Compliance of feed limits, does not mean compliance of food limits

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1 B A S E Bioechnol. Agron. Soc. Environ (S), Compliance of feed limis, does no mean compliance of food limis Leo W.D. van Raamsdonk (1), Jan C.H. van Eijkeren (2), Gerwin A.L. Meijer (3), Monique Rennen (4), Marco J. Zeilmaker (2), L. (Ron) A.P. Hoogenboom (1), Marcel Mengelers (5) (1) RIKILT. Insiue of Food Safey. P.O. Box 230. NL-6700 AE Wageningen (The Neherlands). Leo.vanraamsdonk@wur.nl (2) RIVM Naional Insiue of Public Healh and he Environmen. Posbus 1. NL-3720 BA Bilhoven (The Neherlands). (3) Animal Sciences Group of Wageningen UR (ASG). Division Nuriion and Food. P.O. Box 65. NL-8200 AB Lelysad (The Neherlands). (4) Toegepas Nauurkundig Onderzoek (TNO). Division Qualiy of Life. Urechseweg 48. NL-3704 HE Zeis (The Neherlands). (5) Food and Consumer Produc Safey Auhoriy (VWA). P.O. Box NL CM The Hague (The Neherlands). The carry-over of conaminans from feed o animal food producs is an imporan aspec of he animal producion chain. For a proper conainmen, limis for feed as well food producs are fixed for a series of chemicals, e.g. dioxins and dioxin-like PCBs, lead, cadmium, some chlorinaed pesicides, and aflaoxin B1 (and is meabolie M1 in milk). The relaionship beween feed and food limis is an imporan issue. An ideal goal is o assure ha compliance o a feed limis auomaically resuls in compliance o food limis. In order o collec informaion abou his relaionship, several simulaion s and a large daabase on ransfer facors have been developed. An opimal choice beween eiher a or an applicaion of daa from he Transfer Daabase is based on boh he knowledge level, and on he circumsances of he specific siuaion. To reach and validae such an opimal choice an Exper Sysem Carry-Over is currenly in developmen, conaining four differen modules: 1) he differen calculaion s and he Transfer Daabase, 2) a decision ree for choosing he opimal sraegy, 3) daa ables indicaing knowledge levels of compound/animal/produc parameers, and 4) supporing daabases conaining informaion on consumpion and composiion of daily dies, animal parameers, and amouns of (daily) producion. Calculaions indicae ha for dioxins compliance o feed levels does no necessarily mean ha food limis are complied as well. Besides an esimaion of he compliance o limis, he exper sysem is a ool for feed relaed risk assessmens, and for planning of fuure research. Keywords. Feed safey, animal healh, carry-over, simulaion s, decision suppor sysem, chemical conaminans, dioxin, aflaoxin, cadmium, nickel. 1. INTRODUCTION The major reason o se limis o conaminaion levels of chemicals in animal feeds and feed ingrediens is o ascerain ha safe levels of hose chemicals will be achieved in animal producs inended for food. Limis in food are se for some conaminans o avoid high exposure levels for humans. There is a limied range of chemicals for which limis in feed as well as in food are provided: dioxins and dioxin-like PCBs, Aflaoxin B1/M1, cadmium, lead, and 13 old pesicides (Direcive 2002/32/EC). In mos cases he limis in feed and hose in food are no empirically relaed o each oher: usually feed limis are relaed o conaminaion levels commonly found in pracice, applying he principle of as-low-as-reasonablyachievable (ALARA) if desired, whereas food limis are usually based on olerable daily or weekly inake levels for human consumpion. This siuaion resuls in differen backgrounds for feed and food limis, and is due o he lack of sufficien daa for carry-over from he feed, hrough he inesine and he meabolism of he animal o he arge organ or produc. More recenly, ools for calculaing his carry-over esimaing he final level in he arge organ have become available, in combinaion wih relevan daa from animal sudies. Calculaion s for simulaing he carry-over from feed o food have o be designed and adjused individually o a specific combinaion of conaminananimal-arge produc. This specific se of daa and parameers include he behavior of he conaminan in he arge animal and organs, conaminaion levels in he die componens, composiion of he die and daily consumpion. The level of deail depends on he ype of simulaion applied. I is vial o obain relevan compound and animal relaed daa and a possibiliy o define he correc

2 52 Bioechnol. Agron. Soc. Environ (S), van Raamsdonk L.W.D., van Eijkeren J.C.H. e al. mahemaical for he acual calculaions. Therefore, a group of Duch research insiues ogeher wih he Duch Food and Consumer Produc Safey Auhoriy (VWA) is developing an exper sysem for performing he complex process of collecing he necessary daa, deciding on he simulaion and performing he calculaions. This paper presens a preliminary repor on he developmen of an Exper Sysem Carry-Over. 2. MODELING CARRY-OVER The simulaion of he deposiion or excreion of conaminans from feed o animal producs for human consumpion such as mea, milk and eggs, and of he eliminaion of he compound via meabolism or excreion can be achieved in several ways. Le us assume a siuaion in which an animal is exposed for a cerain period of ime o a chemical compound a a background level, followed by a second period of excessive exposure, and a hird and las period of ime wih (again) exposure a background level. A firs choice migh be he applicaion of an exponenial, which can explain he accumulaion or he eliminaion by a gradual achievemen of a Seady Sae level 1. The slope and final level of he curve depend on several parameers. These are in non-mahemaical erms he carry-over rae o he arge organ or produc, and he half-life ime of he chemical in he arge animal. A schemaic represenaion is given in figure 1 (van Raamsdonk, in preparaion). For his, as applies o he oher approaches as well, daa on he consumpion amoun, composiion of he daily die, composiion of he animal (e.g. age relaed), and weigh of he arge organ or produc are needed for a successful applicaion of he. Anoher more deailed approach is he use of physiological-kineic s, in which differen body comparmens are considered simulaneously (e.g. blood serum, body vs milk fa, differen organs, ec.). Such s allow o predic more precisely he accumulaion or eliminaion in he course of ime, since differen half-life imes migh apply o he differen comparmens. Because of ha, a larger se of parameers is needed. The possibiliy of differen halflife imes is refleced in differen slopes for pars of he curves. In figure 2 he esimaion in he firs par of each of he hree periods of exposure is esimaed more accuraely compared o exponenial ing (e.g. van Eijkeren e al., 2006). 1 A Seady Sae siuaion is defined here as he sae in which he daily inake equals he daily eliminaion by meabolism or by excreion, including eliminaion via milk and eggs. In cerain cases he eliminaion of he chemical compound migh be (almos) zero. The parameer half-life ime is very high or infinie in hese cases. Linear s can easily be applied in which he speed of he accumulaion (he slope of he line) is direcly calculaed from he level of he exposure (Figure 3). On he oher hand, he parameer half-life ime can be (exremely) low. For some chemicals he siuaion applies ha in a few hours or days he balance beween accumulaion and eliminaion has been reached (Seady Sae). In siuaions where only he Seady Sae period is of ineres, he final level can be calculaed wih ignorance of he half-life ime, using he direc relaionship (carry-over rae) beween exposure and Seady Sae level (Figure 4). The availabiliy of parameers, or in more general erms he level of knowledge, for a combinaion of chemical compound/arge animal/arge organ or produc, direcs parly he choice for a paricular. In a large range of cases reliable parameers are no available a all. In such cases daa and resuls from lieraure can be seleced, which describe as good as possible he siuaion a hand. A mea-analysis of published experimens was carried ou. From each daase a ransfer facor was exraced, ha describes he behavior of he conaminan as precise as possible for he specific circumsances. In a more general approach physical parameers for he chemical compound or for he enire group (e.g. heavy meals) can be exraced from lieraure. These physical parameers can be used o predic he behavior of he compound in he animal body. A large Transfer Daabase is available wih daa from lieraure and scienifically approved facors (Leeman e al., 2007). 3. MODEL CHOICE The choice for he opimal or daase depends on wo major aspecs: he level of knowledge as menioned, and he circumsances of he specific siuaion ha leads o performing he calculaions. Reliable applicaion of simulaion s for carryover is no exclusively based on he presence of a (se of) mahemaical equaion and parameers, bu also on he calibraion and validaion of he used. Up o now a se of s is esed and documened for several siuaions in The Neherlands, as are lised in able 1. Models and daa can be used for he verificaion of compliance o feed and food limis. The same ools can be used in case of incidences wih high exposure. I is, however, no obvious in all cases ha he parameers carry-over rae and half-life ime can be used for all possible levels of exposure. For some chemicals (e.g. lead) oher parameers apply in siuaions of

3 Animal carry-over s 53 Exponenial Figure 1. Exposure of an animal in hree sages a respecively moderae, high and moderae level, and he resuling developmen of conaminaion levels in an animal produc, calculaed using an exponenial. Physiologicalkineic Figure 2. Exposure of an animal in hree sages a respecively moderae, high and moderae level, and he resuling developmen of conaminaion levels in an animal produc, calculaed using a physiological-kineic. The difference wih he exponenial is indicaed. Linear Figure 3. Exposure of an animal in hree sages a respecively moderae, high and moderae level, and he resuling developmen of conaminaion levels in an animal produc, calculaed using a linear. The difference wih he exponenial is indicaed. Seady Sae Figure 4. Exposure of an animal in hree sages a respecively moderae, high and moderae level, and he resuling developmen of conaminaion levels in an animal produc, calculaed using a seady-sae.

4 54 Bioechnol. Agron. Soc. Environ (S), van Raamsdonk L.W.D., van Eijkeren J.C.H. e al. Table 1. Documened cases of carry-over of a conaminan o one or more animal producs, wih an indicaion of he ype of used in he Duch Exper group Carry-over. Model approach Chemical conaminan Targe produc/organ Physiological-kineic Dioxins Milk fa, body fa, yolk fa (eggs) Chlorinaed pesicides Egg Exponenial Cadmium Cale kidney Aflaoxin B1/M1 Milk Seady Sae Aflaoxin B1/M1 Milk Linear Cadmium Cale kidney Transfer Daabase Nickel Organs of cale, body fa, milk Sulfamehoxazole (SMX) Organs of poulry, body fa, egg incidenal high exposure compared o moderae (level of feed limis) or low (background) levels. The ype of assessmen and he ype of quesions (are predicions requesed for an expeced wihdrawal period o reach levels below he limi, or for an expeced level) direc he choice for he o be applied as well. 4. NECESSARY DATA Several ypes of daa are necessary o apply successfully he presened s. These are: composiion of he animal daily die: share of compound feed, fodder and oher sources, composiion of he compound feed, amoun of he daily consumpion, animal parameers (animal oal weigh, share of he differen organs or issues, daily producion, growh of he animal), conaminaion levels of he arge chemical compound in feeds and feed ingrediens. For compliance o feed and food limis he limi values can be applied. In he case of an incidence he incidenal high conaminaion levels are o be used, parameers of he chemical compound. In a lo of cases a conaminan is meabolized in he animal, resuling in meabolies wih a lower or higher oxiciy. A siuaion where he conaminans or is meabolies are excreed, an exponenial equaion can be applied, where carry-over rae and half-life ime describe sufficienly such a siuaion. A kineic mass balance beween inake, plasma, organs and excreion can be described by using a physiological kineic, requiring exchange parameers beween he differen comparmens. The applicaion of more han one or parallel running s migh be desired when meabolies have heir own oxic effec and oxiciy level. In all hese cases (large ranges of) parameers should be readily available from sudies and lieraure. As an alernaive esimaions can be made, solely based on physical parameers exraced from he daabase. In all cases informaion on he bioavailabiliy (absorpion in he inesine) need o be available daa on he normal occurring background levels in feed and food producs (Duch daabase KAP). These daa can be used for calibraion of he s. Provided all he daa and parameers from daabases or from lieraure and given he normal (background) exposure of he conaminan in he daily die of he arge animal, he should esimae he normally occurring conaminaion level of he conaminan in he food produc under sudy. The resuls of he calculaions depend for a large exen on he reliabiliy and esimaion of all parameers and daa. Average animals and daily daa can be assumed, bu local or regional differences can deviae largely. Exper judgmen for boh he source and he validaion of parameers and daa is essenial in all cases. 5. EXAMPLE: DIOXIN CARRY-OVER TO MILK Dioxins cause an imporan burden on he producion chain of animal producs for human consumpion. Several incidences have occurred in he pas (e.g. Hoogenboom e al., 2005; 2007). I is imporan o know he relaionship beween he feed and food limis for dioxins in erms of oalteq; comparison is possible since limis for boh feeds and producs of animal origin have been se. Calculaions based on levels of oalteq are allowed for a series of differen dioxin congener specra (van Raamsdonk e al., in preparaion). A ypical se of parameers for he carryover from feed o milk fa consiss of: consumpion of dry maer: 15 kg per day (source: ASG), feed limi: 0.75 ng TEQ. kg -1 (source: Direcive 2006/13/EC), he daily exposure a maximum allowed level: ng TEQ per day,

5 Animal carry-over s 55 animal producion: 1 kg milk fa per day (25 lier milk wih 4% milk fa; source: ASG), food limi: 3 pg TEQ. g -1 milk fa (source: Regulaion 199/2006/EC). The prooype of he decision ree direcs o he applicaion of a physiological-kineic approach. The daa able wih informaion on he availabiliy of a sufficien knowledge level indicaes ha a se of parameers for he compound/produc combinaion is readily available o apply his approach. Calculaions indicae ha wih he menioned parameers and he parameers for he physiologicalkineic a Seady Sae level will be reached jus below he legal limi of 3 pg TEQ.g -1 milk fa (personal communicaion van Eijkeren, RIVM, figure 5). For comparison, exposure of laying hens o he feed limi (0.75 ng TEQ.kg -1 ) will resul in an excess of he food limi in eggs (3 pg TEQ.g -1 yolk fa). The expeced level will be approx. 13 pg TEQ.g -1 yolk fa, depending on he feed regime. In order o reasonably avoid excess of he food limi, feed limis are being prediced o be around 0.17 ng TEQ.kg -1 (van Eijkeren e al., 2006). Oher examples are currenly available in he Duch Exper group Carry-Over: cadmium o kidney in cale (Franz e al., 2008), nickel o cale (Leeman e al., 2007), aflaoxin B1 o M1 in milk (unpublished resuls) and sulfamehoxazole (SMX) o chicken (Leeman e al., 2007). 6. THE EXPERT SYSTEM CARRY-OVER This exper sysem is planned o consis of four differen modules (see also figure 6): Calculaion s. Documened ime based physiological-kineic (van Eijkeren e al., 2006), exponenial and linear s (Franz e al., 2008), as well as Seady Sae s and a comprehensive daabase on carry-over (Leeman e al., 2007) are available (see also able 1). Decision ree. Based on circumsances of he assessmen, he level of experise and he combinaion chemical compound-animal-arge produc, a decision ree guides he user o he opimal choice for a simulaion. Knowledge grid. A able ordered along chemical compounds and arge animal/organ consiss of indicaions for he level of experise currenly presen in he group of expers, and of subables for specific groups of chemicals, e.g. heavy meals, mycooxins, chlorinaed pesicides. Every cell is, when applicable, suppored by a page wih a summary of he lieraure available and of he primary indicaors. Parameers for a range of chemical compounds are published and discussed by Kan e al. (2007). Daabases. Daa on consumpion amoun, composiion of he daily die of major farm animals, background levels of chemical compounds in feeds, overview of legal limis, and daa on composiion of animals and producion of animal producs are colleced in order o provide daa for calculaions. The exper sysem is currenly in developmen and, as already menioned, prooypes of pars are available. A furher developmen is he connecion of animal carry-over s wih soil-plan ransfer s, in order o esimae conaminaion levels in roughage based on he available levels of he conaminan in soil. Esimaions of levels in vegeables and animal producs can be used as inpu for human exposure s. A chain of s including ineracions beween soil, plan, animal produc and human exposure has been used o describe he cadmium conaminaion levels in he food producion chain (Franz e al., 2008). Concenraion (pg TEQ.g -1 fa) ng TEQ.kg ime (day) Figure 5. Physiological-kineic ing of he developmen of he level of dioxins in milk fa during a long-erm exposure a he level of he legal limi in feed (0.75 ng TEQ.kg -1 ). 7. CONCLUSION AND RECOMMENDATIONS The dioxin example shows ha compliance o a feed limi does no necessarily mean ha food limis for all animal producs are no exceeded. I appears possible o esimae he carry-over of a paricular chemical compound o an animal produc by using a calculaion or by derivaion of ransfer facors from he Transfer Daabase. The opimal choice can be direced by using a decision ree based on he circumsances of a specific siuaion and he available knowledge. Supporing informaion on consumpion and producion is presen. An Exper Sysem Carry-Over can provide he necessary means for achieving several goals:

6 56 Bioechnol. Agron. Soc. Environ (S), van Raamsdonk L.W.D., van Eijkeren J.C.H. e al. daa Risk managemen: fixing a limi for conaminan A in feed. Wha level (and risk) can be expeced in animal producs? simulaion Informaion on expeced level C OR: afer period he required level C is reached decision ree Exper Sysem Carry-Over knowledge grid Tool for planning of new research Figure 6. Process of analysing a specific siuaion of compliance o feed limis and esimaion of he level and ime for developmen o reach ha level. The differen modules of he Exper Sysem Carry-Over are illusraed. seing feed and food limis, and esimaing he compliance beween hese limis, calculaion of he ALARA conaminaion level hroughou he producion chain (ingredien-feed produc), deciding on he opimal choice for a calculaion for a paricular incidence (and possible risk) in he chain, providing an overview of experise levels for individual chemical conaminans and groups of conaminans. A useful side-effec of having ables wih summaries of he available experise is he suppor for fuure research planning. I is srongly recommended o coninue he developmen of his exper sysem a a European level. Inegraion of an Exper Sysem Carry-Over wih he oher seps of he food producion chain (e.g. soilplan ineracions and human exposure s) will grealy enhance he possibiliies for risk analysis and managemen of chemical componens. Bibliography European Commission, Direcive 2002/32/EC of he European Parliamen and of he Council of 7 May 2002 on undesirable subsances in animal feed as regards dioxins and dioxin-like PCBs. Off. J. Eur. Communiy, L 140, , 10. European Commission, Commission Direcive 2006/13/EC of 3 February 2006 amending Annexes I and II o Direcive 2002/32/EC of he European Parliamen and of he Council of 7 May 2002 on undesirable subsances in animal feed as regards dioxins and dioxin-like PCBs. Off. J. Eur. Communiy, L 32, , 44. European Commission, Commission Regulaion (EC) n 199/2006 of 3 February 2006 amending Regulaion (EC) n 466/2001 seing maximum levels for cerain conaminans in foodsuffs as regards dioxins and dioxinlike PCBs. Off. J. Eur. Communiy, L 32, , 34. Franz E., Römkens P.F.A.M., van Raamsdonk L.W.D. & Fels-Klerx I., A chain ing approach o esimae he impac of soil cadmium polluion on human dieary exposure. J. Food Pro., 71(12), Hoogenboom L.A.P. e al., Kaolinic clay derived dioxins in poao by-producs. Organohalogen Compd, 67, Hoogenboom L.A.P. e al., A novel source for dioxins presen in recycled fa from gelain producion. Chemosphere, 68(5),

7 Animal carry-over s 57 Kan C.A. & Meijer G.A.L., The risk of conaminaion of food wih oxic subsances presen in animal feed. Anim. Feed Sci. Technol., 133, KAP (daabase). hp://www2.rikil.dlo.nl/kap/index.hml. Leeman W.R., Van Den Berg K.J. & Houben G.F., Transfer of chemicals from feed o animal producs: he use of ransfer facors in risk assessmen. Food Addi. Conaminans, 24(1), van Eijkeren J.C.H. e al., A oxicokineic for he carry-over of dioxins and PCBs from feed and soil o eggs. Food Addi. Conaminans, 23, (10 ref.)