan et al., 2003; Fairhurst, 2000; Henderson et al., 1989; International Programme on Chemical Safety, 2001; Leung and Paustenbach, 1988; Olajos and Salem, 2000; Waterfield and Timbrell, 2000). This may involve the development of biological indices of exposure, possibly using physiologically based pharmacokinetic modeling (Fiserova-Bergerova, 1987,1990; Hays et al., 2007; Kirman et al., 2003; Leung, 1992; Rigas et al., 2001; Thomas et al., 1996; Truchon et al., 2006). However, as the majority of exposures to veterinary medicinal
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products is usually expected to be low or moderate, such measures will only be required on exceptional occasions, and then only for the more toxic substances. 5. Risk assessment In the context of user safety assessment this implies an appraisal of whether there is any likelihood that the hazards identified may be expressed in users of the veterinary medicinal product. Unfortunately, there is rarely sufficient data available for this (British Medical Association (BMA) 1987) because there usually have been no exposures and no measurements of ensuing adverse effects. This means that the process is really one of risk estimation or, to put the problem another way—knowing the biological properties of the molecule, and particularly the NOELs from animal studies or indeed from human use, is it likely that these will be seen in the user of a specific veterinary medicinal product at the levels identified in toxicology or pharmacology studies? In general, the risks should be characterized for the unprotected worker as risk management strategies can be considered in the next part of the process. To make this assessment, the dose likely to be received by the unprotected worker, on the basis of the exposure assessment, should be compared to NOEL from animal studies; if NOEL values are not available, as is sometimes the case, then the lowest observed effect level (LOEL) may be used as an alternative. In doing these comparisons, the likely routes of exposure should be considered and contrasted with the results of the studies using the same route(s) of exposure. Where possible, the duration of the animal experiments should represent the likely duration of exposure. For example, single and intermittent exposures will be best represented by acute toxicity studies. Prolonged exposure may be better modeled by repeat dose studies. If the major route of exposure is inhalation, then inhalation studies will represent the most relevant exposure route in the animal models. However, if the major route of exposure is local e.g. dermal exposure, then skin irritation and dermal sensitization studies may be the most relevant although dermal absorption and potential systemic effects may be important. To assess this possibility, percutaneous absorption data from animal models, from human experience or from in vitro models becomes critical. If absorption is likely to occur, then the degree of absorption needs to be evaluated against the effects noted in dermal toxicity studies. Nevertheless, the potential for local dermal effects should not be overlooked. For example, the antimicrobial drug olaquindox has been reported to cause allergic and photoallergic effects, notably in exposed pig farmers while the macrolide antibiotic spiramycin has resulted in contact dermatitis and bronchial asthma (Bedello et al., 1985; Belhadjali et al., 2002; Davis and Pepys, 1975; Francalanci et al., 1986; Hjorth and Weismann, 1973; Paggiaro et al., 1979; Sanchez-Perez et al., 2002; Woodward, 2005a). The majority of veterinarians and veterinary staff, and certainly members of the pet owning public or farmers, will
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not be exposed to the majority of veterinary medicinal products on a daily basis; the majority of potential exposures will be intermittent and even rare. This needs to be accounted for in the assessment process. In assessing risks, the terms qualitative risk and quantitative risk are sometimes used. These are not particularly helpful terms in user risk assessment. First, the term risk implies probability which in turn implies some degree of quantitative assessment. Second, these are not true risk assessments in that neither the sponsor nor the author of the user safety assessment is trying to define the probability of any particular hazard being expressed. Instead, the applicant and the author, and indeed the regulator is trying to assess how near to a biologically significant dose, identified usually from animal studies, is the user likely to be exposed under normal conditions of use. Freak accidents, extreme misuse or abuse, and absurd user conditions are not normally taken into account. The assessment should be made on the basis of a realistic user exposure scenario bearing in mind the intended mode of employment of the product. For products where oral exposure might occur, the expert could well compare the degree of exposure not only with the NOEL or LOEL, but also with the acceptable daily intake (ADI) value. For drugs used in food animals, the ADI is usually calculated by dividing the NOEL by a suitable safety or uncertainty factor. This is usually 100 although it could be higher, usually in the face of a defective data package or lower, and particularly if the pivotal data for hazard assessment were based on human observations or studies (e.g. determination of a pharmacological dose for use in human medicine). If the product is used only in companion animals, there is no reason why the author of the user safety assessment cannot calculate an ADI value based on the toxicology data available, which in most circumstances is likely to be adequate (see earlier) following the normal approach for this procedure (Herrman and Younes, 1999; Joint FAO/WHO Expert Committee on Food Additives (JECFA), 1957 and 1987; Woodward, 2004b). The degree of exposure, seen as the received dose, can then be compared with the NOEL (or LOEL or ADI value) to determine the margin of exposure (MOE). In considering the MOE a number of factors need to be taken into account including the likely degree of systemic absorption, the nature of the adverse effect and its severity, the numbers of persons likely to be exposed (e.g. small numbers of veterinarians versus larger numbers of companion animal owners), the differences between routes of exposure between the animal models and potentially exposed humans, the likely frequency of exposure and the duration of those exposures and any dose–response relationship, where relevant. If the margin of exposure is very low i.e. the exposure is unlikely to result in adverse effects, then no risk management measures may be required. On the other hand, if the MOE is found to be high, then suitable risk management measures will be needed to protect human health.
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There may be occasions when occupational exposure limits (OELs) for the drug in question have been established by regulatory authorities. These are exemplified by the threshold limit values (TLVs) for substances present in workplace atmospheres first developed by the American Conference of Governmental Industrial Hygienists (ACGIH) in the US in the 1950s (ACGIH, 1950; Paull, 1984). These, or the underlying principles, have subsequently been used by other countries, including the UK and indeed, form the basis for EU-wide OELs (Fairhurst, 2000; Illing, 1991a,b; Zielhuis et al., 1991). Unfortunately, few OELs have been established for products likely to be used as veterinary medicinal products. This in itself need not be a deterrent as OELs can be derived if necessary de novo for airborne materials using the toxicology and pharmacology data generated for the product, assumptions on degree of absorption, and suitable safety factors to allow for interspecies and intraspecies variability and other variables (Fairhurst, 1995,2000; IPCS, 1994; Zielhuis and van der Kreek, 1979) and some of these have focused on pharmaceuticals, admittedly in industrial and manufacturing environments (McHattie et al., 1988; Naumann et al., 1996). In exceptional circumstances, use can be made of physiologically based pharmacokinetic (PBPK) models. These models can reduce the need for specific data on exposure scenarios and have proved to be useful tools in risk assessment (Chiu et al., 2007). However, they do rely on adequate packages of pharmacokinetic data which may not always be available for many veterinary drugs. 6. Risk management Risk management (or risk reduction) sets out the measures necessary to reduce exposure and hence to mitigate any risks and such measures must first and foremost be practicable. This means to a large extent that any precautions, specialist equipment or protective clothing must be readily available and have an expectation for being used and, if this is unlikely to happen, or specialist equipment is unlikely to be available, then there is little reason for making the necessary recommendations. Hence, there is limited or no value in making recommendations for specialist equipment for products intended for use at home by the pet owning public whereas the same recommendations may be wholly appropriate for use on farms or in veterinary clinics. One of the major tools available to control exposure is to restrict distribution of the product, for example, to prescription only although this may still mean that it may be prescribed by a veterinarian for administration at home. However, many other potentially hazardous products, by their very nature, will only be used on-farm or in the clinic by trained veterinary professionals. Examples include anesthetics and euthanasia agents. Closed delivery systems may be used or recommended for some potentially hazardous products while dusty materials such as medicated feeds may have dust-suppressants added to reduce inhalation
exposures. Inert mineral oils, vegetable oils and propylene glycol have been used for this purpose. Packaging and containers may be modified to reduce potential exposure, including accidental exposures such as spillages on to skin and methods of treatment may be modified to reduce exposure e.g. pour-on formulations rather than spraying, where appropriate and practicable, products may be supplied as ready-to-use formulations to reduce exposure to potentially hazardous materials, particularly during dilution procedures. In some circumstances, it may be appropriate to consider smaller rather than larger pack sizes to reduce the amount of material made available for use and left over afterwards. For some products, it may be appropriate to recommend personal protective equipment (PPE). This could include masks, goggles, protective clothing such as impermeable aprons or gloves and breathing apparatus or dust masks. However, as already suggested, such recommendations should only be made where there is confidence that the measures will be observed in practice. They are perhaps more likely to be observed by those trained in or comfortable with their use and inevitably this will mean agricultural or veterinary professionals such as farmers, farm workers, veterinarians and veterinary nurses. The measures should be practicable. It is of limited use recommending heavy protective clothing such as impermeable aprons and gloves, rubber boots, goggles and breathing apparatus for those involved in heavy manual work such as sheep dipping, if the ensuing discomfort associated with sweating and handling sheep means that these will be abandoned in favor of ease of movement and access to cool air and subsequent exposure to potentially toxic materials such as organophosphorus sheep dips. Under these circumstances, one level of protective measures will be appropriate for measuring out the concentrated product and preparing the dip bath and another to dipping and handling the sheep. Whatever recommendations for PPE are chosen, the EU guideline itself recommends that these be ‘‘practicable e.g. PPE must be readily available to the user, and measures should not hamper the use of the product. . .’’ (European Medicines Agency, 2003). Any measures recommended should be appropriate, proportional and adequate to reduce exposures to an acceptable level and should be suitable to the intended use. For example, the materials for suggested gloves should be impermeable to the product and any solvents present. Clearly, there is little point in recommending a glove type only to find that it is permeable to a solvent present in the formulation or worse, a solvent that will ultimately damage or destroy the glove. Respirators recommended for use with dusty materials must be capable of offering the correct degree of protection for the product in question. For example, they should be chosen to protect against fine powders, coarse dusts or aerosols, as appropriate (Brown, 1995; Howie, 2005). They should also have the correct workplace protection factor (WPF) defined as the ratio of the average concentration of the dust or aerosol outside the respirator to that in the respirator, while the device is
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worn in the workplace (Crump, 2007; Nicas and Neuhaus, 2004). Unfortunately, there is extensive within-wearer variation of WPF and variation across populations of respirator users. This has led to the development of assigned protection factors (APFs) for respirators to reduce the effects of these variations and to facilitate the choice of suitable and appropriate equipment (Nicas and Neuhaus, 2004; Vaughan and Rajan-Sithamparanadarajah, 2005), and this aspect must be considered when making any specific recommendations.
To facilitate user compliance, labels for veterinary medicinal products should be as uncluttered as possible and information regarding safe use, contraindications and precautions should be clear, unambiguous and concise. If faced with vast amounts of text and advisory phrases, human nature will ensure that frequently, this will be ignored. The phrases ‘‘keep out of reach of children’’ and ‘‘shake well before use’’ may ensure a degree of peace and encourage physical fitness but may do nothing for safe and effective use of a medicinal product.
7. Risk communication
8. Discussion
The purpose of this is to disseminate information on the hazards and risks associated with a product, and the measures necessary under risk management to reduce exposure and concomitant risks. For veterinary medicinal products, this largely means the information, warnings and recommendations made on the label and in other product literature such as the package insert although it could also include posters or warning notices to be displayed in the workplace. In the EU, these are normally set out in the Summary of Product Characteristics (SPC) for subsequent inclusion in the product literature. The purposes of risk communication are essentially fourfold, to provide information on the risk or risks, to provide advice on what specific exposures to avoid, to suggest how these can be avoided and to suggest what should happen if exposure occurs. An example is given below:
This paper has focused on European requirements for veterinary medicinal products and particularly on those for user safety assessments. However, as many regulatory authorities outside of the EU also have user safety requirements, the concepts, applications and elements of risk assessment discussed here have applicability beyond that of the EU and indeed, are used in other countries and notably in the US. User safety assessment is a logical process that considers the innate hazardous properties of a substance or its formulation into a veterinary medicinal product, the potential routes of exposure for the user and the ensuing risks from the route or routes of exposure likely in practice under normal patterns of use of the product in question. The main aim of this is for the drug sponsor or the author of the user safety assessment to be able to consider and then recommend appropriate risk management measures to reduce exposure to an acceptable level bearing in mind the associated hazards and criteria derived from these such as NOEL or ADI values which have particular value in assessing the risks associated with accidental ingestion. These then appear in the product literature as part of risk communication. Inevitably, regulatory authorities may take a different view from the one proposed by the sponsor and so initial proposals and the views of the author of the user safety assessment may be subject to modification and enhancement. Equally inevitably, many of the judgments made in the assessment process are cautious or precautious in nature (Illing, 1999,2001). That is, they frequently take into account worst case scenarios and ask the question ‘‘what if?’’ In extreme, rare circumstances, risk assessment may conclude that the degree of uncertainty for a particular scenario is so great, for example because of doubts over toxicological safety or exposure assessment, or even over whether or not a particular product can ever be used in a safe manner, that authorization for use may be withheld, but even so, societal benefits e.g. from the use of a product, in this case a drug for which there is no alternative therapy may dictate authorization, but under carefully controlled conditions of use (Illing, 1999; Rogers, 2003). The safety assessment of a veterinary medicine does not stop with the issue of an MA or any other form of registration or approval. Pharmacovigilance activities can and do reveal further insights into the hazards associated with vet-
May cause skin irritation. Avoid contact with skin. Wear protective gloves when diluting product and when dosing animals. In case of contact with product wash affected parts with copious amounts of water. It could go on to state ‘‘In case of skin contamination and severe skin irritation, seek medical advice and show this label to your physician’’. The precise wording will of course be dictated by local regulatory requirements and by national cultural choices, opinions and attitudes. The benefits from all of this will eventually depend on whether or not the user reads the label and observes the recommendations. Failure to do this may have potentially trivial consequences—a mild rash, a transient ocular irritation or no effect whatsoever. However, for potentially toxic materials or for drugs with potent pharmacological activity, failure to read the product literature or a subsequent decision to ignore the advice, may have grave consequences including severe local effects (eye damage) or systemic effects, and in some cases disability or death. A regulator may conclude that if a product cannot be used safely or if evidence suggests that for a marketed product the advice is being routinely ignored, then the product should not be authorized or its MA should be suspended or withdrawn.
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erinary medicinal products (Keck and Ibrahim, 2001; Keller et al., 1998; Woodward, 2005b). The findings from pharmacovigilance programs, including those following human exposures, can further refine hazard evaluations, risk assessment and risk management and risk communication strategies culminating, for example, in modifications or additions to product labeling. One approach to enhance the user safety associated with veterinary medicinal products is the adoption of safe-handling protocols such as those recommended by the National Institute for Occupational Safety and Health (NIOSH) (see, for example, NIOSH, 2004). In fact, these are becoming common place in human medicine in the EU including the UK, especially for potentially toxic materials such as antineoplastic agents which have the potential to induce genetic damage in exposed health-care workers (Anwar et al., 1994; Burgaz et al., 2002; Fucic et al., 1998; Testa et al., 2007). The process of user safety evaluation is rarely straightforward and may be complicated by issues surrounding toxicity evaluation, particular in areas associated with the determination of relevance of findings in animal models to hazard assessment, and in estimating potential exposures. This further emphasizes the need for clear, concise and unambiguous guidelines which can guide a product sponsor, and the author of user safety assessments, to valid scientific conclusions and realistic outcomes. The overall aim should be to balance any risks associated with the use of the product, through the identification of an appropriate MOE, to ensure safe use of the drug and to confer its benefits to both the treated animal and to its owners. Comparing benefits and risks is a challenge even when balancing the therapeutic benefits to a human patient against the known risk (Breckenridge, 2003; Holden, 2003; Meyboom and Egberts, 1999; Miller, 1993) but it takes on an extra dimension when examining the benefits of a pharmaceutical or immunological product to an animal patient versus the potential risks to the user. A well thought out and professionally executed user safety assessment can facilitate this process. References ACGIH, 1950. Threshold limit values for 1950. A. M. A. Arch. Ind. Hyg. Occup. Med. 2, 98–100. Ames, R.G., Brown, S.K., Rosenberg, J., Jackson, R.J., Stratton, J.W., Quenon, S.G., 1989. Health symptoms and occupational exposure to flea control products among California pet handlers. Am. Ind. Hyg. Assoc. J. 50, 466–472. Anon, 1976. Immobilon: why the VPC suspended the licence. Vet. Rec. 99, 156. Anon, 2001. Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products. Official Journal of the European Union, L 311, 1–66 as amended by Directive 2004/28/EC of the European Parliament and the Council of 31 march 2004 amending Directive 2001/82/EC on the Community code relating to veterinary medicinal products. Official J. Eur. Union, L 136, 58–84. Anon, 2002. Cutaneous drug reaction reports. Am. J. Clin. Dermatol. 3, 223–227.
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