Joint FAO/WHO Expert Committee on Food Additives (JECFA) Guidance document for WHO monographers and reviewers evaluating contaminants in food and feed

Transcription

1 Jint FAO/WHO Expert Cmmittee n Fd Additives (JECFA) Guidance dcument fr WHO mngraphers and reviewers evaluating cntaminants in fd and feed DRAFT NOTE: this draft will be tested in preparatin f the 83 rd JECFA meeting and the final guidance published after the meeting Geneva

2 Jint FAO/WHO Expert Cmmittee n Fd Additives (JECFA) Guidance dcument fr WHO mngraphers and reviewers evaluating cntaminants in fd and feed DRAFT February 2016 NOTE: this draft will be tested in preparatin f the 83 rd JECFA meeting and the final guidance published after the meeting Geneva

3 Wrld Health Organizatin 2016 All rights reserved. Publicatins f the Wrld Health Organizatin are available n the WHO website ( r can be purchased frm WHO Press, Wrld Health Organizatin, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: ; fax: ; bkrders@wh.int). Requests fr permissin t reprduce r translate WHO publicatins whether fr sale r fr nncmmercial distributin shuld be addressed t WHO Press thrugh the WHO website ( The designatins emplyed and the presentatin f the material in this publicatin d nt imply the expressin f any pinin whatsever n the part f the Wrld Health Organizatin cncerning the legal status f any cuntry, territry, city r area r f its authrities, r cncerning the delimitatin f its frntiers r bundaries. Dtted and dashed lines n maps represent apprximate brder lines fr which there may nt yet be full agreement. The mentin f specific cmpanies r f certain manufacturers prducts des nt imply that they are endrsed r recmmended by the Wrld Health Organizatin in preference t thers f a similar nature that are nt mentined. Errrs and missins excepted, the names f prprietary prducts are distinguished by initial capital letters. All reasnable precautins have been taken by the Wrld Health Organizatin t verify the infrmatin cntained in this publicatin. Hwever, the published material is being distributed withut warranty f any kind, either expressed r implied. The respnsibility fr the interpretatin and use f the material lies with the reader. In n event shall the Wrld Health Organizatin be liable fr damages arising frm its use.

4 Table f cntents List f abbreviatins... v Preface... vi Chapter 1: Rles and respnsibilities Selectin f cmpunds n the agenda and issuing the call fr data Identificatin f mngraphers and reviewers and assignment f cmpunds and tasks Perfrming a literature search Dealing with the data submissin Evaluating the data Preparing the draft mngraph befre the meeting Preparing the reprt item and finalizing the mngraph at the meeting... 4 Chapter 2: Preparing the mngraph Intrductin General aspects Frmatting Units f measurement Presentatin f dses Presentatin f pint f departure Tables Histrical cntrl data In-text references Miscellaneus Detailed cntent f the mngraph Explanatin Bilgical data Cmments Evaluatin References Chapter 3: Preparing the reprt item Chapter 4: Additinal cnsideratins Dietary expsure estimates in epidemilgical studies Cmmentary n the use f NOEL/NOAEL and LOEL/LOAEL Overall NOAEL Mdelling f dse respnse data Tlerable intakes fr cntaminants Expressin f the tlerable intake and runding prcedures Guidance n establishing acute reference dses Use f the margin f expsure apprach Predicting risks at specified expsure levels References Annex 1: Template fr mngraph Annex 2: Examples f table frmats Annex 3: Template fr reprt item Annex 4: Example f reprt item iv

5 List f abbreviatins ADI ARfD BMD BMDL BMDL 10 BMDS BMR bw CCCF C max CSAF EHC FAO FFQ GEMS/Fd GLP IQ JECFA JMPR LC 50 LD 50 LOAEL LOD LOEL LOQ ML MOE NOAEL NOEL OECD PMTDI POD ppm PTMI PTWI QA RIVM SI T 25 TDI TEF T max URL USEPA WHO acceptable daily intake acute reference dse benchmark dse lwer 95% cnfidence limit n the benchmark dse lwer 95% cnfidence limit n the benchmark dse fr a 10% respnse Benchmark Dse Sftware (USEPA) benchmark respnse bdy weight Cdex Cmmittee n Cntaminants in Fds maximum cncentratin chemical-specific adjustment factr Envirnmental Health Criteria Fd and Agriculture Organizatin f the United Natins fd frequency questinnaire Glbal Envirnment Mnitring System Fd Cntaminatin Mnitring and Assessment Prgramme gd labratry practice intelligence qutient Jint FAO/WHO Expert Cmmittee n Fd Additives Jint FAO/WHO Meeting n Pesticide Residues median lethal cncentratin median lethal dse lwest-bserved-adverse-effect level limit f detectin lwest-bserved-effect level limit f quantificatin maximum level margin f expsure n-bserved-adverse-effect level n-bserved-effect level Organisatin fr Ecnmic C-peratin and Develpment prvisinal maximum tlerable daily intake pint f departure part per millin prvisinal tlerable mnthly intake prvisinal tlerable weekly intake quality assurance Natinal Institute fr Public Health and the Envirnment (the Netherlands) Le Système internatinal d unités (Internatinal System f Units) chrnic daily dse that will give 25% f the animals tumurs at a specific tissue site, after crrectin fr spntaneus incidence, within the standard lifespan f that species tlerable daily intake txic equivalency factr time t maximum cncentratin unifrm resurce lcatr United States Envirnmental Prtectin Agency Wrld Health Organizatin v

6 Preface This guidance dcument replaces the previus guidance fr the risk assessment f cntaminants in fd by Jint FAO/WHO Expert Cmmittee n Fd Additives (JECFA) mngraphers and reviewers, issued by WHO in It is intended primarily fr WHO Experts (mngraphers) wh prepare mngraphs fr JECFA and fr Members (reviewers) wh have been assigned t peer review them. The guidance will als be useful t parties interested in understanding the prcess fllwed by JECFA in the evaluatin f cntaminants that may be present in fd r feed fr example, heavy metals, envirnmental cntaminants, impurities arising in fd r feed additives, slvents used in fd r feed prcessing, ther substances arising frm fd r feed prcesses such as heating, substances migrating frm fd r feed cntact materials, and residues arising frm the use f animal feed additives r the nn-active cmpnents f veterinary drug frmulatins. Detailed scientific guidance n the interpretatin f txiclgical and epidemilgical data may be fund in the mngraph Envirnmental Health Criteria 240 ( In this guidance dcument, reference t JECFA is t JECFA (fd additives and cntaminants). With the aim f harmnizing the wrk f JECFA with that f the Jint FAO/WHO Meeting n Pesticide Residues (JMPR), this guidance dcument takes int accunt the dcument entitled Guidance dcument fr WHO mngraphers and reviewers, prepared by JMPR in 2015 ( The authrs f the JMPR guidance dcument as well as the authrs f this guidance dcument fr the evaluatin f cntaminants in fd and feed are gratefully acknwledged. It is envisined that this guidance dcument will be mdified based upn cmments received and experience gained in using it. Cmments n this guidance dcument and suggestins fr future editins will be gladly accepted by the WHO Jint Secretary, Jint FAO/WHO Expert Cmmittee n Fd Additives, Wrld Health Organizatin, 1211 Geneva 27, Switzerland, at jecfa@wh.int. Separate guidance dcuments fr the evaluatin f fd additives (excluding enzyme preparatins and flavuring agents), enzyme preparatins and flavuring agents and fr the assessment f dietary expsure t fd additives are als available n the WHO website ( chem/jecfa/guidelines/en/). vi

7 Chapter 1: Rles and respnsibilities The rles and respnsibilities f the JECFA Secretariat and f bth mngraphers ( Experts 1 ) and reviewers ( Members ), frm the time they are assigned t their cmpunds thrugh t the pstmeeting finalizatin f their mngraphs, are utlined belw. 1.1 Selectin f cmpunds n the agenda and issuing the call fr data The cmpunds n the agenda fr the next JECFA meeting n cntaminants are selected n the basis f pririty lists established by the Cdex Cmmittee n Cntaminants in Fds (CCCF), requests by FAO and WHO and their Member States, and recmmendatins f earlier meetings f JECFA. The WHO and FAO Jint Secretaries pst a call fr data n the cmpunds n the agenda mnths in advance f the meeting n the Internet, utilizing as brad a distributin as pssible. The deadline fr submissin f data is rdinarily 6 7 mnths befre the meeting. 1.2 Identificatin f mngraphers and reviewers and assignment f cmpunds and tasks The WHO Jint Secretary will cntact ptential mngraphers and reviewers within the existing rster f experts abut their interest and availability t serve as experts fr the next meeting f JECFA n cntaminants in fd and feed. If additinal expertise is needed (e.g. in the areas f dse respnse mdelling, epidemilgy, carcingenicity r gentxicity), the Secretariat may identify additinal experts frm the published literature. Usually the Secretariat assigns several experts t ne cmpund (r grup f related cmpunds) wh have cmplementary expertise and are assigned t draft specific sectins f the mngraph. One f the experts will be assigned t take the verall lead and crdinatin functin fr the drafting f the full mngraph. Fr cmplex evaluatins, mre than ne reviewer may be assigned. In additin t WHO experts, FAO experts will be assigned t the cmpund wh are respnsible fr the evaluatin f analytical methds, including sampling prtcls, ccurrence data, effects n prcessing, and preventin and cntrl. Additinal experts n expsure assessment will als be assigned t the cmpund. The entire grup f experts assigned t the cmpund r grup f related cmpunds is smetimes referred t belw as the evaluatin team. Participants are invited as independent experts in their respective areas, and they d nt represent any rganizatin r gvernment. Participatin is nt cmpensated, althugh WHO is respnsible fr return airfare and prvides a daily subsistence allwance t cver accmmdatin, meals and ther miscellaneus expenses. In accrdance with WHO rules and prcedures fr declaratins f interest, 2 any ptential r perceived interests will be evaluated befre any tasks are assigned. In the interest f transparency and t avid ptential cnflicts, participants are encuraged t be inclusive in the declaratin f their interests. It is imprtant t nte that the fcus shuld be n a cmprehensive declaratin f all interests, nt just thse perceived by the participant as ptentially psing cnflicts. In accrdance with WHO prcedures, declaratins f interest are nt published, but ptential cnflicts f interest that preclude participatin in discussins n particular cmpunds are nted in the meeting reprt. The WHO Jint Secretary will take int accunt whether mngraphers have been invlved with a particular cmpund, which may be perceived as a cnflict r bias. Interests t be cnsidered include the fllwing examples: Mngraphers have perfrmed sme f the studies t be evaluated. Mngraphers have recently been invlved clsely with preparing an evaluatin f a cmpund fr a natinal r anther supranatinal bdy. The latter pint is imprtant as, althugh familiarity with a cmpund and the supprting data can make preparatin f the mngraph easier, there might be the perceptin that the JECFA evaluatin is nt entirely independent f the previus evaluatin. 1 Previusly Temprary Advisers

8 Accrding t WHO rules and prcedures, 3 expert meetings are private in nature, and participatin is by invitatin nly. The data used and discussins held befre, during and after the meeting n the subject matter f the meeting are t be held in strict cnfidence. Discussins held subsequent t the meeting with nn-participants shuld be limited t the public infrmatin made available in the mngraphs and meeting reprt. 1.3 Perfrming a literature search 4 The mngrapher is requested t perfrm a detailed search f the public literature. The literature search shuld be dcumented in detail, listing the exact search terms used, the databases that were searched, the number f references retrieved and the number f relevant references selected, as well as the criteria (bth inclusin and exclusin) fr the selectin f relevant references. The WHO JECFA Secretariat can assist in develping search strategies and in retrieving the full text f relevant publicatins. 1.4 Dealing with the data submissin After a cmpund has been assigned t the lead mngrapher and a reviewer, the Secretariat will ensure that the evaluatin team receives any data submitted, usually by natinal authrities, in respnse t the JECFA call fr data. The evaluatin team shuld review the data submissin in detail and identify any need fr further clarificatin. 1.5 Evaluating the data The basic principles n hw t evaluate txiclgical and epidemilgical data are utlined in Envirnmental Health Criteria (EHC) 240 (IPCS, 2009a). A JECFA mngrapher will already be an experienced assessr f txiclgical, epidemilgical r ther relevant data and will have his r her wn ways f wrking thrugh the txiclgical and epidemilgical database n a cmpund, including published peer-reviewed studies, the grey literature and data submitted during the call fr data. The WHO Jint Secretary will als infrm the mngraphers f any previus evaluatins f the cmpund r f its metablites by JECFA. The JECFA prcess shuld nt require any significant changes t the mngrapher s and reviewer s usual way f wrking thrugh the data, prvided that each study is described and the relevance (including any ptential bias r prblems with study design r reprting f results) is dcumented in a clear and transparent manner. When the mngraph is being prepared, all data are evaluated in a thrugh and independent manner, taking int accunt specific guidance prepared fr JECFA mngraphers n the interpretatin f txiclgical and epidemilgical data (i.e. EHC 240 [IPCS, 2009a] and subsequently published guidance). Given the large amunt f published literature ften available n cntaminants in fd and feed, the mngraphers must be sure t allw sufficient time fr retrieving, rganizing and reviewing references identified during the literature search. The depth f investigatin will clearly vary with the study type, the results and the impact n the verall cnclusin. Fr example, it can be valuable t g dwn t individual animal-level data fr a dg study with a small grup size and a marginal respnse, but this is nt nrmally required fr a rdent study with a larger grup size and clear effects (e.g. 8/10 animals with grade 3 versus 3/10 cntrls with grade 1). If the study authrs have discunted particular findings as nt being treatment related r adverse, the mngrapher shuld pay particular attentin t these t see if he r she agrees with the study authrs cnclusins. If the mngrapher disagrees with the cnclusins f the study authrs, this shuld be highlighted in the mngraph. The mngrapher may ccasinally wish t cntact the study authrs fr clarificatin r t request additinal infrmatin The JECFA Secretariat is currently investigating the applicability f systematic review methdlgy t the wrk f JECFA, with the ultimate aim f develping a wrkable apprach that is manageable and fllws the basic principles n transparency, minimizing risk f bias and reprducibility. 2

9 In presenting findings where descriptive terms are used, it is imprtant t use the precise terms as given in the published study (e.g. in the histpathlgy tables r descriptins f anmalies in develpmental txicity studies). If fr any reasn a revised term is used, there shuld be sme cmmentary abut this, as it can prduce cnfusin fr smene cmparing reviews with the published study. If the term is an unfamiliar r unusual ne that is nt clarified in the published reprt, then there is the ptin t ask the study authr(s) t clarify and/r prvide pictures. Standard texts and websites are available that prvide descriptins f pathlgical and develpmental txicity terminlgy (e.g. see als the guidance belw under specific systems and effects). Where JECFA has its wn criteria fr the interpretatin f txiclgical r epidemilgical end-pints (i.e. EHC 240 [IPCS, 2009a] and subsequently published guidance), these shuld always be used in the preparatin f mngraphs in preference t thse frm natinal r ther supranatinal bdies. Where JECFA des nt have its wn criteria, then general guidance n the evaluatin and interpretatin f txiclgical and epidemilgical data available in the WHO EHC mngraphs ( and elsewhere may be used. It is expected that standard appraches will be applied (e.g. statistical significance, clear dse respnse relatinship, change utside the nrmal bilgical range). If a cnclusin in a mngraph is based n a nn-standard apprach (e.g. the use f a specific cut-ff), then the basis fr this apprach shuld be prvided (r a publicly available supprting guidance dcument shuld be cited). The risk assessment f a cntaminant r grup f cntaminants can result in ne f several pssible utcmes. The first is the establishment f chrnic (tlerable intake; see sectin 4.5) and/r acute (acute reference dse [ARfD]; see sectin 4.7) health-based guidance values. Where these are established, chrnic dietary expsure estimates are used fr cmparisn with tlerable intakes in a risk assessment prcess, and acute dietary expsure estimates, which shuld cver a time perid f fd cnsumptin ver a single meal r 24 hurs, are used fr cmparisn with ARfD values. A secnd pssible utcme is the derivatin f a relative level f cncern the margin f expsure (MOE). Where a cntaminant is fund t be a gentxic carcingen, fr which JECFA cnsiders it inapprpriate t establish a health-based guidance value, JECFA will usually calculate a margin f expsure (MOE) between the critical pint f departure and the dietary expsure fr a high r average cnsumer t prvide guidance fr risk managers. A third utcme is the perfrmance f a quantitative assessment f the risk (e.g. additinal cancer risk) at defined levels f expsure. Which type f utcme (health-based guidance value, MOE, quantitative risk assessment) is apprpriate and pssible fr each cntaminant r grup f cntaminants will be decided by the evaluatin team n a case-by-case basis. 1.6 Preparing the draft mngraph befre the meeting The mngraphers prduce a first draft f the mngraph, based n a critical review f the published literature, the grey literature and data submitted in respnse t the call fr data. Each mngraph includes a main bdy f text as well as an Explanatin sectin, a Cmments sectin and an Evaluatin sectin; these three sectins will be used as the basis fr the meeting reprt item fr the cmpund (see Chapter 3). Detailed guidance n preparatin f the mngraph is prvided in Chapter 2. Examples f recent mngraphs n cntaminants can be accessed thrugh the WHO JECFA searchable database: search.aspx?fc=35. In cases where new r additinal data are prvided t cmplete an evaluatin r t re-evaluate a cmpund previusly cnsidered by JECFA r t establish an ARfD that was nt previusly cnsidered, an addendum t the riginal mngraph shuld be prepared with the summaries f the new studies. It is critical that the evaluatin team (including bth WHO and FAO experts) wrks tgether and discusses critical aspects r studies thrughut the preparatin f the mngraph. The first draft f the txiclgical and epidemilgical mngraph is distributed first t the reviewer(s). The reviewer(s) shuld receive the first draft f the mngraph tw mnths befre the meeting in rder t allw sufficient time t perfrm a thrugh review. It is the respnsibility f the reviewer(s) t crss-check 3

10 critical studies, suggest amendments in bth text and tables, and finalize the Cmments and Evaluatin sectins. The reviewer(s) return the mngraph t the lead mngrapher, wh incrprates agreed changes int the dcument and then sends the revised draft mngraph t the WHO Jint Secretary. During the preparatry phase, usually 4 6 weeks befre the meeting and, as necessary, earlier t clearly define tasks the WHO Jint Secretary rganizes telecnferences fr each cmpund (r grup f cmpunds), invlving all WHO experts assigned t the cmpund, ther JECFA experts, in particular FAO experts assigned t the same cmpund, and the Jint Secretariat. The purpse f these telecnferences is t clarify issues, crdinate the wrk between the WHO and FAO experts and identify infrmatin missing frm the literature search. The lead mngrapher is respnsible fr making any revisins suggested by telecnference participants. The final draft is then sent t the WHO Jint Secretary, wh is respnsible fr sending the draft mngraph t all meeting participants at the latest 10 days prir t the meeting. 1.7 Preparing the reprt item and finalizing the mngraph at the meeting The physical meeting is rganized jintly by FAO and WHO and generally alternates between Rme and Geneva. During the meeting, the mngraphers lead the discussins n their particular cmpunds and prepare the meeting reprt item fr each cmpund under their respnsibility. The reprt item is prepared frm the Explanatin, Cmments and Evaluatin sectins f the mngraph (see Chapter 3) and is mdified during the meeting t incrprate the results f the meeting discussins. In parallel, during the meeting, the mngrapher updates the draft mngraph t ensure that the final versin is cnsistent with the meeting reprt item, t reflect decisins taken during the meeting (e.g. decisins n the NOAELs) and t include any extra details fund t be useful in supprting the cnclusins f the Cmmittee. The lead mngrapher is the main individual respnsible fr revisins and wrks clsely with the ther mngraphers t finalize the mngraph. It is the JECFA Members wh have the final respnsibility fr adpting the reprt. Hwever, during the meeting, cnclusins and decisins are reached by cnsensus frm all participants. Therefre, all mngraphers (and reviewers) shuld cntribute t discussins n all the cmpunds and general cnsideratins. This is particularly the case if the mngraphers (and reviewers) have expertise in a specific area f txiclgy (e.g. histpathlgy, gentxicity, develpmental txicity) r epidemilgy, such that they can bring additinal insights and views t the discussins. It is als imprtant that mngraphers ask questins when they are unclear abut the basis fr a decisin r if the text relating t a tpic is nt well presented. Hwever, mngraphers need t be aware that their reprt items must be cmpleted prir t the cnclusin f the meeting and s must carefully balance the requirement fr the timely preparatin f drafts f their reprt items fr discussin at the meeting and cntributing t discussins n ther cmpunds. During the meeting, the rapprteur is respnsible fr ensuring that all necessary revisins resulting frm discussins have been made t the draft befre the meeting reprt item is again discussed by the Cmmittee. The editr is respnsible fr technical and language editing f each draft reprt item nce the Chair is satisfied that it is in near-final frm. The mngrapher is respnsible fr respnding t any queries raised by the editr during the editing prcess. After the reprt item has been edited, subsequent changes, as suggested by meeting participants during discussins, will be tracked nscreen by the editr, until the Chair is satisfied that the meeting reprt item is in final draft frm. At that time, the editr passes the reprt item n t the FAO rapprteur fr FAO review and incrprates any changes suggested by FAO. Additinal editing may be perfrmed by the editr after the meeting has cncluded (see belw). On the last day f the meeting, all meeting participants (FAO and WHO) review the final versin f the meeting reprt in plenary sessin and suggest any necessary revisins, which are made nscreen by the editr r by the WHO Jint Secretary, and the JECFA Members frmally adpt the reprt befre the meeting is adjurned. The mngrapher needs t prvide an electrnic versin f the final draft f the mngraph t the editr and the WHO Jint Secretary (by uplading it nt the meeting cmputer in the Final mngraphs flder) befre leaving n the final day f the meeting. There is n need fr the mngrapher t update the Explanatin, Cmments and Evaluatin sectins f the mngraph during the final sessin, as the editr will insert the final versins f thse sectins frm the meeting reprt int the mngraph during the editing prcess. 4

11 In the weeks fllwing the meeting, a summary reprt is published and psted n the FAO and WHO websites. It includes the main cnclusins and the health-based guidance values (i.e. tlerable intakes and ARfDs) r ther safety recmmendatins fr all cntaminants evaluated at the meeting. In the mnths fllwing the meeting, the editr edits the mngraphs. The mngraphers are respnsible fr answering any queries raised during the editing prcess in a timely fashin (generally within 1 2 mnths after receiving the mngraph back frm the editr). The meeting reprt is nt published until the mngraphs have been edited, s any errrs in the meeting reprt fund during the editing prcess can be crrected befre its publicatin. The meeting reprt is published by WHO in the Technical Reprt Series, and the mngraphs are published by WHO in the Fd Additives Series (bth available n the WHO website at The meeting reprt is intended fr nn-experts (bth plicy-makers and risk managers) and cntains the descriptin, cncise evaluatin and interpretatin f the key data relevant fr the verall assessment f each substance reviewed by JECFA in terms f its txiclgical, epidemilgical, chemical and analytical aspects, as well as infrmatin n the dietary expsure assessment. Reprts reflect the agreed view f the Cmmittee as a whle and describe the basis fr its cnclusins. Any Members wh d nt agree with the cnclusins can express a minrity pinin, which shuld be nted and described in detail in the meeting reprt, in accrdance with WHO rules and prcedures fr expert cmmittees. The mngraphs are intended fr experts and cntain detailed descriptins f the full database n the bichemical, txiclgical and epidemilgical data cnsidered in the evaluatin, the sectins prepared by FAO experts (n chemical and technical matters), as well as the dietary expsure assessment, in sufficient detail t enable the basis f the cnclusins reached by the Cmmittee t be independently verified. The Cmments and Evaluatin sectins f the mngraphs are in principle identical t the reprt item (with the inclusin f the Explanatin sectin). In exceptinal cases, these sectins culd cntain mre detail than in the reprt. 5

12 Chapter 2: Preparing the mngraph 2.1 Intrductin The mngraph cntains the detailed study descriptins and numerical data used t underpin the meeting reprt item, referred t belw as the reprt item (see Chapter 3). The mngraph must therefre cntain all the elements identified in the reprt item, tgether with sufficient additinal details t permit an independent evaluatin f the cnclusins made. The mngraph als briefly describes data that were nt critical t the evaluatin, in rder t reflect the full database cnsidered. A table f cntents r template fr the mngraph (fr the JECFA current year) will be prvided t mngraphers when they are assigned a cmpund. An example is included in Annex 1. The layut and sequence f the template shuld generally be fllwed, althugh nt all sectins will necessarily be included in all mngraphs, depending n the infrmatin available and n whether a tlerable intake r ARfD is established, an MOE is derived r a quantitative risk assessment is perfrmed. The template fr the current year shuld always be used, as mdificatins may have been intrduced fllwing the previus meeting. 2.2 General aspects General aspects t be cnsidered while preparing the mngraph are utlined belw Frmatting The mngraph (r mngraph addendum) shuld be prepared using Micrsft Wrd r a cmpatible wrd prcessing package. Details f the frmatting requirements (e.g. fnt size, line spacing, line numbering, margins) shuld be btained frm the mngraph template (see Annex 1). Details f the frmatting requirements fr preparing tables are prvided in sectin Units f measurement Le Système internatinal d unités (SI units) shuld be used thrughut. This includes the use f milligrams per kilgram f diet (mg/kg diet) instead f parts per millin (ppm) fr dietary expsure levels and the use f becquerels (Bq) instead f curies (Ci) fr radiactivity. One exceptin is millimetres f mercury (mmhg) fr pressure (the equivalent in kilpascals [kpa] shuld be given in parentheses). When expressing dietary expsure levels in milligrams per kilgram, the wrd diet shuld always be included (i.e. mg/kg diet), t avid cnfusin with the actual dse t the animals (in mg/kg bw, where bw is bdy weight). There are n hyphens between numbers and units, but there is a space. Fr example, 0.5 kg rat (nt 0.5-kg rat r 0.5kg rat) is used. There shuld be n wrds between units and the slidus (/). Fr example, 3 µg Pb/kg bw is nt crrect. Instead, the sentence shuld be rewritten mre clearly as, fr example, a lead dse f 3 µg/kg bw. It is recgnized that there may need t be ccasinal exceptins t this rule in rder t avid extremely awkward wrding. Only ne slidus shuld be used. Fr example, 3 mg/kg bw per day, nt 3 mg/kg bw/day, is used. Figures with mre than fur digits use a space (nt a cmma) t separate grups f three digits n either side f the decimal pint (e.g ; ). Nte that the WHO rule is that in tables, figures with mre than three digits use a space t separate grups f three digits n either side f the decimal pint. The WHO rule is t be fllwed, even thugh the guide fr the use f SI units (Thmpsn & Taylr, 2008) states that the practice f inserting 6

13 spaces in numbers having nly fur digits n either side f the decimal marker is nt usually fllwed except when unifrmity in a table is desired Presentatin f dses Parentheses, rather than cmmas, are used when presenting dse cnversins: X and Y mg/kg diet (equal [r equivalent] t x and y mg/kg bw per day fr males and a and b mg/kg bw per day fr females, respectively). Equal t is used when the cnversins have been calculated using feed r drinking-water cnsumptin and bdy weight data generated fr the animals that had been dsed in a particular study, and equivalent t is used when dse cnversin factrs (i.e. default values) have been used t calculate the dses. Where accurate dses cannt be calculated n the basis f measured bdy weights and feed r drinking-water cnsumptin, apprximate dses can be estimated using the dse cnversin factrs shwn in Table 1, adapted frm EHC 240 (IPCS, 2009a). When dses are cnverted frm ppm, mg/kg diet, mg/l drinking-water, mg/animal per day r percentage f the substance in the diet (ften given when the lwest dse is 1000 mg/kg diet r mre; e.g mg/kg diet = 1%) t mg/kg bw per day, up t tw additinal significant figures can be used fr the cnverted dse, t avid intrducing additinal uncertainty in the calculatin f the final runded tlerable intake r ARfD. As lng as the dse cnversins have been presented at the beginning f a study descriptin, the riginal dses (e.g. in mg/kg diet, mg/l drinking-water r percentage in the diet, but nt in ppm, which must be changed t mg/kg diet r mg/l drinking-water) can be used thrughut the study descriptin until the n-bserved-adverse-effect level (NOAEL) is identified at the end f the study descriptin. Equivalent dses shuld be crrected fr the purity f the cmpund, but nly when this is less than 90%. Dses shuld be crrected fr nn-cntinuus dsing (e.g. 5 days/week dsing) Presentatin f pint f departure Health-based guidance values (i.e. a tlerable intake r an ARfD) are mst ften established using a pint f departure (POD) frm a txicity study in experimental animals. The mst frequently used POD is the NOAEL. Hwever, if the data are adequate t permit dse respnse mdelling, a lwer 95% cnfidence limit n the benchmark dse fr an x% respnse (BMDL x ) r similar POD can (and shuld) be used. In such cases, the basis fr the derivatin f the POD shuld be prvided (fr details, see EHC 240 [IPCS, 2009a]). Past tense shuld be used when presenting the POD: The NOAEL/BMDL x was 10 mg/kg bw per day. The POD used in risk assessment by the Cmmittee shuld be that identified by the mngrapher/cmmittee. When this differs frm the POD identified by the study authr(s), the latter shuld als be reprted, with an explanatin fr the difference. When dses have been derived frm a dietary r drinking-water cncentratin using the feed cnsumptin and bdy weight data frm the study, the POD shuld be expressed as equal t x mg/kg bw per day. If predefined dse cnversin factrs (see Table 1 abve) have been used, the POD shuld be expressed as equivalent t x mg/kg bw per day. The POD, as either equal t r equivalent t dses, can be (but des nt have t be) prvided fr bth males and females in the main text, but nly the lwer value f the tw (usually the value fr males) is used in the Cmments sectin. An exceptin t this rule is where the effect is sex specific, in which case the apprpriate POD fr the sex in which the effect is bserved is prvided. 7

14 Table 1 Apprximate relatinship f mg/kg (ppm) in the diet r mg/l (ppm) in drinking-water t mg/kg bw per day Species Bdy weight (kg) Feed cnsumptin (g/day) a Type f diet 1 mg/kg in feed is equivalent t x mg/kg bw per day Water cnsumptin (L/day) 1 mg/l in water is equivalent t x mg/kg bw per day Muse Dry b 4 b labratry 0.13 b b 0.20 b,c chw Rat (yung) diets Rat d 0.06 (multigeneratin 0.40 d (average: studies) (average: 15) 0.25) Rat (ld) b 18 b 0.05 b 0.05 b 0.14 b,e Hamster 0.14 b 12 b 0.09 b 0.03 b 0.21 b Chick Guinea-pig b 34 b 0.04 b 0.20 b 0.24 b Rabbit b 186 b 0.05 b 0.41 b 0.11 b Dg b 300 b 0.03 b 0.61 b 0.05 b Cat Mist, b 168 b semislid diets 0.11 b 0.15 b 0.10 b Mnkey (e.g rhesus, cynmlgus) Rhesus mnkey 8.0 b 320 b 0.04 b 0.53 b 0.07 b Dg Human Pig r sheep Relatively Pig 80 b b dry grain 0.03 b 5.5 b 0.07 b frage Cw mixtures (maintenance) Cw (fattening) Hrse bw: bdy weight; ppm: parts per millin a Liquids mitted. b Frm Health Canada (1994). Nte that the type f diet has nt been specified in this reference. c EFSA (2012) uses cnversin factrs f 0.18, 0.15 and 0.09 fr mice fr subacute, subchrnic and chrnic studies. The first tw types f studies are assumed t start with mice 5 7 weeks f age. d Bdy weight and feed cnsumptin values vary ver the stages and generatins f the studies. The average values are used in calculating the dse cnversin factr. e EFSA (2012) uses cnversin factrs f 0.12, 0.09 and 0.05 fr rats fr subacute, subchrnic and chrnic studies. The first tw types f studies are assumed t start with rats 5 7 weeks f age. 8

15 The general statement will read as fllws: When the POD is the NOAEL: The NOAEL was x mg/kg diet (equal t y mg/kg bw per day), based n [effects] bserved at z mg/kg diet (equal t a mg/kg bw per day) [where z mg/kg diet is, f curse, the lwest-bserved-adverse-effect level (LOAEL), but this des nt need t be stated explicitly in the text]. When the POD is the BMDL x r similar: The BMDL x [r similar] was y mg/kg bw per day, based n [the effects that serve as the basis f the benchmark respnse x]. When n effects are bserved up t the highest dse tested, it is nt pssible t determine a BMDL x. In such cases, the highest dse tested is the NOAEL, which serves as the POD fr this study. Cnsistent language shuld be used when expressing the NOAEL in such circumstances: The NOAEL was x mg/kg bw per day, the highest dse tested. OR The NOAEL was x mg/kg diet (equal t y mg/kg bw per day), the highest dietary cncentratin tested. When effects are bserved at all dses, it is nt pssible t identify a NOAEL. In such cases, it might be pssible t determine a BMDL x r similar POD. Otherwise, the POD fr the study is the LOAEL. Cnsistent language shuld be used in such circumstances: N NOAEL culd be identified, as effects were bserved at all dses. The LOAEL was x mg/kg bw per day, the lwest dse tested. OR The LOAEL was x mg/kg diet (equal t y mg/kg bw per day), the lwest dietary cncentratin tested. If an effect is cnsidered nt relevant fr determining the POD fr a study, a statement shuld always be made n the reasn fr this fr example, the effect was cnsidered nt t be txiclgically relevant r the effect was cnsidered nt t be substance related (with an explanatin as t why, if pssible), t make the basis fr POD determinatin clear t the reader. Determinatin f verall NOAELs (see sectin 4.3) r ther PODs is usually reserved fr the Cmments sectin Tables It is ften preferable t present numerical infrmatin in the frm f a table rather than in the text (e.g. t illustrate the results f acute txicity and gentxicity studies). It is the chice f the mngrapher as t whether data are presented in tables r text, as lng as it is pssible fr readers f the mngraph t perfrm an independent evaluatin f the data and reach their wn cnclusins. Pasting tables frm PDF dcuments int the mngraph is nt recmmended and shuld be dne nly if there is n realistic alternative (in which case the editr will need t re-enter the tables in Micrsft Wrd frmat in rder t edit them accrding t WHO style). Tabs shuld nt be used t create the table clumns. All tables must be cited in the text, in cnsecutive numerical rder frm 1 t x. Tables shuld be placed in the text immediately fllwing the paragraph in which they are first cited, r as near t this as is practical. Repeating header rws can be used where the table extends ver mre than ne page. The cntents f a table shuld be restricted t the data relevant t decisin-making. If a 200- rw table cntains 16 rws f data that shw n changes with dsing, it is difficult t identify the data that are imprtant. There shuld be n blank cells in the table (unless the cells are in a heading rw). If a cell des nt cntain text r figures, then a 0, dash, NA (fr nt applicable r nt available) r ND (fr nt determined r n data), r smething alng these lines, is needed, depending n the table, with a clear definitin f the terms used included belw the table. Data in tables shuld be quted t an apprpriate number f significant figures (e.g. quting rgan weights relative t bdy weight t six significant figures is nt apprpriate, as it implies spurius accuracy six significant figures implies that a change f % culd be determined with cnfidence and is bilgically significant). The apprpriate number f 9

16 significant figures t be used may vary with the situatin but shuld be sufficient t shw differences in utcme while being prprtinate t the variance (r standard deviatin). In sme instances, it may be useful t include the standard deviatin (r ranges) in additin t mean values. An indicatin f statistical significance shuld be included wherever apprpriate. Bldface type t indicate a statistically significant treatment-related effect can be used, but must be explained in a ftnte. Alternatively, superscripts such as * and ** may be used t indicate statistical significance, with definitins included belw the table (see next bullet pint). A listing f all abbreviatins used in the table is included belw the table, in alphabetical rder (e.g. BUN: bld urea nitrgen; Hb: haemglbin), immediately fllwed, n the same line, by a descriptin f any P-values used (e.g. *: P < 0.05; **: P < 0.01), tgether with a descriptin f the statistical test used in parentheses (e.g. Fisher exact test). Fr tables cntaining multiple studies using different statistical tests (e.g. epidemilgical studies), this infrmatin can be included in the bdy f the table. Table ntes (given with lwercase superscripted letters: a, b, c ) appear immediately belw the listing f abbreviatins. Table ntes shuld be inserted manually, nt using the Wrd ftnte functin. Within the table itself, lettered table ntes are t appear sequentially in alphabetical rder, reading acrss and then dwn the table (i.e. rw by rw). The table surce (Surce: Smith & Jnes (1999)) is given belw the abbreviatins and any table ntes (superscript a, b, c ). Nte that permissins t reprint (t be requested by the WHO Jint Secretary) are usually required fr any tables (r figures) that are taken directly frm published surces. Given this requirement, it is preferable t avid the direct cpying f illustrative material (tables and figures) taken frm published surces wherever pssible. Additinal miscellaneus pints relating t table frmats fllw: Clumns f figures are aligned t the decimal pint, where pssible. Clumns f text are aligned at the left-hand side. The alignment f clumns f figures and text cmbined shuld be decided n a case-by-case basis. Clumn headings may be set left r centred ver the clumns as apprpriate (usually centred when the clumns cntain figures and aligned at the left-hand side when the clumns cntain text). The first clumn heading is nrmally aligned at the left-hand side. Clumn headings shuld increase in number frm the tp t the bttm (e.g. ne clumn heading ver three subheadings, each f which is itself ver tw sub-subheadings). All clumn headings are aligned at the bttm f the header rws. Clumn headings are in bldface type. Figures with mre than three digits n either side f the decimal pint shuld have a space inserted after each grup f three digits (e.g ; ). This rule applies t tables nly (in the text, figures with mre than fur digits have a space after each grup f three digits). As nted abve, this is nt an SI requirement, but a WHO ne. Each table entry shuld ccupy its wn rw t ensure that alignment remains crrect when the table is edited. It is preferable t have nly ne r tw rw heading levels, in which case the first rw heading is flush left and the subheading is indented belw it. Where several different rw heading levels are needed in the first clumn, the general rder f heading is (1) bld, (2) rman and (3) indented rman (where three levels are needed), (1) bld, (2) italics, (3) rman and (4) indented rman (where fur levels are needed) and (1) bld, (2) italics, (3) rman, (4) indented rman and (5) rman fllwing a dash (where five levels are needed). The bld heading rw may be shaded fr emphasis. Sme examples f table frmats are prvided in Annex 2. Additinal examples may be fund in published JECFA mngraphs ( 10

17 2.2.6 Histrical cntrl data Histrical cntrl data shuld be reprted if cnsidered useful and apprpriate fr interpreting study findings. Histrical cntrl data are ften presented fr tumurs and develpmental effects, but can be used in an attempt t determine whether the bserved results fr any end-pint in test animals fall within the nrmal bilgical range. Histrical cntrl data are mst useful when they are frm the same strain f animal, cme frm the same labratry and are reasnably cntemprary t the study with which they are being cmpared (ideally frm tw years befre the start f the study t tw years after the end f the in-life phase). If they d nt match these criteria, this shuld be identified in the text. If pssible, the histrical cntrl data shuld have been submitted such that the results in each study in the database can be seen separately. As an abslute minimum, the number f studies must be given tgether with the mean and range (just the upper range is nt acceptable, as this culd be skewed by ne atypical study). The mngrapher shuld seek cnfirmatin frm the data prvided that there were n changes in interpretative r investigative techniques between the histrical cntrl studies and the ne n the test cmpund In-text references References are cited by ne (Brwn, 1999), tw (Brwn & Jnes, 1999) r three authrs (Brwn, Smith & Jnes, 1999), r first authr plus et al. fr fur r mre authrs (Brwn et al., 2000). Nte the use f an ampersand instead f the wrd and and the use f a cmma befre the year. If the same authr(s) published mre than ne reference in the same year, a, b, etc. shuld be used t differentiate between the references (Jnes & Brwn, 1999a,b; Smith, 2000c). This rule als applies t et al. references, even if the ther authrs are nt the same in each reference (Brwn et al., 1999a,b). In the rare case where different authrs with the same surname have published a paper in the same year, initials are used t differentiate between the references (Y. Li et al., 2000; R. Li et al., 2000). These references must nt be cited as Li et al. (2000a,b). References are cited in the text in increasing chrnlgical rder (but all references by the same authr(s) are given tgether) and alphabetically when published in the same year (Brwn, 1988, 2003; Brwn & Smith, 1989; Smith & Brwn, 1989, 1991; Brwn, Smith & Jnes, 1990; Brwn et al., 1991; Jnes, 1999a,b). Reprts and mngraphs frm previus JECFA meetings are cited in the text as (Annex 1, reference xxx) and are nt included in the reference list. Annex 1 refers t the list f previus JECFA publicatins that is included at the back f bth the meeting reprt and the publicatin cntaining all f the mngraphs frm the meeting. Persnal cmmunicatins and ther unpublished infrmatin are cited in the text nly, nt in the reference list. They shuld be cited as fllws: [name f authrity cited], [name f institutin], unpublished data r unpublished bservatins r persnal cmmunicatin, [date]). Fr infrmatin n the frmatting f references fr the reference list at the end f the mngraph, see sectin Miscellaneus Mngraphs shuld be cncise dcuments, with nly as much detail as is necessary t be able t understand and reprduce the evaluatin; t much detailed descriptin f irrelevant studies and t many nn-critical tables shuld be avided. Mngraphers need t make every effrt t reduce the length f their mngraphs withut eliminating essential infrmatin. Overall, the mngraph shuld give a clear descriptin f the full database cnsidered and 11

18 prvide sufficient details regarding critical data t permit an independent evaluatin f the cnclusins made. The physical meeting is referred t as the meeting (e.g. the meeting was held in April); the grup f meeting participants is referred t as the Cmmittee (e.g. the Cmmittee established a prvisinal maximum tlerable daily intake (PMTDI) f 0.3 mg/kg bw). JECFA is referred t, rather than the JECFA. Reference t previus Cmmittees shuld be made by number (e.g. the thirty-sixth meeting f the Cmmittee) rather than by year, because in many cases reprts were nt published in the same year as the meeting and in sme years mre than ne meeting was held, which creates cnfusin. It is cnventinal t list cuntries alphabetically, and cuntry names must crrespnd t the mst current listing f Member States and Assciate Members f WHO, as given in the current versin f the WHO style guide r an interim updated list f Member States and Assciate Members f WHO. Where the POD is a NOAEL, this is identified, as it is ne f the dse grups used fr example, 0.5 mg/kg bw per day was identified as the NOAEL. Health-based guidance values (tlerable intake, ARfD) are established fr example, the Cmmittee established a PMTDI f 0.1 mg/kg bw. Each study summary shuld prvide a shrt descriptin f the methdlgy used in the study. Where studies cmply with an Organisatin fr Ecnmic C-peratin and Develpment (OECD) test guideline r equivalent natinal guideline, there is n need t prvide lengthy descriptins f the methdlgy. Attentin shuld be drawn t any deviatins frm the test guideline, either missins r significant additins. If in-life examinatins such as phthalmscpy and bld sampling are perfrmed at multiple time pints, these time pints shuld be identified. This is particularly useful when there is a need t establish an ARfD, as such early measurements in repeated-dse studies may prvide the critical effect fr such a health-based guidance value. Studies perfrmed befre the implementatin f gd labratry practice (GLP) will be cnsidered n a case-by-case basis, with careful cnsideratin f the quality and apprpriateness f the study. JECFA style is t use free-flwing text rather than large numbers f subheadings fr each particular level f investigatin. Overall cnclusins f the Cmmittee regarding, fr example, the carcingenicity and gentxicity f a cmpund shuld generally be reserved fr the Cmments sectin. Cnclusins f the Cmmittee regarding specific studies (e.g. when the Cmmittee disagrees with the study authrs cnclusins) are given in the bdy f the mngraph. WHO huse style uses a mix f British and Nrth American spellings. Examples f spellings f sme cmmnly used wrds in JECFA mngraphs are as fllws: anaesthetize, analyse, antimicrbial, caesarean, centre, cenzyme, clur, cperate, criticize, decisin-making, diarrhea, end-pint, estrgen, et al., etilgy, faeces, feed (fr animals, nt fd), fetus, haemglbin, hmepage, hypcalcaemia, in vitr, in viv, leukcyte, litre (L, nt l), metaanalysis, metablize, mdelled, neurbehaviural, edema, esphagus, xidize, paralyse, pharmacpeia, pstmrtem, pstnatal, pstpartum, pretreatment, prgramme, re-examine, repen, side-effect, subgrup, sublethal, sulfur, tumur, webpage, website, wrldwide, X-ray. Abbreviatins are defined the first time they are used in the text; thereafter, nly the abbreviatin is used. A list f abbreviatins shuld be prepared fr each mngraph. This list will be incrprated by the editr int an verall list f abbreviatins fr all mngraphs published after the meeting. Mngraphs will be edited accrding t the mst recent versin f the WHO style guide. Mngraphers can request a cpy f the WHO style guide frm the WHO Jint Secretary. 12

19 2.3 Detailed cntent f the mngraph The guidance in this sectin appraches the cntent f the mngraph frm the viewpint f the end result f the meeting that is, the prductin f the reprt item. As mentined abve, the mngraph shuld cntain sufficient infrmatin t permit all the details required fr the reprt item t be identified and independently cnfirmed. If a mngrapher is in dubt abut whether t include extra detail, it shuld be added t the mngraph s that it is available fr thers t see; it can always be deleted fllwing discussin at the meeting. Until the final changes are made by the mngrapher at the end f the meeting, the mngraph is a draft dcument t supprt the discussin. It is therefre ften helpful, in the preparatin f the mngraph befre the meeting, t include cmment bxes r highlighted text that draws attentin t ptentially imprtant r cntentius aspects f the evaluatin, as lng as these are subsequently deleted. It is als ften useful t include verview tables summarizing the similar txiclgical studies and their NOAELs/LOAELs, fr discussin purpses nly. It is imprtant fr the mngrapher t recgnize that the final mngraph is the prduct f the Cmmittee and nt f the mngrapher. If n studies were available fr ne f the main headings in the template, this shuld be nted in the mngraph. Fr mngraph addenda, it may nt always be sufficient just t cnsider new data, especially if there have been changes in evaluatin criteria since the last evaluatin (e.g. check fr findings early n in studies that might be relevant t establishing an ARfD). An apprpriate descriptin f any such studies that were cnsidered in the present evaluatin shuld be included in the mngraph addendum. Smetimes, it may be sufficient t cpy and paste relevant sectins frm the previus mngraph, in which case they shuld be s indicated (e.g. indented, italics r smaller fnt). Details that shuld appear in each sectin f the mngraph are described in the fllwing sectins. Nte that the sectin numbering used fr the headings (shwn in red) is that used in the actual mngraph (see als Annex 1). A table f cntents generated frm the final headings used in the mngraph shuld be included n the first page f the mngraph, belw the title, authrs and authrs affiliatins. All individuals cntributing t the preparatin f the draft mngraph fr the meeting shuld be listed as authrs. As the end prduct reflects the discussin f the Cmmittee at the meeting, the listing f authrs is preceded by the phrase First draft prepared by Explanatin 1. Explanatin This part f the mngraph will frm the basis fr the first few paragraphs f the reprt item. The editr will insert the final versin f the Explanatin sectin (fllwing the adptin f the meeting reprt) int the final draft f the mngraph. The mngrapher can indicate whether any detailed infrmatin that was deleted frm the Explanatin sectin during the preparatin f the reprt item shuld be retained in the final mngraph. The first paragraph shuld prvide a brief descriptin f the cntaminant, its rigins and its ccurrence. If the Cmmittee has evaluated the cntaminant previusly, the number f the meeting at which the previus evaluatin was perfrmed shuld be indicated (e.g. The Cmmittee previusly evaluated cntaminant X at the seventy-seventh meeting ) and referenced by number using the standardized reference list f JECFA publicatins, which may be fund in Annex 1 f recent JECFA reprts (WHO Technical Reprt Series) and txiclgical evaluatins (WHO Fd Additives Series). Thus, the reprt f the seventy-seventh meeting n certain fd additives and cntaminants wuld be referenced as (Annex 1, reference 214), and the mngraphs prepared after the seventy-seventh meeting wuld be referenced as (Annex 1, reference 215). Reasns fr the present re-evaluatin shuld be given and, if a full mngraph n a cntaminant that has been evaluated previusly is being prepared, a statement shuld be made t the effect that the previusly published mngraph has been expanded and is reprduced in its entirety belw. If the Cmmittee has nt previusly evaluated the cntaminant, the reasn fr it being placed n the agenda shuld be given. Fr example, [Cntaminant X] has nt previusly been 13