′SS ′0254 20(1),37 ‐ 48(1999) CharaCteristics of quantitative data in to×icity rodents qq 。Questioning the usenllnessofBartlett'stest varlance to introduce 節 rhomogeneity a rank test. KATsUM 騒音議論鴬数多質量 “慰霊駕諭吉資金茅食器冨還暦観望要望麗子.NOU BiosafetyResearch Center,Foods,Drugsand Pesticides,(An.PyoCenter),582 ‐2, Arahama,Shioshinde Fukude.cho,lwata ‐gun,Shizuoka437 ‐1213, Japan 2Shizuoka sangyo Universiけ ,owara, ーwata‐shi,Shlzuoka438 ‐0043, Japan Public Health,Hamamatsu Universiけ Schooi of Medicine,3600 Handa-cho,Hamama きsu-≦ Shizuoka431.3124, Japan University of A9ricu-ture,1-1-1,Sakuragaoka,Setagaya-ku,Tokyo156 ‐8502, Japan 3Departmentof 4Tokyo [Received:I ABSTRACT :“ ′e investigated the changes quantitative data between m t弓も and compard varianees ofbody W′e conclude : Statisticalanalysis - Ba 【let 【's test - Humogcneity in their variances 11ltroduction lntoxicitystudiesinwhichverylarge amount ofhighly toxic substancesare administered ‐in a determlnlng studies,and in preliminarystudies appropriate in thesecond dosages half for 命 rfurther of lo4‐week studies,thereiscommonlyaconsiderable decrease in the number ofsamples,a 夢「eater variability in the meanandg ゴビeatervarlance(FvaluesbyFtest) compared to the control analyze the quantitative long‐term studythatincludes (Table1),the group.Tostatistically dataobtained in a varlousparameters sひ called "decision VVeil,1986)is widely dif発 rence in the means tree “ (Gad used toevaluate betweeneach * ノα‘“m ′げ E〃y ′ro〃〃ie ′血 ′β ′o′ogy 濯 inthesecond ls publishcd and the dosage halfof 【he long‐term 16‐35% practical to tesl the signine副nt difference anlongmean are heterogeneous annong values by parametnc - Toxicity study - Rodents. g, ごoup and the control group.ln Bartlett's test 免 r homogeneity employed this in【he dose forthe parameters groups. ofvariance there ーng control group tests and organ weigbts werehigher diffcrcnces by Barlett's test was Key period, rate ofsignmcantdifferencesus 総 neachdosegroupandthe 【s,thenumberofanimalsdecrcase even short lhedetection 「encesbetw procedures, Words with time and caーculated the F va萱ues f。r vanous wcight,f ood consumption,hematological that,it secms if the data March l9981 io long‐tcrm studies using 9,280 rodents by the so‐called statisticalanalysis. “ ′e thenexamined groups than in the controls, The detection rate ofsigni6cant examincd. numbers the incidenceofsignincantdifie obtained with and without Banlett'stest,Asaresul studies,and sample control and each treated group 官om "decision tree" For computerized Bmlett's JanuaIy l998;Accepted:27 mal ▽ instan ‘ of‐varianceE as the first step ofthedecision are no significant 熊 st, i.e., if the tree di稀erencesdetected vadances are homogene- among the group,thequantitativevalues are tl examined byparametric 鎧 sbs,0ntheother ha if there are significant differences,1, he 熊 rogeneous variances betweeneach group, individual values are arranged in order 貸 om largest andtheir コ l smallest to the subjected necessity to nonparametrictes 絹 ,Toevaluate l of Bartlett's test in the statisti4 ranking analysis of toxicity study results,we exami 【 how measured values changewith time,and h by KiralI Dalela from l/20G,VikasNaga Lucknow-226022(INDI ノ 38 Katsumi the use of Bartlett,s test eぼects theresult8 entire statistical analysis based toxicity(14studies), of the onsubchronic carcinogenicity Pesticides and carclnogenicity/chronictoxicity studies(30 studies)whichwereper 長)rmedinourcenter us・ng rats and n・ice. Studies using (3)De toxicity F344 male 蛇 cziのる mze of oもごのれZれg szg自粛旅ereたces も βαrz磨ごS fe〆 :We determ1 ℃ ratc of obtaining significant differenBartlett's tcst(lmamizo e云〆 .,1987)l br( 総 weights perfbrmed in fburteen dose toxicity studies ofmedical fbodortoxicitystudiesofPesticides ioxZcご紗 sz“dぞesofPes ごicides:Wechose14studies, mice,and uslng male and 危 male B6C3F1 mice {Japan SLC)and 7 studies usingmaleand F344 rats (Charles River JaPan)(560males 560 females,total were 4 gごoups 1 l,120).ln including female a・d 1 eachstudy, there the control 印「ouP, (2)C αrc加増 e塀α好 sz"dies o′ med!cd drugs,5 studies using 2,400(male of of and 危 male)B6C3F,m ・ce and 5studies using (maleand 熊 male)F344rats(tota15,280),lo carc・nogenicity studies ofmedical drugs 2,880 other using 2,00o male F344 rats,and lo carcinogenicity/ chronic toxicity studies ofpesticidesusing 2,880 male F344 ra絹 . Param ーeters:The significant main di爺erence differences 魚 ctors caus ・ng in Bartlett'stest in var・anceamong are groups.ln (4)Comp grouP this and below due to drugs,we examined F344 malerats 危 r l04weeksin studies of medical drugs. the same been Parameters the change in the eachg1FouP comPared distribution the F values comsumption ln each contro1 that group of bodyweight dose ofcarc1nogenicity uslng F344 control in studies g・ouP I 角 od in the in the ofmedical dose hadbeen lo drugs hematological 1nesurements in each that and tothose obtained rats,and male measurements,biochemical weights grouP hadbeen studies organ ofParameters asaresultSofdrugadministration,we g1 ・ouP and tothose obtained in the in the lo as deternlined l Ba] tree stahtin Bartlett's tesl listed in(2)and(3) YUKMS L CO.Ltd.,Tokyo).F, a Probability value of P < 0.04 as statistically significant. Resu 【is Change in the number of lo4 ‐week using 鱒ごouP(Table 2),Until start ofthe studies,themean high high Nu11 口ber around 78week control g1 「ouP,andthe rats declined ‐gradually of surIJIV1ng Change carclnogenicity low,n ・iddl tolower values at vveek ・04the ra 総 was 26,with in F va1ues data With of F344male studies a飯 ofsur1 (46 to 49).l number of surl while the mean survivalrates the other grouPs, quantitative rats carcinoge ー 50 F344-ral number dose 厚 ouPs wassimilar dose group,themean othergrouPs,and of sam survlv ・ngmale lnvestigated for lo studies ofmedicaldrugs rats ofthe (2)C んmzge 劇 F ひα彰 eszo 劫九 Zime;Toevaluate grouP α αムー989)with (5)sz の ZsflcαZ α“αむ ses:AI1analyses carried outusingYUB 頭嘱SStatisticaI Software( The sur1〉ival rate of locarc1nogenicity analy studi e×amined. The (1)C たの zge iれご庇 “"mber of 肌肌〆 es:To evaluatethechangeinthenumberoftestanimals dose tcst(Fig.1),andbythedecision variance analysiswithout identi お the causes of signi 行cant diflerences in Bartlett's test usingdata obtaincd in acutal toxicity studies. itemslisted each decision tree(lnoue analyses the 鯖 isoれ oヂ≠膨 Z冗cide肥 e s増〃 pesticides(study number15,5 groups eac] 80 male ra総 /girouP),weinvestigated the n of significantdifferences betwcen the c regarded lnvestigated of n 霞銃eだれces はs顔 gz 膨 dec おわれごree wi≠ ′i oru to study,we us・ngre lo carcinogenicitystudies toxicity stu drugs or carcinogenicity/chronic Pesticides us・ng rats and nlice, a large a 1・d 13‐week re drugs m・xe βα厚 ZezZS ごesご ;ln thestatistical carc ・nogenicity/chronic toxicity dmgs ≧ic zoxici妙 sf“dies 口 ′〆 mrcmoge 形 cご方 /cんro′ 刀e郡ごcides: 汎re chose lo carcinogenicitystudies medical effi biochf measurements,urinemeasuremen Exa11 ・ined: (1)Z3 ‐wee を rep釦 Zed dose foヱic ご夢 ""dies oず medicqZ dr"gs m な ed witi; 危 o偽 αれd sαもめ ro欄 c 7 studies stud rats, body weight, food consumption,fbod hematologicalmeasurements, Mーaterials and ハ4eth。ds The carc ・nogenicity/chronic Kobayasl cfmedical tha mean nt a m ・n-mum were 39 to T皇me:Usin rats drugs 台o al 9uestioning Table the l : one use ん lness example ofBar 【letrs of the standard ltems to be tested test お rtoxici け tests number of tests fortwo ・yeartoxicityStudies No. ofstatistica-ana-yses uslng rats. Contents(lncludingtimesofanatys BodyWeight(B.W.) 66x2* EVe Week Foodconsumption 104x2* Eve Week Foodefficiency 52x2* Eve Week Hematoiogy 16 items x 4 times x 2* 26,52 ′78and B1oodchemist 20 items x4times Ditto Urinalysis 2 items x 4 times x 2* D1tto organWeight 5 orgs ‘x4 Ditto organWeighyB.W.ratio Ditto x 2* timesx2* for26 Weeks ーs) and thereafter eve otherW unti152 Weeks l04Weeksafteradministration Ditto 860 .860 Total ,Both males and females. Table 2 : Changes in the number NO.of Dose levet ‘ . ・ studies Control of sunvlv-ng nnale rats in lO Carcinogenicity studies. l0 ・ ,. o ;ラ ≠ 50 コキラ ▼ , ・ r Weeksduringthedosingpertod 52 58 50r士 1 49 ± 1 65 71 78 84 91 97 49 土 1 49 ± 1 48 ± 1 47 ± 土1 45 ±2 ▲ 44 ±2 ・ Low l0 50 :> 50 ±0 50 ±0 49 ± 1 49 ± 1 48 ± 1 47 ± 1 46 ±3 44 ±4 Middie l0 50 ココ 50 ±0 50 ±0 50 ± t 49 ± 1 49 ± 1 48 ± 1 47・±2 44 ±2 Hi9h lo ・50 尋坤 50 ±0 ‘49 土 1 49 ± 1 49 ± 1 46 ± 4 43 ±8 39 ± t1 35 ± 14 Values are expressed Tabーe 3: Middle with the control value of body ・.13 weight of ma1e rats in l04‐Weeks long‐term 26 40 52 66 7892 1 IO 1.1 ± 0.2 1.4 ± 0.6 1.3 ± 0.3 1.2 ± 0.2 1.2 ± 0.2 1.4 ± 0.3 1.3 ± 0.2 1.4 ± 0.3 1.6 lo 1.1 ± 0.3 1.4 ± 0.4 1.4 ± 0.3 1,4 ± 0.3 1.4 ± 0.3 1.6 ± 0.5 1.6 ± 0,9 1.9 ± 1.t 2.0 lo 1・0 ± 0・0 1.3 ± 0.3 1.4 1.4 ± ± 0.3 0.3 1.5 ± 0.4 15 ± 0,5 1.5 ± 0.6 L6 ± 0.3 1,5 土○.5 as mean ± standard 4 : Variation in F vaTues eompared 1.6 ± deviation.: ≠ :8 studies. with the contro1 Vatue of body Weight of mare rats in l04‐week tong‐term stu WeeksduringthedosingPeriod No.of studーes 1evel 26: deviation. compared 0 are expressed Dose 41 WeeksduringthedUsingPeriod No.of Studies LOW Table ± standard Variation in F values Dose tevel Values as mean 1. 1 13 26 39 52 65 78 91 IO 1.4 ± 0.3 1,5 ± 0.4 13 ± 0.2 1.2 ± 0.2 1.4 ± 0.5 2.0 ± 1.3 1.3 ± 0.3 1.7 ± 0.4 2.1 Middle lo 1.5 ± 0.6 1.5 ± Q5 1.2 ± 0.3 1,4 ± 0,3 1.3 ± 0.4 1.5 ± 0.5 1.8 ± 0.9 1,9 1,9 ± ± 0.9 0.9 1.7 High lo 1.6 ± 0.6 1,6 ± 0‘7 L5 ± 0,5 1.5 ± 0,4 L3 ± 0.4 1.4 ± 0,3 1.6 ± 0.7 2.0 ± 1.5 LOW Values are expressed as mean ± standard earc ・nogenicity/chronietoxicity pesticides,the mean F valueswith control grouP middle and high (1)Body with time were calculated dose ofcach dose gl ・cup studies of respect to the 危 r cach ofthe low, control group in the F valucs respeet to the are shown inTable 3.The F va ofthelowdosegroup were l.l at VVeek o and t increased to l.2-1,6,1n the middle dose gr, they with 1.8 ± 1 deviation,; ≠ :8 studies. g・oups. 1 weig 骸 ;Changes 10 were 1.4‐2.0.The group was l.l at VVeek pattern similar o and of increase to that then lnerease- in the high in the middle( { 40 Katsunli Table 5 : variation in F values 1ong-term stud;es ・ Paranneterand dosereve1 ComPared Wjlh the control value of hema ーologica1 examinations N。.ofstud ーes Kobayas of male コ rats in Weeksduringthedosingperiod 26十 52 78 104 Hemat αorit Low Middle High lo l0 l0 l.6± 0.4 2.6 ± 1.6 2.5 ± 1.7 2,2 ± 1,4 3.7 ± 3.4 2,5 ± 1.5 2,5 ± 1:2 2.5 ± 1.6 3.1 ± 2.7 7.2 ± I 14,6 ± ; 9.2 ± 2( l0 l0 l0 4.5 ± 6.4 4.3 ± 3.1 2.8 ± 1.1 6.2 ± 12.7 5.6 ± 6.0 6.0 ± 6.4 5.2 ± 5.6 87.4 ± f07 2.9 ± 2.4 1,9 ± I 3.6 ± E 2,2 ± 1, Low Middle High l0 l0 lo 2.2 ± 0.7 5.1 ± 6.f 2,9 ± 2.1 2.2 ± i.6 2,5 ± 1.8 3.1 ± 3.6 3.4 ± 2.4 3.0 士 2.5 3.o ± 2,5 1,9 ± O 2,4 ± 2 2.o ± I, LOW Middle High IO lo lo I.6± 0.9 l.9± 1.4 l.5± 0.4 2.6 ± 1.3 2.9 ± 2.8 4.1 ± 2.7 5.6 ± 7,3 7.4 ± 11.3 3,9 ± 5.1 7.6 ± 1( 74.3 ± 2 13.5 ± 21 ‐cw 1 Middle High lo l0 l0 12,1 ± 20.7 2,7 ± f.3 2.7 ± 1.3 7.1 ± 12.6 9.5 ± 15.0 6.8 ± 9.1 5.6 ± 8.8 5.9 ± 8.7 2,9 ± 2,3 5‘7 ± 7 23,3 ± 5 7.6 ± 1I I0 l0 l0 8.2 ± 14.2 4.9 ± 2.7 2.5 ± 1.1 17.8 ± 48.7 6.8 ± 9.7 4.3 ± 5,2 7,3 ± 10.3 5.1 土 8.4 3.1 ± 3.2 5.4 ± 6, 9.6 土 11 5,3 ± 4.: I0 l0 l0 2.8 土 1,5 2.6 ± 1.1 2.8 ± 1.5 1,7 ± 0.5 2.3 ± 1.4 2.0 ± 1.8 9,0 士 16,3 16.4 ± 44.0 10.6 ± 22,0 3.2 土 2, 2.6 ± 1. 2,6 士 2,f l0 l0 l0 3.0 ± 1.9 3.0 ± 2,2 2,6 ± 1.3 2,5 ± f.1 2.9 ± 1,4 2,4 ± f.6 2.4 ± 1.1竹 5.7 ± 6.9汁 2.9 ± 1.8↑↑ 9.6 ± 16 4,6 ± 3. 7,0 ± 5.‘ Hemogiobin Low Middie High RedbloodCell MCV MCH MCHC LOW Middle High Piatelet LOW Middle High W′hitebloodCeiI Low Middie High Values are expressed group, reaohing as mean ± standard deviation.; 十 :5studies, 竹 a nnax"numofl.3-1.6duringdrug :9studiesand ≠ :8studies. (2) 屈ooα co九s"′7r 切 “○九 ;Changes adnlinistration. va1ues ヤヤーth time tothe dfeach controlgroup in l dosegroup are shown with inTable Battlett Not sig. Sig. ANOVA sig. No.of Dunnett Fig. 1, Decision Kruskal Not sig. ‐Wallis Sig. Not sig. s山D1p1e Duncan tree fbr statistical analysis Non ofdata obtained pa にa Dullllett in toxicological examinationonroden 開, h 4.D 9uestionlng Table the use 短 lness ofBartletrs 6 : vaiiation ln F Values 1ong‐term studies. Parameterand dose ーeve1 ComPared 【est lbrtoxicity tests with the control value of blood No. of 8tudies chemisl W6ek8duringthedos 26十 examinations of male rals in ーng perlod 52 78 104 1浄土 1.4 l.7 ± 1.3 2.3 ± 1.5 2,1 ± 1,4 4,3 ± 4,3 2.9 ± 2,2 12,4 士 27 7.4 ± f4 8UN LOW Middle IO lo . High lo l,1±0.2 2.4± f.5 45.7 ± 125 13,6± 29 I0 l0 l0 3.1 ± 1,ア 2.6 ± 1.1 3,2 ± 1,6 4.7 土 3.4 1.9 士 0.6 3‘1 ± 3.1 4,4 ± 5.8 4,2 士 5.5 10.2 ± 14.6 3.1 ± 1.・ 5.7 土 5.・ 16.9◆± 26. lo l0 fo l,1 ± 0.2 2.7 ± 2.1 l.3 士 0.4 2.6 ± 1.6 4,1 ≠ 5,7 3.5 ± 2.7 16,4 ± 26.5 19.4 土 24.2 18.1 ± 25.8 13.0 ± 22 26,5 士 60 43,7 ± 1: l0 l0 l0 2.6 ± 1.0 2.9 ± 1,3 22 ± 1,2 3.9 ± 3.7 3.5 士 2,5 2.8 ± 2,0 2.8 ± 1,6 4.5 土 7.9 4,6 ± 4.1 3.0 ± 2,I 2.7 士 1.毛 2,0 ± 2.○ I0 l0 l0 4,5 ± 4.8 2.5 ± 1.3 3.4 ± 2.2 29 土 2.8 3,2 ± 3.1 5.f 土 5.4 26.4 ± 61.8 6.6 ± 8.4 36,7 ± 72.7 11.4 士 11, 5.3 ± 4.a 3.6 土 2.7; l0 lo l0 3.7 ± o二8 14.8 ± 27.5 2.0 ± 1.4 3.3 ± 2.8 3.6 ± 4,6 2.f ± 1.4 8,9 ± 18.1 2.6 ± 1.6 3,1 ± 1,6 3,i ± 2.4 3.6 ± 4.5 3.4 ± 2, 10 l0 lo 2.f ± 1,2 6,5 ± 10,0 l.9 ± 1.2 2,1 士 1.3 2.2 ± 1,3 2.2 ± 2,5 5.8 土 7.6 2,0 ± 1,8 5.6 ± 4.8 2.1 士 1.2 2.6 ± 2,4 3.8 ± 3.2デ Creatinine LOW Middre High TCtalbilirubin Low Middle High Gーucose Low Middle High TotaICholeste 「oI LOW Midd-e High TotaIProtein Low Middle High A1bumin LOW Middle High Uric acid 務電業誓fe vatues 曇曇綴 are exPressed drug as nnean 士 standarddeviation,; administration,the groupwere middle Fvalues l.1‐2.1,whilethey dose group,and group,both showing inthe were ., similar 喜警1 了手書茎器す.;5studies,and low dose l,2-1.9 in the 2.o in the high dose Changes, Fvalues dosegloupwithrespectto determined lbr each thecontrol parame of・each g,roup were 熊 r at VVeeks 26,52, 78 and l04 during the dosing period(Table and 7),Large parameters compared observed F values of the with high the in v▽eeks 78 wereobserved 5,6 in any ormiddle dose group controlgroup and were and 5,3 ± 5,1≠ ≠ ;8studies. (1) ヱ3‐wee ただ Pe αfeddose iD鴬Zcまごツ s“6cんroたたごo諺 ci妙 siαdies ′ Sご“dies “s乙後g rα ごs:The detection rat signi賃cant diaierences by Bajrtlett'stest was (3)五百em α ごoZogic餌 ,ゎZooα〆粥川おごり α“dor8 αれ zoe省栃粥弧 8“remems:These 量票g l04compared ・"′ith VVeek 26. The Detectionrates of significant DifferencesbyBartlett'sTest(Tables8atld9): (6/196) in body weight,11%(20/182)in consumption,14%(25/182)infbode 伍 ciency, (41/136)in heamatology exanlination,; (7も ′202)in biochemical examination,15%(3/2{ urinalysis,12%(12/104)inorgan weights and (17/104)in orga山偽ody weight ratio.The ov( detection rate of significant Bartletぜs testin allparame 126). di" erences 熊 rswas18%(19 S1αdZes "s 顔 g mZce : The detection signi行Cant di団erences by Bartlett'stest rate; was (16/196) in body weight,7%(12/182)in 董 consumption, ≦ 18% (33/182)inlbodefficiency, 42 Katsunll.Kobayashi Table 6 : (Continued) Weeksduringthedosingperiod Parameterand doselevel No.of studles 52 78 104 1・0 ± 0・0 ・ 1 0 ± 0・0 1・0 ± 0・0 2.2 ± 2.6 2.2 ± 2.6 1.3 ± 0.9 1.6 ± 1.3 2.2 ± 2,6 L6 ± 1,3 1.7 ± 1.3 1.2 ± 0.5 1.4 ± 1,1; 2.4 ± 1.0 3.7 ± 6.I 2.2 ± 1.I 2.8 ± 2.O 2.0 ± 1,3 1,4 ± 0.9 3.4 ± 3.6 2,8 ± 1,5 3.1 ± 2.2 2,1 ± 1,2 1.9 ± ・ 1 4ヲ 1.6 ± L3 2,4 ± 2.6 1β ± 1.3 2.5 ± 2.6 1・ 0 ± 0・0 1.6 ± 1,3 2.2 ± 2.8 2.4 土 2.6 1.6 ± 1.3 1.6 ± 1.3 2.3 ± 1.5 2.9 ± 2‘7; lo lo 10.1 ± 13.5 6.7 ± 10.8 7.6 ± 9.9 9.4 ± 6.9 3,8 ± 5.8 7.9 ± 8.6 6.4 ± 7.9 5,7 ± 7,0 5.6 ± 7.5 lo 2.4 ± 1.7 3.3 ± 2.3 lo lo lo 5.9 ± 5.2 6,0 ± 3.3 6.0 ± 10.0 4,2 ± 3,2 3.1 ± 2.5 9.2 ± 7.7 5.1 ± 7.5 9,2 ± 21.I 2.4 ± 2.2 2.6 ± 1.3 9,3 ± 9.3 4.0 ± 4.4 8,4 ± 14.7 14.0 ± 32.8 23.6 ± 28. 5.2 ± 6,O 9.6 ± 12.2 9.7 ± 20.6 2.8 ± 1,5 2.9 ± 2.4 3.7 ± 2,7 23 ± 0.9 14.4 ± 20 」 12.7 ± 23. 8.9 ± 11,2 2.7 ± 3.1 2.4 ± 1.4 ‐4.3 ± 5.I 3.3 ± 4.5 26十 Sodium Low lo lo lo Middre High 000 f イー ▼ ▲ イー▲ 1 1 Potassium Low Middre High 2.0 ± 0,7 Chloride lo lo lo Low Middle Hi9h Calcium Low Middーe High lncrganicphosphate Low Middle High 000 LDH Low Middle High 0 00 GOT Low Middle High 8.0 ± 14.8 2.8 ± 2.O 7.9 ± 13.O 2.7 ± 1,8 4.0 ± 4.6 11.9 ± 16.5 3.1 ± 4,α 3.1 ± 1,6 5.1 ± 8.9 6.4 ± 8.5? 8.3 ± 13,モ 6.4 ± 9.4 GPT Low lo Middle High lo lo Low lo 1.9 ± 0.3 2.4 ± 1.8 Middle lo lo 2.i ± LI 7.7 ± ＼14.7 2.6 ± 1.8 2.4 ± 2.2 3.3 ± 3.3 5.6 ± 4.8 ・ ‐ 15.6 ± 31.; 8.8 ± 12.S 3,6 ± 4.9 21.7 ± 55.6 4.8 ± 3.37 ALP High Values are expressed as mean (20/82)in hematological in biochemical weights 2.8 ± 2.5 ± standard deviation.; 十 :5 studies,and examination,35%(19/54) examination,12%(12/104) and 16%(17/104)in in organ orgaiy偽odyweight ratio.The overall detectionrate of significant diぼerencesbyBartlett,ste8tinallparameters was 14% (129/904). ln the studiesrusingratsandmice, theoveralldetectionrateofsignilicant by Bartlett's test in all parameters dill 当erences was 16% (327/2,030). szはdges “s酬らg rαお :Thedetection rate of significant dif危 rences by Bartlett's test was 31% (204/500)in body weight,37%(375/1,020) consunlption,39%(155/390)infbode in fbod 伍 ciency,39% 6.6 ± 11,G 12.4 ± 20.! 23.7 ± 64.9 26.9 土 63.8 23.9 ± 64,8 17.0± 282 ≠ :8studies. (120/304)in (187/440)in hematological examination, biochemical examination,18%(1, ln urinalysis,30%(58/192)inorgan weights 44% (85/192)in orgah)(body weight ratio. overall detectionrate of significant Bartlett's test in allparameters di鎖erencE was 379 198/3,278). sご" 〆Zes " 腐れg 刀ばce sig1oi行cant (2) C αrcmog のむごcZzy αれα cαrcご ′zoge 川 cl妙 / cんro元iC考o工ic比γ stαd1es: ‐ di爺erences : The incidenc by Bartlett'stest was (311/660) in body weight,16%(161/1,020)in consumption,38%(150/390)infbode (137/280)in (58/138)in 鎖 ciency, hematological organ examination, weights and orga 印他 odyweightratio.Theoverall of signi 賃cant dif ョerences by 47%(65/13 モ detection Bartlett'stest ii 7 : Va 【ation in F v aーUes c omparE1d Parameterand dose leYeI ・ w 曲 the control value of absolute organ weight N0, 。fstudies of male lats in lo ◆ wefek long・term s tudies. Weeksduringthedosingperiod 26十 52 78 104 1.7 ± 0‐7 Brain Low l0 2‐5 ± 1‐4 3.0 ± 1.6 5.2 ± 0.9 Middle lo l.9 ± 0.7 2.1 ± 1.2 1‐9 ± 0.5 High l0 35 土 2・4 2.3 ± 1.1 1.7 士○ ・4 Middle 10 lo 3‐5 土 3.9 l.8 ± .9 2,1 ± 0.7 1‐8 ± 0.8 9.1 土 14‐7 5.4 ± 6.1 High lo l.9 ± 0.5 2.3 ± 0.8 11.8 ± 24.4 I0 2.3 ± 1.0 2.1 土・.7 1 3.○土 4.○ ,54.6 土 166 l0 ・0 2.9 ± 1.3 2.1 ±○ ・6 2.0 ± 0.9 ・2.6 ± 2.6 5.7 ± 9.1 5.0 ± 3‐7 13.3 ± 34.4 148 ± 408 ≠ Adrenalglands Low Midd1e lo l0 .8.o ± 13.o 2.1 ± 1.2 High lo l.9±0 ・6 Liver Low 1.9 ± 1.O 7.4 土 16・& ≠ 2‐3 ± 1.2 1.9 ± 0.6 1.6 ± 0.5≠ K idneys LOW Middle High ・ l.7 ± 1.o 2.7 土 1.6 8.7 ± 14.5 11.8 ± 22.4 2.9± ・ 2o 91・5 ±25・・ 33 o ± 996 210 ± 638 646 ± 1785 ≠ Test 範 Low lo Middle l0 High lo Values are e×Pressed as mean 土 Standatd . 1‐ 6 ± 0.6 ・ 2.9 土 2.3 3‐6 土 3.1 deviation.; 十 :5 s tudies,and ≠ :8studies. 6.4 ± 9.9 2.6 ± 1‐7 3.7 土 4.3 2.1 士 1.0 2.0 ± 1.I 1・4 ± 0.6 2.7 ± 1.6 1.7 ± 0‐5 1.7 ± 0.4 ≠ のこのの “6コ旨帆洋のこののきヨommo﹁切巴ご袋[メー◎の什ぎ﹃ 8益会そ什鳶続 Table Tabーe 8 : lncidence rates of significzlntd沼eren(治 by 8anle は's test for palametnc Ra 協 1 cデゼ Q 2 week repeated 謂 [ 獣・ . 4 ・ o dose s tudies using rodents. organWeights E 賢』お - 4 3 「 o l &120 8裟20 16 影 16 16/112 1/16 1/16 19/152 3 1 1 7 10/24 臥輯翌4 1/14 1/14 31/176 4 1 6 3 た 9 22 15焔料 1餌羽14 名14 咲y168 5 0 3 3 Z726 9/42 0/4 1/14 1/14 24/180 6 0 4 8 霊22 19/34 0舟刀 16 考 16 3iB/172 7 Tota[ 。 ,。 9 in1 こ、 o げ .十 data obtained 一宿に0" こ0=QEコのCooboo止 sPecies and 0 2 0 6月 96 20/182 25/182 ( )(1r)(1r) テ徽 ,5 ‘翌 41月36 74だ Q2 . α4 ′ , ,4 引 ,4 &俊P 12ソ104 17/104 ◎ %)(37%)(15%)(1 ー 9 4 2 4 10 1 3 8 20 一 27′* 198′104 餓 )(16%"6%) - - 幻 18 - ‐ α 16 彩・6 16/112 18 1/18 23/154 2′14 16/108 2′14 11 4 0 2 1/22 ‐ Q/14 刀 14 9/130 12 0 1 5 9/20 11/18 考 14 材 14 鋤 146 13 0 3 4 ‐ - 1/14 14 14 . 0 2 4 ′20 5 6ハ8W14 Total 16/196 12/182 33/182 20/82 19/54 Sumt。ta‘ (89%) 2も惚92 (18%) 58/364 (24%) 61尾と18 (35%) 93だ56 (289%) (36%) (6%) , ▽%) 3a664 (9%) []:Numberoftotal analyses by Ba 【1eは's test lncidence of signifiCant di・行erence 断 th BanletrsteS 仇 0錠al analyses Significant d沼erence was detenmined at the 5% ーevel. (16%) by Banle ぱ stest. 10/108 斜14 2似I{硲 12/104 17/104 129/904 {-) 匁20 .(129%) 24惚08 (16%) 34だ08 (14%) 327像030 (15%) (12%) (16%) (16%) 9 ; ーncidence and は tesofsign With rodents for 2 yeais. 態 ob 娘 inedinchronicfeedin こ0=ローヒコ切にoo口oo墾 16 ばstestforpa1amemcda 葦 97 88 49 6 11 6 14復2 18 24 15 19/38 2 14 81 18 - - - 脳 20 - - - - - 8 11 15 醐お拳 Ra 篤 ‐15 d+ Q 爺cantdi 能陀 m:ebyBame E 闘 17 7 鳩如 18 4 67 25762 .- 鰯縛 y 蝋餅 on{×}genic 鵡 studiesand Urin 蜘メー9 胎Reia w 駿w 祁w前轍 w 矧「絶附鰯三 26w殺w 酬概醐 w52w 褐w 掘醐 w 洲殉w,偶醐附釦俊 - s, 鞘 9だ 0 0 0 1/4 4 3 , 。 - *9 3 - 。。。綿 , - 8 17醐 , αarcinogenidtystudies ,= 7/14 11/14 6 4 - ,,, 臥 10 雲 3 11月 4 391/ 786 - 12′14 144/ = 繍盗享 - ,“ - , 9/10 120/ ,ふま1 826 Tota1 204/G;60 375′1040 15引390 120/304 (31%)(36%)(39%) Mice .20 110 , げキQ 35 187/440 (39%) 36 5・ . (43%), 10だ 0 役郷 26 縄川輔 m- 24 41 103 16 22 23 6 Sum tota- 85′192 1198/ (18%) (30%) {44%) 3298 - 1覇120 - - & 吃0 - 11/14 一 - 15 ・ ‐ 一 1冴 14 227/ ,m, ‐ ‘ ,喜 311 ′660 161パ040 15Q ′390 (47%) {15%)(38%) 51引13鴻泉絹だ080 305 780 (39%)(279%)(39%) 874 ‐ 7/16 - - 8′16 12 臥 - 5′10 一惰 9/10 17 印 31 822 一 To樋1 58/192 ・(36%) 8 23 14/80 - 137な80 (44%) - 25“584 (44%) ・ - - - - - 一一 , 一 - 5引138 (42%) 65/138 (47%) 770 88 2646 " 欲330 (35%) 150/339 (45%) (33%) 2080/ S944 のに o史ざコヨ袋写るこのo⋮ヨQのめo﹃m巴虚の=が霜復さ﹁8巴o ーQ 富め冴 Tabie Table lo :ーncidenCe combined ぜ stestinthedecision ・theeforparametncdataobtained in a mo ‐year Hemato,bgy 日 bgy 醐 B1ood Chemist , or9anweights chemi 敏 Urin 蜘 Ab… 1瞭覆一0"Eコの言油 orwithoutBanle .Urina,ysis ネ0この一宮ニニ○ooo脹ヒー三一Aー巨ーコのこooooo止瀞切 .-蚕 of significantd 旧erence(P 〈0,05)flbmthe. 仰 ntrolgroupw chronic、feedingahdoncogenicit) ′Studyusing[a 懐き. 厳鋪… 言 Myith Baitle帆'ste くst Midd 緯 dose 28 o 19 35 23 1 6 6 3 0 . 5 8 4 1 0 0 0 0 0 ・ 6 3 1 11 4 13 2 0 0 0 0 0 Highdose 83 57 20 11 8 “ 6 25 25 15 12 0 0 0 0 6 Topdose 13〇 126 ・ 36 15 15 15 12 25 29 24 18 0 1 2 1 5 o o o o 0 7 1 5 2 ^U -1 ^3 ^6 Lowdose1 1 0 0 2 1 科 0 0 0 1 0 97 4 6 8 12 7 324 6 8 9 12 11 511 2 0 4 2 1 92 0 0 0 2 1 111 3 6 9 11 ・ 7 323 6 8 9 11 M内観 ÷10阻 Bartlett'Stest l, 7 Highdose 85 Topdo6e13 α 29 15 3 5 3 0 ・ 34 18 6 5 4 2 13 8 55 20 11 12 11 5 26 25 122 41 15 16 15 13 26 28 26 6 11 .7 1 o oo 6 3 o o 15 9 o oo 13 1 1 o 2 6 0 1 3 災;e 2 1 5 Lowd Middーed 災;e 6 10511 9uestionlng the parameters us・ng usefulness was rats ofBartletrs test lbrtoxicity 34%(882/2,626),ln alld n・ice,the significant di径 erences parameters was by are thestudies overalldetection rate Bartlett'stest of in all of thelncidence of Sig 「11ificant Differences inStatisticaI With or Without Ba 戸tlett's Test(Table Wだhen Bart1ett,s testwas,used,andthe Test lo): statistical analysis involved both Para1netric and ‐ nonParametric tes絹 ,the incidence of sig口i行cant dif …erences was 84 in the1ow dose コroup, g 97 in the middle dosegroup,324in thehighdose and511inthet 。 n theotherhand, when 。pdosegroup, the varlance data was without subjected Bartlett's low do8e group,11l group.The values group test,it was of low and n・iddle dose ・to the parametric notes the Toxicology 409,1992),body comparison statistically analyzing used quantitative for dataobtained whereas commonly viau used fbr the (okamoto registration ofdrugs d αZ.」 1994;sakai in U.S.A. 〆 .,1994;Lertratanangkoone ー993;verschoy.eetq in “ メリー994; ez のリー994). 1n toxicity journals (Huuskonen" ごメリムー993),however;Bartlett,s test is scarcely used,andinstead analysis varlanceandmultiplecomparisolyrange of tests are ftequentlyused. ln this numbers and observed in the studies due great in the changes second to the agmg.Sixteenper obtained in the 35% ‐ decreases in m the were e爺ect of test substances long‐term toxicitystudies ofthe su 朝 ected to a rank and mark thatshowed it,showing if a rank test, ＼ qlean rank a sig草ificant di郡erence that it is significantly di稀erent,butinmanyinstancesamarkindicating significant mean ± difference S.D..Because expressmgtheresults isassociated of such with the inconsistency ofstatistical were an ‘ ・ D unnett's as 1995) ml or Wil hematological,biochemical and tend detection analysis,there with between ofstatisticaI eachdose in g bod we obsen ′ednodi rates control g 1roup whether were to show comPar ・son 俵 Signi group an Bartlett's test was detectionrates oflow without test.Therefore,wewould u; andmiddle slightly 停ビeaterthanthose Bar recommend quantitative data obtained in to〆icity st ▼should.be lirst exalnined byanalysis of va1 and if there analyzed by is a significant difference, D"nnett's,Turky's, Duncan'sn ・ultiplecomParisor A零 thenew tendency1nusing are tried to avoid Sheffe も/range test,or, Bartlett's test non-parametric procedul reasons,Hayashi .reported in toxicology studythat signil dif ばコerencelevel is set 登 om 5 to l% and repo 比 (Handa,1995)is Therefbre,this alsosuggesting. methodg ゴvesmoreconvl reasoningand avoids col1nplication and comp ・・ in data analysis due to the coexistence of tes態 , Additionally,longtermtoxicity these test.lngeneral be approPrial 窄 toindicatethe data and showed 熊 st,and a significant diI1;erence is de 族 ≧ctお din it would were long-tern ・ cent of the quantitative data short‐termt oxicity studies and signi行cant diagerencesinBartlett's data the ・sample varlance8 half.of weights such muchaspossiblefbrthese study, ≦ (Dunn, 1964)orshirle ゾsmultiplecomparisc (Shir.ey,1977),presumably because clihicを not,these in toxicity studies using roden 歯 ,Th e first steP of thc decision tree is Bartlett's test,which is Japan the 1 Proー享 am(NTPrepo] test(Dunnett, dif 髭 r,ences isgenerally between and organ parametllctests in the Discusslon tree this in ol relationship thedil白日erencesinranks(Takizawa,19 the NationaI by whetl ーetric testwaS however,itisnecessarytospecify cha 亭ges(variance)in lbrmer, decision are stating test or a nonparam understand and the value(Kobayashi,1993).There organweights,A1though A difl℃re showing biochemicalmeasurements 鱒 ouPswereslightlyhigher(9to14%)inthelatter comPared a significant twogroups wereanalyzed by nonparal 92 in the 」 measurements tests such as Dunn'g multiplecompariso1 group,.323 and 51l in the toP dose inthe mean in which between multiplecompar1sontest(VVilliams,1971& toanalysis in the middledose in the high dose grouP cases detected reportswithout 35%(2,089/5,904). 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