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How to deal with safety assessment tolerance and toxicological aspects Alberto Mantovani Vice-chair of EFSA FEEDAP Panel Director of Food and Veterinary Toxicology Unit Istituto Superiore di Sanità, Roma [email protected] EFSA FEEDAP Panel additives and products or substances used in animal feed. (www.efsa.europa.eu/en/feedap/feedapscdocs.htm) A large and heterogenous group of compounds Comprising natural compounds, xenobiotics microorganism-derived substances - different usages/exposure patterns of animals/humans/environment - different biological properties = - different critical points for risk assessment and Risk assessment what does it mean ? To integrate characterization of hazards and exposure so to assess “whole-cycle” safety based on intended conditions of use for the animal (target species/category for which use is intended) the consumer of products of animal origin the user/worker the environment = safe for consumer does not mean (necessarily) safe Let’s go stepwise throughout these aspects Product characteristics should be defined, including Safety relevant information - Undesirable substances (“source impurities”) (toxic elements, dioxins, mycotoxins, infectious or toxigenic bacteria. Presence and maximum traces under EC regulation) -process impurities (e.g., residual solvents), especially if limited information or structural alerts (e.g., genotoxicity) (care about product specification) - Stability of, e.g., vitamins: if not guaranteed, risk of deficiency may occur in target species Dusting potential, respirable fraction: Key parameter to user exposure assessment TOLERANCE IN TARGET SPECIES, “Tolerance = a limited evaluation of the short-term toxicity for the target animals Means that a full toxicological package for the target species is out of scope Does NOT mean that safety of use can be demonstrated using just zootechnical parameters Check gross (and histo-, if indications) pathology, blood haematology and chemistry, focus on appropriate markers for a given substance (e.g., gastric lesions in pigs for benzoic acid 2005, 2007) Derive margin of safety = test at use level and at overdosing (up to 10-fold) for sufficient time (see FEEDAP Guidance on tolerance/efficacy 2011) CONSUMER SAFETY Hazard identification (what does it do ?) Toxicological studies for xenobiotics (e.g., coccidiostats) The usual full-package, but mind: Keep updated with new developments e.g. - OECD guidelines (e.g. new “extended one-generation” would replace two-generation study using less animals) -EFSA Scientific Committee (2011) has defined that in vivo genotoxicity is a self-standing effect, not just a “predictor of carcinogenicity” (thus, a negative carcinogenicity study does not rule out a positive genotoxicity assay) CONSUMER SAFETY Hazard identification (what does it do ?) (cont) For enzymes, probiotics, specific forms of nutrients a limited testing package -90-day rodent + in vitro/in vivo genotoxicity- to show any specific/unexpected toxicological effect of the compound (e.g., organic forms of trace elements) For nutrients in general a Upper Tolerable Level (“the nutrient ADI”) has been defined by the EU SCF (till 2003) or by the EFSA Panel NDA (2003 onward), based –in most cases- on human studies. In a few cases (e.g., vitamin A, 2009) the FEEDAP has searched and used guidance values more updated than the UL. HAZARD CHARACTERIZATION: the use of dose-response data FEEDAP has been an early user of Benchmark Dose (EFSA Scientific Committee 2009) (derive threshold value from a dose-response and 95% confidence limits for critical effect) Ractopamine (2009): beta-agonist, proposed as growth promoter in fattening pigs and beef No firm basis to derive a NOAEL for pharmacological (cardiovascular) adverse effects from human data This is the case to apply Benchmark dose a “safe level” could not be established, as to exclude the critical changes (e.g., + 20 % in heart rate), the lower confidence limit of the benchmark dose would be 0 mg. Thus, with the current database a ADI could not be CONSUMER SAFETY: EXPOSURE What can tell us experimental studies Kinetics What are the target tissues/products for residues ? What is the residue marker (biologically significant and representative – in a given ratio- of total residues ?) For xenobiotics (like coccidiostats) are the same metabolites being present in laboratory animals and in target species ? Means: are relevant metabolites being tested in toxicological studies ? Re-assessment of nicarbazin (2010) Toxicological assessment of nicarbazin is relevant to target species safety and user exposure But in tissue most residues are represented by the 4,4 dinitrocarbaniline (DNC) moiety of nicarbazine, which, thus is the marker residue and the one relevant to consumer exposure DNC has a much lower toxicity than nicarbazine /ADI 0,77 mg/kg bw vs. 0.05 mg/kg bw, respectively) CONSUMER EXPOSURE Residue studies (basis for consumer's exposure) Take care: assess residues at maximum recommended dose for realistic intake time (at least three sampling points after withdrawal) in all edible tissues (meat, fat, liver, kidney, fish flesh) and products (milk and eggs) of major species (if many species) or of target species as appropriate. (Feed additives: mass continuous exposure, long withdrawal time is undesirable) Deposition studies for nutritional (specific forms of vitamins, trace elements) Target: measure any increase of the substance related to the specific form (e.g., Se-yeast, 2011) to be tested Animals fed the highest intended level of use AND with total feed content compliant with the maximum EU allowable content (if this exists: Se, Cu, Vitamin A; if not, it should be compatible with good animal husbandry practices: Vitamin E or water-soluble vitamins) Mind: measure the background level in feed N.B. No residue studies are required for enzymes/probiotics, technological additives that do not remain in feeds, substances not absorbed CONSUMER SAFETY Risk characterization Xenobiotics: derive ADI and (if required) Maximum Residue Limits compatible with ADI Nutrients: if UL exists considers exposure from tissue deposition in supplemented animals + Background intake (EFSA data) If no UL and unsolved concerns for consumers safety (e.g., Manganese): assess whether the use of the feed additive does increase the consumers exposure over the background in any significant way (e.g., Mn Mintrex, 2008, 2009, 2010) MIND: Specific forms of nutrients (in particular organic forms of trace elements) have higher bioavailability = tissue Risk characterization requires comparison between ADI/UL and consumer exposure (guidance on consumer safety, 2012) Established approach using default daily adult human consumption figures for relevant foods of animal origin (used for veterinary drug residues by EMA) it assumes: only adults/only chronic/all consumers -Alternative approach: default values from EFSA Comprehensive European Food Consumption Database: high intake (95th percentile) of consumers only for each food item -More realistic, differentiates between chronic and acute intake as well as between adults and children (e.g., hemp as feed material, 2011; Se-yeast, 2011) USER SAFETY: A relevant issue that has always to be taken into account (FEEDAP guidance, 2012) Apparently a rather straight (even though tiresome) data set Toxicity testing on “site effects” Dermal//eye irritancy. Skin sensitisation (no appropriate test for respiratory sensitization) Human data if available Acute inhalation toxicity: repeated dose assessment if significant systemic exposure may occur Exposure: Particle size distribution and the content of the active substance(sin dust following the measurement of the dusting potential. USER SAFETY: A model for calculating daily exposure of workers in a premixture plant to the active substance is provided by Guidance. What outcome ? Precautionary measures may be proposed to reduce or eliminate exposure. Use of personal protective devices should only be regarded as a measure of last resort to protect against any residual risk once other control measures are in place, e.g., reformulation of the product. Can we recommend restriction on a feed additive solely for user safety ? YES Cobalt salt and user safety (2009) a general background opinion - Co supplementation to diets for ruminants, horses and rabbits should be maintained as it meets animal physiology - Co has remarkable toxicity including carcinogenicity - However (considering uncertainties) non-B12 Co in animal tissues/products + background intake will provide less than 0.05 mg/day vs. a UL of 0.6 mg/day - Co compounds (dichloride and sulfate) are skin and respiratory sensitizers and carcinogenic by inhalatory route. No detailed user exposure for authorised compounds in feeds, but user exposure cannot be avoided. - (i) restrict the use of Co to ruminants, horses and rabbits, (ii) limit feed supplementation to < 0.3 mg, (iii) reduce the max. Co in feed from 2 to 1 mg/kg for all species except fish. No negative consequences on animal health and production are expected. ENVIRONMENTAL SAFETY: EXPOSURE-DRIVEN (Guidance 2008) Natural compounds: show whether the use in feed and presence in animal excreta may change background environmental concentrations (unlikely) Otherwise, stepwise, multi-tier assessment: Phase I (additives not intended for farm animals or providing an insignificant predicted environmental concentration-PEC) Phase IIA: PEC + Predicted No Effect Concentration (PNEC) values for ground and water compartment based on a limited set of fate and effect (acute) studies Phase IIB: detailed ecotoxicological studies in the environmental compartment(s) in which Phase IIA studies indicate possible concern ENVIRONMENTAL SAFETY Additives of potential concern include Coccidiostats (highly active and highly excreted in active form; however, low persistence/bioaccumulation: e.g., nicarbazin, 2010) Some trace elements like Zinc or Copper: recent opinion on Zn sulphate monohydrate (2012) rules out any impact from use in aquaculture or for agricultural soil compartment, but potential environmental concern related to drainage and run-off of zinc to surface water. Most vulnerable for these processes are acid sandy soils Additional data are required SOME (hopefully not too) RANDOM SUGGESTIONS for making steps forward; traslational research (from bench to risk analysis) -Impact on feed additives (including probiotics/enzymes) on the nutritional quality of animal feeds and human foods - Adverse interactions between feed additives and between feed additives and feed materials - Refine consumer exposure (consumer’s niches) - bioavailability and safety of different nutrient forms (e,g, folic acid vs folates) for target species and consumers -- Risk-benefit of “risk reducing” additives (e.g., intended to lower nitrogen output or bind contaminants) -. Refine environmental exposure and effects SOME REFERENCES FROM US Mantovani A, Maranghi F, Purificato I, Macrì A. (2006) Assessment of feed additives and contaminants: an essential component of food safety. Ann Ist Super Sanita 42, 427-32. Mantovani A, Frazzoli C, La Rocca C. (2009) Risk assessment of endocrine-active compounds in feeds. Veterinary Journal 182, 392-401. Mantovani A, Frazzoli C, Cubadda F. (2010) Organic forms of trace elements as feed additives: assessment of risks and benefits for farm animals and consumers. Pure and Applied Chemistry. 82, 393-407. That’s all Folks…