The Health and Consumer Protection Directorate General of the European Commission (DG-SANCO) is mandated to "ensure food and consumer goods sold in the EU are safe, that the EU's internal market works for the benefit of consumers and that Europe helps protect and improve its citizens' health." In the context of regulatory toxicology, DG-SANCO is responsible for developing frameworks for the safety assessment and regulation of:
Additionally, DG-SANCO is the lead Commission service for coordinating the development of a Community Action Plan on the Protection and Welfare of Animals.
Pesticides
Pesticides are authorized at EU level for all Member States according to the provisions of Directive 91/414/EEC, as amended, concerning the placing of plant protection products on the market. This regulation applies to manufactured chemical (e.g., organophosphate), bio-chemical (e.g., pheromones), and biological (e.g., microorganisms) pesticides for agricultural use, as well as to the non-pesticidal ingredients within a formulated product. Non-agricultural pesticides (also known as "biocides") are subject to a separate regulatory regime established by DG-Environment.
Animal testing requirements specified in Directive 91/414/EEC call for dozens of human health and ecotoxicological evaluations of each "active ingredient" in a pesticide formulation, including:
- Acute systemic toxicity in rodents and/or rabbits via oral, inhalation and dermal routes
- Eye and skin irritation in rabbits
- Skin sensitization in mice or guinea pigs
- Subacute and/or subchronic studies via the dermal route
- Subchronic (3 month) oral studies in rodents and dogs
- Chronic (12-24 month) oral studies in rodents and dogs
- Lifetime (18-24 month) carcinogenicity studies in rats and mice
- Mutagenicity and genotoxicity studies of at least 2 varieties
- Reproductive toxicity in at least 2 generations of rodents
- Prenatal developmental toxicity in rodents and rabbits
- Metabolism and toxicokinetic studies in rodents
- Acute aquatic toxicity to fish of two or more species
- Partial or full life-cycle toxicity to fish of two or more species
- Acute and/or dietary toxicity to birds of two or more species
- Reproductive toxicity to birds
- And many more
In addition, each formulated pesticide product is required to undergo separate acute toxicity testing via the oral, dermal and inhalation routes, skin and eye irritation, and skin sensitization (known as the acute toxicity "six-pack") for labeling purposes. Recognized testing methods include the internationally harmonized OECD Test Guidelines, as well as methods published in Annex V of Council Directive 67/548/EEC. In some cases, independent scientific advice may be sought regarding pesticide risk assessments and data needs, in which case the Standing Committee on Health and Environmental Risks (SCHER) and/or the European Food Safety Authority Panel on plant protection products and their residues (EFSA PPR Panel) may be consulted.
It is estimated that upwards of 12,000 animals may be consumed in the toxicological evaluation of each pesticide product on the EU market. Such high costs prompted the creation of a multi-stakeholder technical committee under the auspices of the ILSI Health and Environmental Sciences Institute (HESI) with a mandate to develop integrated testing strategies for pesticide safety assessments that minimize redundancies, use fewer animals, and use resources more wisely. The strategies proposed by the HESI technical committee have been peer reviewed and endorsed by the EFSA PPR Panel.
Work is currently underway to revise both the legislative text of Directive 91/414/EEC as well as the testing requirements, which may lead to a reduction in animal testing if certain requirements are eliminated (e.g., mouse cancer bioassay, 1-year dog study, etc.), and an increase in others, as new requirements (e.g., developmental neurotoxicity, endocrine effects, etc.) are established.
Food Additives, Flavorings & Food-Contact Materials
Under EU legislation, additives – including colorants, sweeteners, preservatives and emulsifiers – must be explicitly authorized at EU level before they can be used in foods. The overall legal framework for the regulation of these substances is provided by Directive 89/107/EEC, together with implementing Directives 95/2/EC, 94/35/EC and 94/36/EC. With respect to safety assessments, the framework Directive provides that: "Food additives can be approved only provided that … they present no hazard to the health of the consumer at the level of use proposed, so far as can be judged on the scientific evidence available." Moreover, "To assess the possible harmful effects of a food additive or derivatives thereof, it must be subjected to appropriate toxicological testing and evaluation. The evaluation should also take into account, for example, any cumulative, synergistic or potentiating effect of its use and the phenomenon of human intolerance to substances foreign to the body."
Guidance prepared by the European Commission's former Scientific Committee on Food – which has since been replaced by the European Food Safety Authority (EFSA) Food Additives, Flavorings and Food Contact Materials (EFSA AFC) Panel – outlines a battery of "core tests," including the following:
- Subchronic (3 month) toxicity studies in rodents and dogs
- Chronic (12-24 month) toxicity and carcinogenicity studies in rats and mice
- Mutagenicity and genotoxicity studies of at least 3 varieties
- Reproductive toxicity in at least 2 generations of rodents
- Prenatal developmental toxicity in rodents and rabbits
- Metabolism and toxicokinetic studies in rodents
With respect to food flavorings, the core legislation, Directive 88/388/EEC, provides that, "Member States shall take all measures necessary to ensure that ... flavorings do not contain any element or substance in a toxicologically dangerous quantity…."
Specific toxicological testing requirements are not laid down under this directive. Consequently, data needs are left to the discretion of the EFSA AFC Panel. In the case of smoke flavoring, however, specific testing requirements are imposed pursuant to Regulation (EC) 2065/2003. These include:
- Subchronic (3 month) toxicity studies in rodents and dogs
- Mutagenicity and genotoxicity studies of at least 3 varieties
Food contact materials are regulated under the framework Regulation No. 1935/2004, which establishes general requirements for all food contact materials, as well as a number of specific directives authorizing the use of individual substances and groups of substances. The framework regulation requires that any materials coming into contact with food must be sufficiently inert to preclude contamination of the food or endangerment of human health. Guidance concerning toxicological testing requirements for food contact materials has been prepared by the EFSA AFC Panel and provides for a tiered approach based on a substance's potential to be transferred into food. In the worst case, for "high-migration" substances, the core set of required toxicological tests includes the following:
- Subchronic (3 month) toxicity studies in rodents and dogs
- Chronic (12-24 month) toxicity and carcinogenicity studies in rats and mice
- Mutagenicity and genotoxicity studies of at least 3 varieties
- Reproductive toxicity in at least 2 generations of rodents
- Prenatal developmental toxicity in rodents and rabbits
- Metabolism and toxicokinetic studies in rodents
Nutritional Supplements
The EU defines supplements as "concentrated sources of nutrients or other substances with a nutritional or physiological effect whose purpose is to supplement the normal diet." Directive 2002/46/EC relating to food supplements establishes harmonized rules for the labeling of food supplements and introduces specific rules with respect to vitamins and minerals in food supplements. Specific toxicological testing requirements for food additives and flavorings are not laid down in the Directive; however, the Scientific Committee on the Food Chain and Animal Health committee may be consulted with respect to toxicological findings and data needs for individual substances.
Contaminants
Foods of animal or plant origin may present intrinsic hazards due to microbiological contamination (e.g., Salmonella), for which general EU-wide criteria have been established under Regulation (EC) No 2073/2005. Separate criteria have also been established for testing of oysters, scallops and other shellfish for toxins that can cause sickness ranging from indigestion to paralysis and death under Regulation (EC) 2074/2005 and Regulation (EC) No 1664/2006. These regulations prescribe the use of often-lethal animal tests to detect three different classes (paralytic, amnesiac and diarrhetic) of shellfish toxins, yet also permit the use of validated, non-animal techniques such as the Lawrence method of high performance liquid chromatography under certain circumstances. Scientific input to DG-SANCO in relation to foodborne contaminants is provided by the SCFCAH – Biological Safety of the Food Chain committee.
Genetically Modified Organisms
Through modern biotechnology, numerous plants, animals and microorganisms have been modified genetically to produce characteristics desirable for agriculture (e.g., increased productivity, resistance to inclement conditions, and endogenous pesticide/toxin production). Numerous EU regulations have been established to control the creation, study, release and transport of genetically modified organisms (GMOs). Among the most significant from a toxicological testing standpoint are Directives 90/220/EC on the deliberate release into the environment of GMOs, and Regulation (EC) 1829/2003 concerning the placing on the market of GMOs intended for food or feed and of food or feed products containing, consisting of, or produced from GMOs feed.
The framework Directive requires the submission of a technical dossier of information including a full health and environmental risk assessment, which in turn should include information on potential "pathogenicity: infectivity, toxigenicity, virulence, allergenicity, carrier (vector) of pathogen, possible vectors, host range including non-target organism," as well as "toxic or allergenic effects of the non-viable GMOs and/or their metabolic products." Interpretive guidance developed by the EFSA GMO Panel states that requirements of toxicological testing in the safety assessment of food/feed derived from GMOs "must be considered on a case-by-case basis and will be determined by the outcome of the assessment of the differences identified between the GM product and its conventional counterpart, including available information on intended changes."
In the case of newly expressed proteins, toxicological assessments generally emphasize short-term effects (e.g., 1-month subacute toxicity studies in rodents, allergenicity), whereas the core set of tests for new constituents other than proteins normally consists of the following:
- Subchronic (3 month) toxicity in rodents
- Chronic (12-24 month) toxicity and carcinogenicity studies in rats and mice
- Mutagenicity and genotoxicity studies of at least 3 varieties
- Reproductive toxicity in at least 2 generations of rodents
- Prenatal developmental toxicity in rodents and rabbits
- Metabolism and toxicokinetic studies in rodents
In some cases, testing of whole GM foods may be required, generally using a modified subchronic (3 month) feeding study in rodents. In addition, where doubt exists regarding wholesomeness and nutritional value of a GM food, separate feeding studies in fast-growing farmed animal species (e.g., broiler chickens or lambs) may be carried out.
Nanoscale Particles
The potential effects of engineered nanomaterials on human health and the environment is the subject of global significance. Within DG-SANCO, independent advice is being provided by the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR), which recently authored the report on the appropriateness of existing testing methods for assessing the risks of nanoparticles. A key finding of the report is that: "In vitro testing has provided mechanistic data on particle toxicology in general and many in vitro assays demonstrate convincing differences between low and high toxicity particles; it is therefore considered appropriate that in vitro testing is used in situations involving nanoparticles."
Alternatives Policies & Actions
Directive 86/609/EEC regarding the protection of animals used for experimental and other scientific purposes stipulates that "[a]n experiment shall not be performed if another scientifically satisfactory method of obtaining the result sought, not entailing the use of an animal, is reasonably and practicably available," and further, "[i]n a choice between experiments, those which use the minimum number of animals, involve animals with the lowest degree of neurophysiological sensitivity, cause the least pain, suffering, distress or lasting harm and which are most likely to provide satisfactory results shall be selected." The 3Rs mandate imposed by Directive 86/609 applies to all Commission services, EU Member State authorities, and animal users throughout Europe. Accordingly, new and revised Community and Member State legislation must conform to the letter and spirit of this Directive.
Extramural funding for the development and validation of 3Rs methods is provided through the Research Framework Programs coordinated by DG-Research. As 3Rs methods are standardized and optimized, they may be eligible for pre-validation and validation through the European Centre for the Validation of Alternative Methods (ECVAM), a division of DG-JRC. The results of validation studies may be subject to independent peer review by the ECVAM Scientific Advisory Committee (ESAC), and if endorsed, may be considered for regulatory acceptance at EU-level and/or internationally.
Given the EU's centralized processes for the development, validation and acceptance of 3Rs methods, individual DGs tend to have little direct involvement in these activities, apart from being represented on ESAC. DG-SANCO is an exception to this rule, as the lead Commission service for coordinating the development of a Community Action Plan on the Protection and Welfare of Animals. The current Commission working document includes a section on application of the 3Rs principles for animals used for experiments, stating: "Further work will need to be carried out to reinforce a full implementation of the 3Rs in all areas of animal use, ensure coherence between Directive 86/609/EEC and legislation requiring animal experiments, as well as examining in more detail the mutual acceptance of data and mutual recognition agreements as a means of reducing the numbers of animals used in experiments. The installation of a Community Reference Laboratory for the Validation of Alternative Testing Methods should further enhance the quality of alternative testing methods and speed up the validation process."
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