• No results found

The relevance of developmental toxicity endpoints for acute limit setting | RIVM

N/A
N/A
Protected

Academic year: 2021

Share "The relevance of developmental toxicity endpoints for acute limit setting | RIVM"

Copied!
88
0
0

Bezig met laden.... (Bekijk nu de volledige tekst)

Hele tekst

(1)

5,90UHSRUW 7KHUHOHYDQFHRIGHYHORSPHQWDOWR[LFLW\ HQGSRLQWVIRUDFXWHOLPLWVHWWLQJ 070YDQ5DDLM3$+-DQVVHQ$+3LHUVPD 7KLVLQYHVWLJDWLRQKDVEHHQSHUIRUPHGE\RUGHUDQGIRUWKHDFFRXQWRI7KH0LQLVWU\RI3XEOLF +HDOWK6SRUWVDQG:HOOEHLQJZLWKLQWKHIUDPHZRUNRISURMHFW$FXWHWR[LFLW\DQG ULVNDVVHVVPHQW 5,9032%R[%$%LOWKRYHQWHOHSKRQHWHOHID[

(2)

SDJHRI5,90UHSRUW

6DPHQYDWWLQJ

7R[LFRORJLVFKHOLPLHWHQRSEDVLVYDQJH]RQGKHLGVHIIHFWHQYRRUGHPHQVVWDDQLQGH EHODQJVWHOOLQJ ELMYRRUEHHOG$5I'VHQ$(*/V 2QWZLNNHOLQJVWR[LFLWHLWZRUGWLQKHW DOJHPHHQEHVFKRXZGDOVHHQUHOHYDQWHLQGSXQWYRRUKHWYDVWVWHOOHQYDQDFXWHOLPLHWHQ'LW VRRUWWR[LFLWHLWZRUGWQRUPDDORQGHU]RFKWLQGLHUVWXGLHVGLHZRUGHQXLWJHYRHUGYROJHQV YDVWVWDDQGHULFKWOLMQHQZDDUELMGLHUHQJHGXUHQGHGDJHQWLMGHQVGHRUJDQRJHQHVH ZRUGHQEORRWJHVWHOG(FKWHUKHWLVGHYUDDJRIGH12$(/VGLHLQGH]HVWXGLHVZRUGHQ YDVWJHVWHOGDOWLMGUHSUHVHQWDWLHI]LMQYRRUHHQppQPDOLJHEORRWVWHOOLQJ,QGLWUDSSRUWZRUGHQ 12$(/VHQ/2$(/VYDQppQPDOLJHEORRWVWHOOLQJHQYHUJHOHNHQPHW12$(/VHQ/2$(/V YDQVWXGLHVPHWKHUKDDOGHEORRWVWHOOLQJJHEDVHHUGRSGHULFKWOLMQHQ'LWZHUGJHGDDQYRRU GLYHUVHHLQGSXQWHQDI]RQGHUOLMN PDWHUQDOHWR[LFLWHLWUHVRUSWLHVIRHWDDOOLFKDDPVJHZLFKW DDQWDOIRHWXVVHQPHWPDOIRUPDWLHVHIIHFWHQRSKHWVNHOHWHQVSHFLILHNHPDOIRUPDWLHV ,QGLHQ HUJHHQRIZHLQLJYHUVFKLOZRUGWJHYRQGHQWXVVHQ12$(/V/2$(/VYDQppQPDOLJHHQ KHUKDDOGHEORRWVWHOOLQJVWXGLHVZRUGWKHWHLQGSXQW GH12$(/ XLWGHKHUKDDOGH EORRWVWHOOLQJVWXGLHEHVFKRXZGDOVUHSUHVHQWDWLHIYRRUHHQppQPDOLJHEORRWVWHOOLQJ,QGLHQHU JURWHYHUVFKLOOHQZRUGHQJHYRQGHQLVGH12$(/YRRUHHQEHSDDOGHLQGSXQWXLWGHKHUKDDOGH EORRWVWHOOLQJVWXGLHQLHWUHOHYDQW 2SEDVLVYDQGH]HDQDO\VHZRUGWJHFRQOFXGHHUGGDWPDWHUQDOHWR[LFLWHLW OLFKDDPVJHZLFKW YRHGVHORSQDPHRUJDDQJHZLFKWHQNOLQLVFKHYHUVFKLMQVHOHQ JHHQJHVFKLNWHLQGSXQWLVYRRU KHWYDVWVWHOOHQYDQOLPLHWHQYRRUDFXWHEORRWVWHOOLQJ'HUHOHYDQWLHYDQIRHWDO OLFKDDPVJHZLFKW HQYHUWUDDJGHRVVLILFDWLH YRRUKHWYDVWVWHOOHQYDQDFXWHOLPLHWHQPRHW ZRUGHQJHsYDOXHHUGELQQHQGHWRWDOHFRQWH[WYDQHIIHFWHQRSGHIRHWXVHQGHPRHGHU 5HVRUSWLHVZRUGHQEHVFKRXZGDOVUHOHYDQWHHLQGSXQWHQYRRUDFXWHOLPLHWHQ0DOIRUPDWLHVHQ HIIHFWHQRSKHWVNHOHWZRUGHQEHVFKRXZGDOVUHOHYDQWHHLQGSXQWHQWHQ]LMHULQIRUPDWLH EHVFKLNEDDULVGLHDQGHUVXLWZLMVW+HWJHEUXLNHQYDQHHQ12$(/XLWHHQRQWZLNNHOLQJV VWXGLHYROJHQVGHJDQJEDUHULFKWOLMQHQ KHUKDDOGHEORRWVWHOOLQJ YHUVFKDIWWHDOOHQWLMGHHHQ FRQVHUYDWLHYH YHLOLJH LQVFKDWWLQJYDQGH12$(/ELMHHQppQPDOLJHEORRWVWHOOLQJ

(3)

5,90UHSRUWSDJHRI

6XPPDU\

+HDOWKEDVHGOLPLWVIRUDFXWHH[SRVXUHRIKXPDQVKDYHUHFHLYHGLQFUHDVLQJDWWHQWLRQ HJ $5I'VDQG$(*/V 'HYHORSPHQWDOWR[LFLW\LVLQJHQHUDOFRQVLGHUHGWREHDUHOHYDQW HQGSRLQWIRUVHWWLQJVXFKOLPLWV'HYHORSPHQWDOWR[LFLW\LVQRUPDOO\LQYHVWLJDWHGLQ µJXLGHOLQHEDVHG¶DQLPDOVWXGLHVZKLFKLQYROYHUHSHDWHGGRVLQJIRUGD\VGXULQJ RUJDQRJHQHVLV+RZHYHULWFDQEHTXHVWLRQHGZKHKWHU12$(/VREVHUYHGLQVXFK GHYHORSPHQWDOWR[LFLW\DUHUHSUHVHQWDWLYHIRUVLQJOHH[SRVXUHVLWXDWLRQ,QWKLVUHSRUWWKH 12$(/VDQG/2$(/VRIVLQJOHGRVHVWXGLHVZHUHFRPSDUHGWRWKH12$(/VDQG/2$(/V LQQRUPDOµJXLGHOLQHEDVHG¶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µJXLGHOLQHEDVHG¶UHSHDWHGGRVHGHYHORSPHQWDOWR[LFLW\VWXG\DOZD\VSURYLGHVDZRUVWFDVH HVWLPDWLRQRIWKH12$(/LQDVLQJOHGRVHH[SRVXUH

(4)

SDJHRI5,90UHSRUW

&RQWHQWV

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

(5)

5,90UHSRUWSDJHRI

 ,QWURGXFWLRQDQG2EMHFWLYHV

$FXWHH[SRVXUHLQULVNDVVHVVPHQW $FXWHH[SRVXUHWRWR[LFVXEVWDQFHVDQGWKHULVNDVVHVVPHQWRIVXFKH[SRVXUHVKDYHUHFHLYHG LQFUHDVLQJDWWHQWLRQLQWKHODVWGHFDGH7KLVLV±LQSDUW±GXHWRDQXPEHURIFKHPLFDO LQFLGHQWVLQWKH1HWKHUODQGV$SDUWIURPWKLVDFXWHH[SRVXUHKDVEHFRPHDQLPSRUWDQWLVVXH DOVRLQVRPHUHJXODWRU\IUDPHZRUNV([DPSOHVDUHVHWWLQJRIWKH$FXWH5HIHUHQFH'RVH $5I' IRUSHVWLFLGHVVHWWLQJRI$FXWH([SRVXUH*XLGHOLQH/HYHOV $(*/V RUVLPLODU HPHUJHQF\UHVSRQVHYDOXHVDQGULVNDVVHVVPHQWRIELRFLGDOSURGXFWVWKDWDUHXVHGRQO\RQFH RULQORZIUHTXHQF\ ZLWKLQWKHVFRSHRIWKH'XWFK3HVWLFLGH$FW ,WKDVEHFRPHFOHDUWKDWIRU VHYHUDODVSHFWVRIWKHDFXWHULVNDVVHVVPHQWWR[LFRORJLFDONQRZOHGJHLVOLPLWHG,QWKHSURMHFW µ$FXWHWR[LFLW\DQGULVNDVVHVVPHQW¶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

(6)

SDJHRI5,90UHSRUW WRK$5I'LVIRUK WKLVW\SHRIH[SRVXUHUHVHPEOHVPRUHDUHSHDWHGGRVLQJUHJLPH$ RQHGD\H[SRVXUHRIDSUHJQDQWZRPDQFRYHUVOHVVWKDQRIWKHWRWDOJHVWDWLRQSHULRG 7KHREVHUYHGHIIHFWVDWWKHHQGRIWKHJHVWDWLRQSHULRG DWDERXW*' LQDQDQLPDOVWXG\ PD\DFWXDOO\UHIOHFWUHSHDWHGGRVHWR[LFLW\UDWKHUWKDQDFXWHWR[LFLW\HIIHFWV,WFRXOGEH DUJXHGWKDWWKH12$(/VRIYDULRXVHIIHFWV HQGSRLQWV REVHUYHGLQUHJXODUGHYHORSPHQWDO WR[LFLW\VWXGLHVDUHKLJKO\YDULDEOHZLWKUHVSHFWWRWKHLUUHOHYDQFHDVDVWDUWLQJSRLQWIRUDFXWH OLPLWVHWWLQJ,QWKLVUHVSHFWD12$(/WKDWLVEDVHGRQWHUDWRJHQLFHIIHFWVFRXOGEH FRQVLGHUHGUHOHYDQWIRUDFXWHOLPLWVHWWLQJEHFDXVHRIWKHFULWLFDOZLQGRZFRQFHSW,QFRQWUDVW PRUHRUOHVVJHQHUDOIHWRWR[LFHQGSRLQWVVXFKDVIHWDOERG\ZHLJKWUHGXFWLRQRUGHOD\HG VNHOHWDORVVLILFDWLRQPD\LQPDQ\FDVHVEHFRQVLGHUHGOHVVUHOHYDQWIRUDFXWHH[SRVXUHVLQFH WKH\PD\EHWKHFRQVHTXHQFHRIUHSHDWHGGRVHH[SRVXUH+HQFHWKH12$(/IRUVXFK HQGSRLQWVLVQRWFRQVLGHUHGWREHDQDSSURSULDWHVWDUWLQJSRLQWIRUDFXWHOLPLWVHWWLQJVLQFHWKH 12$(/IRUVXFKDQHIIHFWLVSUREDEO\PXFKKLJKHULQDVLQJOHGD\H[SHULPHQW ,QDVLWXDWLRQZKHUHDQDFXWHOLPLWLVGHULYHGIURPDVWXG\XVLQJDORQJHUH[SRVXUHGXUDWLRQ WKHDFXWHOLPLWPD\EHVHWWRRORZLHWRRFRQVHUYDWLYH7KLVPD\KDYHXQGHVLUDEOH FRQVHTXHQFHV,QFDVHRIDWRRORZ$5I'VRPHSHVWLFLGHPD\EHGHQLHGDFFHVVRQWKHPDUNHW RUDFWXDOULVNDVVHVVPHQWZLOOEHKDPSHUHGLQFDVHRIUHVLGXHVWKDWH[FHHGWKHOLPLWV,QFDVH RI$(*/VWKDWDUHWRRFRQVHUYDWLYHXQQHFHVVDU\HPHUJHQF\UHVSRQVHDFWLRQVZLOOWDNHSODFH ZKLFKPD\LQIDFWSURYLGHPRUHKD]DUGWRWKHSXEOLF HJLQFDVHRIDQHYDFXDWLRQ WKDQWKH FKHPLFDOKD]DUGLWVHOI7KHUHIRUHLWLVLPSRUWDQWWKDWDFXWHOLPLWVDUHVHWRQWR[LFRORJLFDO HQGSRLQWVWKDWDUHUHOHYDQWIRUDFXWHH[SRVXUH$OWKRXJKPRVW$5I'¶VKDYHEHHQVHWXVLQJD WRWDODVVHVVPHQWIDFWRURIDOVRVPDOOHUIDFWRUVPD\EHXVHGGHSHQGLQJRQWKHGDWD DYDLODEOH(PHUJHQF\UHVSRQVHJXLGHOLQHVYDOXHVDUHPRVWO\VHWXVLQJVPDOOHUDVVHVVPHQW IDFWRUV ± 7KHUHIRUHDGLIIHUHQFHEHWZHHQWKH12$(/VLQJOHDQGWKH12$(/UHSRIDERXW IROGPD\DOUHDG\KDYHVHULRXVFRQVHTXHQFHVIRUVHWWLQJDQDFXWHOLPLW $WSUHVHQWIRUDERXWRIWKHVXEVWDQFHVWKH$5I'¶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

(7)

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

(8)
(9)

5,90UHSRUWSDJHRI

 0HWKRGV

,QWKLVLQYHVWLJDWLRQ12$(/VDQG/2$(/VIRUVSHFLILFHIIHFWVLQVLQJOHGRVHGHYHORSPHQWDO WR[LFLW\VWXGLHVDUHFRPSDUHGZLWKWKH12$(/VDQG/2$(/VIRUWKHVDPHHIIHFWVLQD UHJXODU±UHSHDWHGGRVH±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Š(7,& 'DWDEDVH KWWSWR[QHWQOPQLKJRYFJLELQVLVKWPOJHQ"'$57(7,&  )RUWKRVHVXEVWDQFHVIRUZKLFKVLQJOHGRVHVWXGLHVZHUHLGHQWLILHGDQDGGLWLRQDOVHDUFKZDV SHUIRUPHGWRREWDLQUHSHDWHGGRVHGHYHORSPHQWDOWR[LFLW\VWXGLHV,QDGGLWLRQPRQRJUDSKV HJ$76'5SURILOHV(QYLURQPHQWDO+HDOWK&ULWHULD:+2-035 DQGGDWDEDVHV HJ ,8&/,'GDWDEDVH ZHUHXVHGWRREWDLQUHSHDWHGGRVH JXLGHOLQHEDVHG GHYHORSPHQWDO WR[LFLW\VWXGLHV5HSHDWHGGRVHVWXGLHVVKRXOGKDYHDGRVLQJVFKHGXOHRI˜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

(10)

SDJHRI5,90UHSRUW

7KURXJKRXWWKLVUHSRUWWKH12$(/VDQG/2$(/VIURPWKHVLQJOHGRVHVWXGLHVDUHH[SUHVVHG DVDSHUFHQWDJHRIWKH12$(/VDQG/2$(/VIURPWKHUHSHDWHGGRVHVWXGLHV6RSHUFHQWDJH UHVXOWVUHSUHVHQW12$(/12$(/RU/2$(//2$(/FRPSDULVRQV+RZHYHUWKLV

FRPSDULVRQDORQHLVQRWVXIILFLHQW)RUH[DPSOH12$(/VLQJOHDQGWKH/2$(/VLQJOHFDQERWK EHRIWKHLUFRUUHVSRQGLQJUHSHDWHGYDOXHVEXWWKH12$(/VLQJOHPD\VWLOOEHORZHUWKDQ WKH/2$(/UHSGHSHQGLQJRQWKHFKRLFHRIGRVDJHVLQWKHVWXGLHV,QWKDWFDVHWKHUHPD\QRW EHDWUXHGLIIHUHQFHEHWZHHQVLQJOHDQGUHSHDWHGGRVLQJ7KHUHIRUHZHDOVRFDOFXODWHGWKH UDWLREHWZHHQWKH12$(/VLQJOHDQGWKH/2$(/UHSHDWHGVLQFHDPHDQLQJIXOGLIIHUHQFHEHWZHHQ VLQJOHDQGUHSHDWHGGRVHVLVRQO\LGHQWLILHGZKHQQRHIIHFWVRFFXULQDVLQJOHGRVHVWXG\DW OHYHOVWKDWGRLQGXFHHIIHFWVLQDUHSHDWHGVWXG\7KH12$(/VLQJOH/2$(/UHSUDWLRLV DEEUHYLDWHGDV1/5LQWKLVUHSRUW

)LJXUH6FKHPDWLFUHSUHVHQWDWLRQRIUHSHDWHGDQGVLQJOHGRVHUHVSRQVHFXUYHVDQGWKHFRQVHTXHQFH

IRUWKH12$(/VLQJOH/2$(/UHSUDWLR 1/5 :KHQ1/5!WKHUHLVDWUXHGLIIHUHQFHEHWZHHQWKH

VLQJOHDQGWKHUHSHDWHGGRVHUHVSRQVHFXUYH 6RWKH15/SURYLGHVWZRW\SHVRILQIRUPDWLRQ)LUVWDQ15/!FRQILUPVWKDWWKHUHLVD WUXHGLIIHUHQFHLQWKH12$(/VRIVLQJOHDQGUHSHDWHGGRVHVWXGLHV6HFRQGWKH15/ SURYLGHVDQGLQGLFDWLRQVKRZODUJHWKHGLIIHUHQFHLVEHWZHHQVLQJOHDQGUHSHDWHGGRVLQJ 7KHSHUFHQWDJHDQG1/5UHVXOWVDUHSUHVHQWIRUHDFKVXEVWDQFHVSHFLHVURXWHFRPELQDWLRQ VHSDUDWHO\DQGLQDGGLWLRQPHDQYDOXHV“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

(11)

5,90UHSRUWSDJHRI

 5HVXOWV

,QIRUPDWLRQIRUVLQJOHRUVKRUWWHUPH[SRVXUHVZHUHIRXQGIRUWKHVXEVWDQFHVOLVWHGLQ7DEOH 7KHVSHFLHVDQGURXWHRIH[SRVXUHDUHLQFOXGHG$OOWKHLQGLYLGXDOGDWDIRUHDFKVXEVWDQFH DVZHOODVUHIHUHQFHVWRWKHRULJLQDOSXEOLFDWLRQVXVHGDUHSURYLGHGLQ$SSHQGL[% 7DEOH2YHUYLHZRIDYDLODEOHGDWD 6XEVWDQFHV 6SHFLHV 5RXWH 5HSHDWHGGRVH DYDLODEOH 6LQJOHGRVH DYDLODEOH

$UVHQLFWULR[LGH UDW RUDOJDYDJH \HV <HV

%HQRP\O RUDOJDYDJH \HV <HV %URSLULPLQH RUDOJDYDJH \HV <HV %XW\O%HQ]\O 3KWKDODWH UDW RUDOJDYDJH \HV <HV &DGPLXP PLFH 6F <HVRUDOJDYDJH <HV &DGPLXP PLFH ,S <HVRUDOJDYDJH <HV &DUEHQGD]LPUDW 2UDOJDYDJH <HV \HV &DUERQ WHWUDFKORULGH RUDOJDYDJH <HV <HV &KORUSURSKDPPLFH \HV <HV

'LQEXW\OSKWKDODWH UDW RUDOJDYDJH <HV <HV

(78 UDW RUDOJDYDJH <HV <HV

(78 KDPVWHU RUDOJDYDJH <HV <HV

0HWKDQRO UDW RUDOJDYDJH \HV <HV

0HWKDQRO UDW ,QKDODWLRQ <HV 1R

0HWKDQRO PLFH LQKDODWLRQ <HV <HV

0HWKR[\HWKDQRO UDW RUDOJDYDJH <HV <HV

0HWKR[\HWKDQRO PLFH RUDOJDYDJH <HV <HV

PHWKR[\HWKDQRO UDW GHUPDO <HV <HV

1LFNHO UDW LP <HV <HV

3DFOREXWUD]ROH RUDO <HV <HV

3KHQ\WRLQ UDW RUDOJDYDJH <HV <HV

5HWLQ\OSDOPLWDWH UDW RUDOJDYDJH <HV <HV

7KLDEHQGD]ROH UDW RUDO <HV 1R

7KLDEHQGD]ROH PLFH RUDOJDYDJH <HV <HV

7ULEXW\OWLQ &O2 UDW RUDOJDYDJH <HV <HV

7ULFKORURHWK\OHQH UDW RUDOJDYDJH <HV <HV

$OWKRXJKVLQJOHGRVHDQGUHSHDWHGGRVHVWXGLHVZHUHDYDLODEOHQRWDOOVWXGLHVLQFOXGHGD UHSRUWRQWKHIXOOUDQJHRIGHYHORSPHQWDOWR[LFLW\HQGSRLQWV7KHUHIRUHVRPHWLPHV

LQIRUPDWLRQRQRQO\RQHVSHFLILFHQGSRLQW HJIXOOOLWWHUUHVRUSWLRQV ZDVDYDLODEOHZKLOHIRU DUDQJHRIRWKHUHQGSRLQWV HJIHWDOERG\ZHLJKWDQGVNHOHWDOHIIHFWV LQIRUPDWLRQZDV ODFNLQJ7KHUHIRUHWKHQXPEHURIVXEVWDQFHVIRUZKLFKUDWLRVDUHDYDLODEOHDUHVRPHZKDW

(12)

SDJHRI5,90UHSRUW YDULDEOHGHSHQGLQJRQWKHHQGSRLQW12$(/DQG/2$(/UHVXOWWDEOHVDVZHOODVUHIHUHQFHV WRWKHVWXGLHVXVHGFDQEHIRXQGLQ$SSHQGL[$ ,QWKHIROORZLQJVHFWLRQVWKHUHVXOWVIRUDQXPEHURIVSHFLILFHQGSRLQWVDUHGLVFXVVHG

 *HQHUDO

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µQRUPDO¶JXLGHOLQHEDVHGUHSHDWHGH[SRVXUHVWXG\ EDVLFDOO\DQ2(&'VWXG\ PD\GLIIHU IRUWKHYDULRXVHQGSRLQWVDVZHOODVFKHPLFDOVXEVWDQFHV

 0DWHUQDO7R[LFLW\

0DWHUQDOWR[LFLW\LVRIWHQRQO\LQYHVWLJDWHGE\JURVVSDUDPHWHUVVXFKDVIRRGFRQVXPSWLRQ DQGERG\ZHLJKWJDLQUHGXFWLRQ6RPHWLPHVDOVRRUJDQZHLJKWVRUVSHFLILFSK\VLRORJLFDO GLVWXUEDQFHVKDYHEHHQPHDVXUHGHVSHFLDOO\LQPHFKDQLVWLFVWXGLHV,QWKLVLQYHQWRU\ PDWHUQDOWR[LFLW\LVEDVHGRQO\JURVVSDUDPHWHUV ERG\ZHLJKWIRRGLQWDNHRUJDQZHLJKWV  QRGLIIHUHQWLDWLRQKDVEHHQPDGHEHWZHHQWKHSDUDPHWHUVPHDVXUHG$12$(/IRUPDWHUQDO WR[LFLW\KDVEHHQHVWDEOLVKHGDWWKHKLJKHVWGRVHDWZKLFKWKHRULJLQDOSXEOLFDWLRQVUHSRUWHGQR HIIHFWVRQWKHGDPV+RZHYHULQWKHPDMRULW\RISXEOLFDWLRQVXVHGPDWHUQDOWR[LFLW\ZDV UHSUHVHQWHGE\ERG\ZHLJKWDQGRUIRRGFRQVXPSWLRQHIIHFWV 7KHSULPDU\GDWDIRUPDWHUQDOWR[LFLW\DUHSUHVHQWHGLQ$SSHQGL[$,QILJXUHWKH12$(/V DQG/2$(/VIURPVLQJOHGRVHH[SHULPHQWV 12$(/VLQJOHDQG/2$(/VLQJOHUHVSHFWLYHO\ DUH H[SUHVVHGDVSHUFHQWDJHVRIWKH12$(/DQG/2$(/VIURPWKHUHSHDWHGGRVHH[SHULPHQWV 12$(/UHSDQG/2$(/UHSUHVSHFWLYHO\ (VVHQWLDOO\DYDOXHRILQGLFDWHVWKDWWKH 12$(/LQDVLQJOHGRVHVWXG\LVHTXDOWRWKH12$(/RIDUHSHDWHGGRVHVWXG\2QO\ FRPSDULVRQVIRUZKLFKERWKWKH12$(/VDQG/2$(/VDUHDYDLODEOH\LHOGYDOLG FRPSDULVRQV7KLVKROGVWUXHIRUVXEVWDQFHV $UVHQLFWULR[LGH%%3&DGPLXP &DUEHQGD]LP'HOWDPHWKULQ0HWKDQRO RUDOUDWLQKDOPRXVH 0( GHUPDOUDW  3KHQ\WRLQDQG7KLDEHQGD]ROH 2QDYHUDJHWKH12$(/VLQJOHLV“RIWKH

12$(/UHSZKLOHWKH/2$(/VLQJOHLV“RIWKH/2$(/UHSDQGIRUPRVWVXEVWDQFHV WKHYDOXHVDUH˜7KLVLQGLFDWHVWKDWIRUWKHGDWDEDVHVWXGLHGRQDYHUDJHDIROGKLJKHU GRVHLVQHHGHGRQDVLQJOHGD\WRLQGXFHPDWHUQDOWR[LFLW\FRPSDUHGWRWKHGRVHXVHGLQWKH UHSHDWHGH[SHULPHQW

(13)

5,90UHSRUWSDJHRI

)LJXUH6LQJOHGRVHDQGUHSHDWHGGRVHFRPSDULVRQIRUPDWHUQDOWR[LFLW\5HVXOWVUHSUHVHQWWKH

12$(/VLQJOHDQG/2$(/VLQJOHYDOXHVH[SUHVVHGDVSHUFHQWDJHRIWKHFRUUHVSRQGLQJ12$(/DQG

/2$(/YDOXHVIURPUHSHDWHGGRVHH[SHULPHQWV7KHVROLGOLQHPDUNVWKH LHQRGLIIHUHQFH OLQH 7DEOH1/5UHVXOWVIRUPDWHUQDOWR[LFLW\ 6XEVWDQFH 1/5YDOXH &DUEHQGD]LP1/5 &DGPLXP0HWKDQRO LQKDOPLFH  3KHQ\WRLQ ”1/5 $UVHQLFWULR[LGH%%3'%30HWKDQRO RUDOUDW 0( RUDOPLFH  ”1/5 &KORUSURSKDPGHOWDPHWKULQ(78 RUDO UDW 0( RUDOUDW 0( GHUPUDW  7KLDEHQGD]ROH 1/5• 0 D W H U Q D O  7 R [ L F L W \             $ U V H Q L F  W U L R [ L G H % H Q R P \ O % U R S L U L P L Q H % X W \ O  % H Q ] \ O  3 K W D O D W H & D G P L X P & D U E H Q G D ] L P & D U E R Q  W H W U D F K O R U L G H & K O R U S U R S K D P ' L  Q  E X W \ O S K W D O D W H ' H O W D P H W K U L Q ( 7 8 ( 7 8 ) 0      7 0 0 D Q J D Q H V H 0 H W K D Q R O 0 H W K D Q R O   0 H W K R [ \ H W K D Q R O   0 H W K R [ \ H W K D Q R O   P H W K R [ \ H W K D Q R O 1 L F N H O 3 D F O R E X W U D ] R O H 3 K H Q \ W R L Q 5 H W L Q \ O  S D O P L W D W H 7 K L D E H Q G D ] R O H 7 U L E X W \ O W L Q  & O   2 7 U L F K O R U R H W K \ O H Q H  / 2 $ ( / 1 2 $ ( /

(14)

SDJHRI5,90UHSRUW 7KH1/5LVRQDYHUDJH“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

)URPWKHVHUHVXOWVLWDSSHDUVWKDWWKHGRVHOHYHOVWKDWLQGXFHPDWHUQDOWR[LFLW\LQDUHSHDWHG GHYHORSPHQWDOH[SHULPHQW LHQRUPDOJXLGHOLQHEDVHGVWXG\ DUHQRWUHSUHVHQWDWLYHIRUD VLQJOHH[SRVXUH0DWHUQDOWR[LFLW\LVDSSDUHQWO\DJJUDYDWHGE\UHSHDWHGH[SRVXUHWRWKHWHVW VXEVWDQFHRYHUDQXPEHURIGD\V7KHXVHRID12$(/IRUPDWHUQDOWR[LFLW\IURPDUHSHDWHG H[SHULPHQWLVWKHUHIRUHKLJKO\FRQVHUYDWLYHLQYLHZRIDFXWHWR[LFLW\OLPLWVHWWLQJ

 5HVRUSWLRQV

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±RIWKHUHSHDWHGGRVHYDOXHVLQGLFDWLQJIROG KLJKHUGRVDJHVDUHQHHGHGLQDVLQJOHGD\VWXG\WRLQGXFHUHVRUSWLRQV2QDYHUDJHWKH 12$(/VLQJOHLV“RIWKH12$(/UHSWKH/2$(/VLQJOHLV“RIWKH /2$(/UHS

7KHPHDQ1/5LV“7KH1/5UHVXOWVDUHSUHVHQWHGDVFDWHJRULHVLQ7DEOH7KHVH UHVXOWVFRQILUPWKDWIRUPRVWVXEVWDQFHVWKHUHLVDWUXHGLIIHUHQFHEHWZHHQWKH12$(/VLQ VLQJOHGRVHDQGUHSHDWHGGRVHVWXGLHV

(15)

5,90UHSRUWSDJHRI

)LJXUH6LQJOHGRVHDQGUHSHDWHGGRVHFRPSDULVRQIRUUHVRUSWLRQV5HVXOWVUHSUHVHQWWKH

12$(/VLQJOHDQG/2$(/VLQJOHYDOXHVH[SUHVVHGDVSHUFHQWDJHRIWKHFRUUHVSRQGLQJ12$(/DQG

/2$(/YDOXHVIURPUHSHDWHGGRVHH[SHULPHQWV7KHVROLGOLQHPDUNVWKH LHQRGLIIHUHQFH OLQH 7DEOH1/5UHVXOWVIRUUHVRUSWLRQV 6XEVWDQFH 1/5YDOXH %HQRP\OSKHQ\WRLQ 1/5 $UVHQLFWULR[LGH%%3&DUEHQGD]LP &KORUSURSKDP'%30HWKDQRO RUDOUDW  0HWKDQRO LQKDOPLFH 7KLDEHQGD]ROH ”1/5 %URSLULPLQH(78 RUDOKDPVWHU 0( RUDOUDW 1LFNHO7ULFKORURHWK\OHQH ”1/5 0( RUDOPLFH 0( GHUPUDW  1/5•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

(16)

SDJHRI5,90UHSRUW :LWKUHVSHFWWRUHVRUSWLRQVWKHHYLGHQFHLQGLFDWHVWKDWVRPHVXEVWDQFHVLQGXFHUHVRUSWLRQV DIWHUDVLQJOHH[SRVXUHDWWKHVDPHGRVHOHYHODVDIWHUUHSHDWHGH[SRVXUHDOWKRXJKIRUPRVW VXEVWDQFHVDERXWKLJKHUGRVHVDUHQHHGHG

 )HWDOERG\ZHLJKW

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

12$(/VLQJOHDQG/2$(/VLQJOHYDOXHVH[SUHVVHGDVSHUFHQWDJHRIWKHFRUUHVSRQGLQJ12$(/DQG

/2$(/YDOXHVIURPUHSHDWHGGRVHH[SHULPHQWV7KHVROLGOLQHPDUNVWKH LHQRGLIIHUHQFH OLQH ) H W D O% R G \ : H LJ K W                  $ U V H Q LF  WU LR [ LG H % H Q R P \ O % UR S LU LP LQ H % X W \ O% H Q ] \ O3 K WD OD W H & D G P LX P & D U E H Q G D ] LP & D U E R Q  WH W U D F K OR U LG H & K OR U S U R S K D P ' LQ  E X W\ OS K WD OD W H ' H OWD P H WK U LQ ( 7 8 ( 7 8 ) 0     7 0 0 D Q J D Q H V H 0 H WK D Q R O 0 H WK D Q R O   0 H W K R [ \ H WK D Q R O   0 H W K R [ \ H WK D Q R O   P H W K R [ \ H WK D Q R O 1 LF N H O 3 K H Q \ W R LQ 3 D F OR E X W UD ] R OH 5 H W LQ \ OS D OP LWD W H 7 K LD E H Q G D ] R OH 7 U LE X W\ OW LQ  & O 2 7 ULF K OR U R H WK \ OH Q H  / 2 $ ( / 1 2 $ ( /

(17)

5,90UHSRUWSDJHRI &KORUSURSKDP'%3(78 RUDOKDPVWHU 0H2+ LQKDOPRXVH 0( RUDOPRXVHRUDO UDW DQG7KLDEHQGD]ROH 7KHILJXUHVKRZVWKDWIRU0HWKDQRODQG7KLDEHQGD]ROHWKH 12$(/DQG/2$(/FRPSDULVRQVKRZVDYDOXHDURXQGLQGLFDWLQJQRGLIIHUHQFHLQ 12$(/VEHWZHHQVLQJOHDQGUHSHDWHGGRVLQJ+RZHYHUWKH0HWKDQROUHVXOWLVGRPLQDWHGE\ REVHUYDWLRQVIURPDVLQJOHH[SRVXUHRQGD\ZKLFKLVQRWLQFOXGHGLQWKHQRUPDOUHSHDWHG GRVHVWXG\ZKLFKVWDUWVDWGD\,QDGGLWLRQWKHH[SHULPHQW\LHOGLQJWKHORZHIIHFWOHYHOVIRU WKHVLQJOHGRVHH[SHULPHQWVGLGQRWLQFOXGHDFRQFXUUHQWFRQWUROJURXS(IIHFWVKDGWREH FRPSDUHGWRRWKHUFRQWUROJURXSVLQWKHVDPHSXEOLFDWLRQVZKLFKPD\KDYHLQGXFHGVRPH ELDV)RU7KLDEHQGD]ROHWKH12$(/VLQJOHLVGHWHUPLQHGIURPDVLQJOHVHWRIH[SHULPHQWV VKRZLQJIHWDOERG\ZHLJKWHIIHFWVDWPJNJEZZKLOHWKHVDPHSXEOLFDWLRQDOVRFRQWDLQHG DVHFRQGVHWRIVLQJOHGRVHH[SHULPHQWVZKLFKVKRZHGQRHIIHFWVDWIHWDOERG\ZHLJKWXSWR PJNJEZ VDPHVWUDLQGRVHGRQWKHVDPH*' 6RWKH12$(/VLQJOHDQG/2$(/VLQJOHIRU 7KLDEHQGD]ROHFRXOGEHDERXWIROGKLJKHUGHSHQGLQJRQWKHLQWHUSUHWDWLRQRIWKHSULPDU\ GDWD:KHQWKHKLJKHU12$(/ZRXOGEHXVHGWKH12$(/VLQJOHDQGWKH/2$(/VLQJOHZRXOG EHDQGRIWKHUHSHDWHG12$(/YDOXHVUHVSHFWLYHO\)RUWKHRWKHUVXEVWDQFHVWKH 12$(/VDQG/2$(/VRIWKHVLQJOHGRVHVWXGLHVDUHDERXW±RIWKHUHSHDWHGGRVH YDOXHVLQGLFDWLQJIROGKLJKHUGRVDJHVDUHQHHGHGLQDVLQJOHGD\VWXG\WRLQGXFHD

GHFUHDVHLQIHWDOERG\ZHLJKW2QDYHUDJHWKH12$(/VLQJOHLV“RIWKH12$(/UHS WKH/2$(/VLQJOHLV“RIWKH/2$(/UHS

7KHPHDQ1/5LV“,Q7DEOHWKH1/5UHVXOWVDUHSUHVHQWHGLQFDWHJRULHV)RU PRVWVXEVWDQFHVWKH1/5LV!ZKLFKFRQILUPVDWUXHGLIIHUHQFHEHWZHHQ12$(/VIURP VLQJOHDQGUHSHDWHGGRVHVWXGLHV 7DEOH1/5UHVXOWVIRUIHWDOERG\ZHLJKW 6XEVWDQFH 1/5YDOXH &DUEHQGD]LP0HWKDQRO7KLDEHQGD]ROH 1/5 %HQRP\O&DGPLXP&KORUSURSKDP0( RUDOPLFH  ”1/5 $UVHQLFWULR[LGH%%3'%3(78 RUDO KDPVWHU 0( RUDOUDW 3KHQ\WRLQ ”1/5 )00( GHUPUDW 1/5•

 3HUFHQWDJHIHWXVHVZLWK0DOIRUPDWLRQVRU9DULDWLRQV

7KHSULPDU\GDWDRIWKHDQDO\VLVIRUPDOIRUPDWLRQVDQGYDULDQWVLVSUHVHQWHGLQ$SSHQGL[$ ,QILJXUHWKH12$(/VDQG/2$(/VIURPVLQJOHGRVHH[SHULPHQWVDUHH[SUHVVHGDV SHUFHQWDJHRIWKH12$(/DQG/2$(/VIURPWKHUHSHDWHGGRVHH[SHULPHQWV(VVHQWLDOO\D

(18)

SDJHRI5,90UHSRUW

YDOXHRILQGLFDWHVWKDWWKH12$(/LQDVLQJOHGRVHVWXG\LVHTXDOWRWKH12$(/RID UHSHDWHGGRVHVWXG\

)LJXUH6LQJOHGRVHDQGUHSHDWHGGRVHFRPSDULVRQIRUIHWDOERG\ZHLJKW5HVXOWVUHSUHVHQWWKH

12$(/VLQJOHDQG/2$(/VLQJOHYDOXHVH[SUHVVHGDVSHUFHQWDJHRIWKHFRUUHVSRQGLQJ12$(/DQG

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

(19)

5,90UHSRUWSDJHRI

DERXW± RUPRUH RIWKHUHSHDWHGGRVHYDOXHVLQGLFDWLQJIROGKLJKHUGRVDJHV DUHQHHGHGLQDVLQJOHGD\VWXG\WRLQGXFHDQLQFUHDVHLQWKHQXPEHURIIHWXVHVZLWK

PDOIRUPDWLRQVDQGRUYDULDQWV2QDYHUDJHWKH12$(/VLQJOHLV“RIWKH12$(/UHS WKH/2$(/VLQJOHLV“RIWKH/2$(/UHS

7DEOH1/5UHVXOWVIRUWKHQXPEHURIIHWXVHVZLWKPDOIRUPDWLRQVYDULDQWV 6XEVWDQFH 1/5YDOXH %HQRP\O'%33KHQ\WRLQ 1/5 %%30HWKDQRO RUDOUDW 0HWKDQRO LQKDO PLFH 0( RUDOPLFH 7KLDEHQGD]ROH ”1/5 (78 RUDOKDPVWHU )0 ”1/5 &DUEHQGD]LP'HOWDPHWKULQ0( GHUP UDW 0( RUDOUDW 5HWLQ\OSDOPLWDWH 1/5• 7KHPHDQ1/5LV“7KH1/5UHVXOWVDUHSUHVHQWHGLQFDWHJRULHVLQ7DEOH7KHVH UHVXOWVVKRZWKDWEHVLGHWKHVXEVWDQFHVZLWKD1/5 %HQRP\O'%33KHQ\WRLQ WKHUH DUHDGGLWLRQDOVXEVWDQFHVSHFLHVURXWHFRPELQDWLRQVZLWKDOLPLWHGGLIIHUHQFH 1/5 2QO\FRPELQDWLRQVKDYH”1/5+RZHYHUFRPELQDWLRQVKDYHD1/5•LQGLFDWLQJ DODUJHGLIIHUHQFHLQ12$(/VDQG/2$(/VEHWZHHQWKHVLQJOHDQGUHSHDWHGGRVH H[SHULPHQWV,WDSSHDUVWKDWWKHUHPLJKWEHWZRVHWVRIVXEVWDQFHV2QHJURXSIRUZKLFKQR GLIIHUHQFHEHWZHHQWKH12$(//2$(/VLQVLQJOHGRVHDQGUHSHDWHGGRVHH[SHULPHQWVLV REVHUYHGRUWKHGLIIHUHQFHLVDWOHDVWDQGDQRWKHUJURXSRIVXEVWDQFHVIRUZKLFKWKH GLIIHUHQFHLVODUJH

 6NHOHWDOHIIHFWV

6NHOHWDOHIIHFWVGRIUHTXHQWO\RFFXULQGHYHORSPHQWDOWR[LFLW\VWXGLHV3DUWO\WKLVPD\EHD VSHFLILFWHUDWRJHQLFHIIHFWEXWSDUWO\WKHVHHIIHFWVDUHWKHUHVXOWRIIHWDOJURZWKUHWDUGDWLRQRU JHQHUDOHPEU\RIHWRWR[LFLW\ VHHDERYH ,Q7DEOHVXEVWDQFHVSHFLHVURXWHFRPELQDWLRQV DUHSUHVHQWHGIRUZKLFK12$(/DQG/2$(/FRPSDULVRQVZHUHDYDLODEOHEHWZHHQVLQJOHDQG UHSHDWHGGRVHH[SHULPHQWV7KHVNHOHWDOHIIHFWVLQWKLVDQDO\VLVRQO\LQFOXGHIXVHGDUFKHV IXVHGYHUWHEUDHIXVHGVWHUQHEUDHIXVHGULEVZDY\ULEVGLJLWDOHIIHFWVDQGVKRUWHQHGULEV 2WKHU VSHFLILF HIIHFWVLQFOXGLQJGHOD\HGRVVLILFDWLRQDUHH[FOXGHG$OWKRXJKWKLVSRROLQJ RIGLIIHUHQWHIIHFWVPLJKWREVFXUHDQ\VSHFLILFGLIIHUHQFHEHWZHHQVHSDUDWHHIIHFWVIXUWKHU VSOLWWLQJRIHIIHFWV\LHOGVDWRROLPLWHGQXPEHURIFRPELQDWLRQV1HYHUWKHOHVVWKHUHVXOWVLQ 7DEOHDUHGRPLQDWHGE\IXVHGVWHUQHEUDHDQGIXVHGDUFKHVYHUWHEUDH

(20)

SDJHRI5,90UHSRUW 7DEOH6NHOHWDOHIIHFWV12$(/DQG/2$(/FRPSDULVRQVEHWZHHQVLQJOHDQGUHSHDWHGGRVH H[SHULPHQWV 1/5YDOXHV 6XEVWDQFH 6SHFLHV 5RXWH 12$(/VLQJOH RI12$(/UHS /2$(/VLQJOH RI/2$(/UHS 5DWLR 12$(/VLQJOH /2$(/UHS %%3 UDW 2UDOJDYDJH    7KLDEHQGD]ROH PRXVH 2UDOJDYDJH    3KHQ\WRLQ UDW 2UDOJDYDJH    0HWKR[\ HWKDQRO PRXVH 2UDOJDYDJH    0HWKDQRO PRXVH ,QKDODWLRQ   

3DFOREXWUD]ROH UDW 2UDOJDYDJH   

'%3 UDW 2UDOJDYDJH   

)0 UDW ,QKDODWLRQ   

(78 KDPVWHU 2UDOJDYDJH   

'HOWDPHWKULQ UDW 2UDOJDYDJH   

&DUEHQGD]LPUDW 2UDOJDYDJH   

0HWKR[\ HWKDQRO

UDW GHUPDO   

0HWKDQRO UDW 2UDOJDYDJH   

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

(21)

5,90UHSRUWSDJHRI 7DEOH5HWDUGHGRVVLILFDWLRQ12$(/DQG/2$(/FRPSDULVRQVEHWZHHQVLQJOHDQG UHSHDWHGGRVHVWXGLHV 1/5UHVXOWV 6XEVWDQFH 6SHFLHV 5RXWH 12$(/VLQJOH RI12$(/UHS /2$(/VLQJOH RI/2$(/UHS 5DWLR 12$(/VLQJOH /2$(/UHS 3KHQ\WRLQ UDW 2UDO   

0HWKDQRO UDW 2UDO   

(78 KDPVWHU 2UDO    )0 UDW ,QKDODWLRQ    0HWKR[\ HWKDQRO UDW 'HUPDO   

 6SHFLILF0DOIRUPDWLRQV

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

5HWLQ\OSDOPLWDWH UDW 2UDOJDYDJH   

(78 KDPVWHU 2UDOJDYDJH   

([HQFHSKDO\

5HWLQ\OSDOPLWDWH UDW 2UDOJDYDJH   

'LODWLRQRIUHQDOSHOYLV LQFO+\GURQHSKURVLV 3KHQ\WRLQ UDW 2UDOJDYDJH    '%3 UDW 2UDOJDYDJH    &DUEHQGD]LPUDW 2UDOJDYDJH    1HXUDOWXEHGHIHFWV 0HWKDQRO PRXVH ,QKDODWLRQ    )URPWKLVWDEOHLWDSSHDUVWKDWIRUPRVWVXEVWDQFHVSHFLHVURXWHFRPELQDWLRQVDKLJKHUGRVH LVQHHGHGLQDVLQJOHH[SRVXUHWRLQGXFHWKHVSHFLILFPDOIRUPDWLRQFRPSDUHGWRDUHSHDWHG

(22)

SDJHRI5,90UHSRUW H[SRVXUHH[SHULPHQW 12$(/VDQG/2$(/VDUHDOO! $OWKRXJKWKH1/5LV!IRU PRVWFDVH H[FHSWIRU3KHQ\WRLQ LQGLFDWLQJDGLIIHUHQFHEHWZHHQVLQJOHDQGUHSHDWHGGRVLQJ WKH1/5LVRQO\DERXW H[FHSWIRU&DUEHQGD]LP 7KHGLIIHUHQFHLQGRVHUHVSRQVHFXUYHV IRUVSHFLILFPDOIRUPDWLRQVDSSHDUVWRVKRZDOLPLWHGGLIIHUHQFHEHWZHHQWKHGRVDJHVLQVLQJOH DQGUHSHDWHGH[SRVXUHV+RZHYHUVLPLODUWRWKHVLWXDWLRQZLWKUHWDUGHGRVVLILFDWLRQWKH DYDLODEOHLQIRUPDWLRQLVWRROLPLWHGWRGUDZJHQHUDOFRQFOXVLRQV

 2WKHULQGLFDWLRQVIRUDFXWHYVUHSHDWHGHIIHFWV

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• SSP 5HGXFHG%:JDLQ&16 HIIHFWVDW•SSP &16HIIHFWVDW• SSP5HGXFHG%:JDLQ DW•SSP )HWDOERG\ZHLJKW 5HGXFHGDWSSP 1RHIIHFWDWSSP 1RHIIHFWRQIHWDO%: 1RHIIHFWRQIHWDO%: 6NHOHWDOYDULDWLRQV 3UHVHQWDW•SSP 1RHIIHFWDWSSP 3UHVHQWDW•SSP 1RHIIHFWRQSSP 1RHIIHFWRQVNHOHWDO SDUDPHWHUV ” SSP WKFHUYLFDOULE LQUHSHDWHGGRVHDQGVLQJOHKVWXG\ UHWDUGHGRVVLILFDWLRQ

(23)

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

(24)

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

(25)

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

(26)
(27)

5,90UHSRUWSDJHRI

 'LVFXVVLRQ

7KHHIIHFWVRIDFXWHH[SRVXUHWRFKHPLFDOVKDVEHFRPHDPRUHLPSRUWDQWDFWLYLW\LQWKHULVN DVVHVVPHQWDFWLYLWLHVRI5,906,5)RUVRPHWLPH6,5KDVEHHQLQYROYHGLQWKHULVN DVVHVVPHQWLQFDVHVRIH[FHHGLQJRIKHDOWKEDVHGOLPLWYDOXHVPRVWO\OLPLWVIRUFKURQLF H[SRVXUH,QDGGLWLRQLQWKHODVWGHFDGHVRPHDFWLYLWLHVKDYHEHHQLQWURGXFHGZKLFKSULPDULO\ IRFXVRQWKHSXEOLFKHDOWKULVNRIDFXWHH[SRVXUHWRVXEVWDQFHV7KLVLQFOXGHVULVNDVVHVVPHQW RIFRQVXPHUSURGXFWVDQGELRFLGHVZLWKORZIUHTXHQF\XVHWKHVHWWLQJRI$5I'¶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¶V QRZDYDLODEOHKDYHEHHQVHWRQWKHEDVLVRIGHYHORSPHQWDOWR[LFLW\ GHSHQGLQJRQWKH RUJDQL]DWLRQRUFRXQWU\LQYROYHG ,QDGGLWLRQIRUDERXWRIWKHVXEVWDQFHVZLWK'XWFK ,QWHUYHQWLRQ9DOXHVIRUKD]DUGRXVVXEVWDQFHV KRXUHPHUJHQF\UHVSRQVHYDOXHV WKH$*: YDOXHV‚KDYHEHHQVHWRQWKHEDVLVRIGHYHORSPHQWDORUUHSURGXFWLRQWR[LFLW\HQGSRLQWV$VDQ H[WUDDVSHFWVRPHRUJDQL]DWLRQVFRQVLGHUGHYHORSPHQWDOHIIHFWVWREHYHU\VHYHUHVXFKWKDW H[WUDPRGLI\LQJVDIHW\IDFWRUVDUHDSSOLHG +RZHYHURQHVKRXOGFRQVLGHUWKDWDQRUPDOµJXLGHOLQHEDVHG¶GHYHORSPHQWDOWR[LFLW\VWXG\ LQUDWVRUUDEELWVLQYROYHVDGD\H[SRVXUHRQVXEVHTXHQWGD\V$OWKRXJKLQFRPSDULVRQ WRPRVWRWKHUVWXGLHVLQDµVWDQGDUG¶GDWDEDVHWKLVH[SRVXUHSHULRGLVUHODWLYHO\DFXWHWKLV H[SHULPHQWDOWUHDWPHQWVKRXOGEHFRQVLGHUHGUHODWLYHO\µUHSHDWHG¶LQYLHZRIWKHOLPLWVWKDW ZLOOEHVHWRQWKHEDVLVRIWKHVHHIIHFWV)RUH[DPSOHDGD\H[SRVXUHSHULRGLQUDWVFRYHUV DERXWRIWKHWRWDOJHVWDWLRQSHULRG,QFRQWUDVWWKH$5I'DQG$(*/VDUHOLPLWVIRUD VLQJOHH[SRVXUHODVWLQJK $5I' RU”K $(*/V $VLQJOHGD\H[SRVXUHRIDSUHJQDQW ZRPDQFRYHUVOHVVWKDQRIWKHWRWDOKXPDQJHVWDWLRQSHULRG

(28)

SDJHRI5,90UHSRUW 7KHµFULWLFDOZLQGRZ¶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µJXLGHOLQHEDVHG¶UHSHDWHGGRVHVWXGLHVKDVEHHQLQYHVWLJDWHGIRUVHYHUDO HIIHFWVGHWHUPLQHGLQGHYHORSPHQWDOWR[LFLW\VWXGLHV2XUK\SRWKHVLVZDVWKDWIRUVRPH GHYHORSPHQWDOHIIHFWVWKH12$(/VDQG/2$(/VLQVLQJOHGRVHH[SHULPHQWVZRXOGEHHTXDO WRWKH12$(/VDQG/2$(/VLQUHSHDWHGGRVHVWXGLHVDQGWKHUHIRUHWKHVH12$(/VDUH UHOHYDQWIRUVHWWLQJDFXWHOLPLWYDOXHV:KHQDVSHFLILFHIIHFWUDWKHUUHTXLUHV±RULV DJJUDYDWHGE\±VRPHIRUPRIUHSHDWHGGRVLQJWKH12$(/VDQG/2$(/VLQVXFKDVWXG\ ZLOOEHOHVVUHOHYDQWIRUVHWWLQJDFXWHOLPLWYDOXHVEHFDXVHLQDVLQJOHGRVHH[SHULPHQWWKH 12$(/ZRXOGEHDFWXDOO\KLJKHU$WUXHGLIIHUHQFHZRXOGEHREWDLQHGLIWKH12$(/VLQJOH ZRXOGEHFOHDUO\KLJKHUWKDQWKH/2$(/UHSLHWKHUDWLRRI>12$(/VLQJOH/2$(/UHS@• 1/5  7KLVDQDO\VLVKDVEHHQSHUIRUPHGIRUVXEVWDQFHVSHFLHVURXWHFRPELQDWLRQV+RZHYHUIRU PRVWHQGSRLQWVRQO\GDWDIRUDERXWFRPELQDWLRQVZHUHDFWXDOO\DYDLODEOH,QWKHVHFWLRQ EHORZDOLVWRIOLPLWDWLRQVDQGTXHVWLRQVDUHGLVFXVVHGWRSODFHWKLVLQYHVWLJDWLRQLQ SHUVSHFWLYH

 /LPLWDWLRQVRIWKHDQDO\VHV

/LPLWHGQXPEHURIREVHUYDWLRQV 7KHDQDO\VLVLVIRUPRVWHQGSRLQWVEDVHGRQDYHU\OLPLWHGQXPEHURIVXEVWDQFHV,Q DGGLWLRQVRPHVXEVWDQFHVRFFXUPRUHWKDQRQFHLQWKHDQDO\VLV(78KDVEHHQVWXGLHGLQUDWV DQGKDPVWHUV ERWKRUDO PHWKDQROKDVEHHQVWXGLHGLQUDWV RUDO DQGPLFH LQKDODWLRQ DQG 0HWKR[\HWKDQROKDVEHHQVWXGLHGE\WKHRUDOURXWHLQUDWVDQGPLFHDQGE\WKHGHUPDOURXWH LQUDWV,WLVQRWFOHDUDWSUHVHQWKRZUHSUHVHQWDWLYHWKLVDQDO\VLVLVIRUWKHZKROHUDQJHRI FKHPLFDOVXEVWDQFHV VHHDOVREHORZ   ‚$*: $ODUPHULQJVJUHQVZDDUGH VLPLODUWR$(*/

(29)

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

(30)

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±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

(31)

5,90UHSRUWSDJHRI

 ,QGLFDWLRQVDQG&RQFOXVLRQV

 0DWHUQDOWR[LFLW\

7KHUHVXOWVRIRXUDQDO\VLVVKRZWKDWJURVVPDWHUQDOWR[LFLW\±FDSWXUHGRQO\E\ERG\ZHLJKW FKDQJHVIRRGLQWDNHFOLQLFDOVLJQVDQGRUJDQZHLJKWV±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

 5HVRUSWLRQV

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

(32)

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

 )HWDO%RG\ZHLJKW

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

Referenties

GERELATEERDE DOCUMENTEN

• Exposure duration: the total time the exposed person is in the room where the substance is being released. • Product amount: the amount of product used in one event. •

Overall PFGE typing results 20 th EURL-Salmonella interlaboratory comparison study (2015) on typing of Salmonella

Aanbieders die meer dan tweederde van het maximum aantal punten scoorden (boven de 30 punten voor labtesten en boven de 28,7 voor thuistesten) werden als voldoende beoordeeld,

I) Determinanten en kenmerken van een stralingsincident. II) De gevolgen van een stralingsincident. III) De maatregelen die genomen kunnen/moeten worden om de nadelige gevolgen

In order to compare the impact of this energy demand with impacts of other parts of the drinking water production process and with an alternative drinking water production scheme,

Voor de berekening van het totale directe plus indirecte energiegebruik per persoon voor periode tussen 1980 en 1996 is uitgegaan van cijfers die gepresenteerd zijn in de

Medewerking van paramedisch personeel Tijdsinvestering van het personeel Gebruik van de gegevens Invoerprogramma Opsporen van patiënten met een centrale of arteriële lijn Opsporen

Otte PF, Onderzoek naar het aandeel verpakkingen in gescheiden ingezameld papier en karton uit Nederlandse huishoudens 1994, RIVM rapport 776201020, Bilthoven, juli