<b>Bijsluiter</b>. De hyperlink naar het originele document werkt niet meer. Daarom laat Woogle de tekst zien die in dat document stond. Deze tekst kan vreemde foutieve woorden of zinnen bevatten en de opmaak kan verdwenen of veranderd zijn. Dit komt door het zwartlakken van vertrouwelijke informatie of doordat de tekst niet digitaal beschikbaar was en dus ingescand en vervolgens via OCR weer ingelezen is. Voor het originele document, neem contact op met de Woo-contactpersoon van het bestuursorgaan.<br><br>====================================================================== Pagina 1 ======================================================================

<pre>    DEPARTMENT OF HEALTFI AND HUMAN SERVICES                 Public Health Service
                                                             Centers for Disease Control and Prevention
                                                             National Institute for Occupational
                                                               Safety and Health
                                                             1090 Tusculum Avenue
                                                             Cincinnati OH 45226-1998
                                                            September 12. 2014
The Health Council of the Netherlands
Attn: Dr. G.B. van der Voet
P0 Box 16052
2500BBTheHague
The Netherlands
Dear Dr. van der Voet:
Thank you for the opportunity to review the drafi report on Adriamycin prepared by the
Dutch Expert Committee on Occupational Safety (DECOS). Comments are enciosed that
were prepared by Thomas Connor, NIOSH/DART, 1090 Tusculum Ave., Cincinnati, OH
45226-1998 and Liying Rojanasakul, NIOSHIHELD, 1095 Willowdale Rd., Morgantown, WV
26505-2888.
1f yciu have any questions regarding the cornments, please contact me at 513-533-8260
(telephone) or by Email at tb17@cdc.gov.
                                                     Sincerely yours,
                                                     ThomfJ. Lentz, Ph.D., M.P.H.
                                                     Branch thief
                                                     Document Development Branch
                                                     Education and Information Division
1 Enciosure
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<pre>                  NIOSH review comments on DECOS draft Adriamycin
                 by Thomas Connor, NIOSHIDART, 1090 Tusculum Ave.,
            Cincinnati, OH 45226-1998 and Liying Rojanasakul, NIOSHIIIELD,
                     1095 Willowdale Rd., Moraantown. WV 26505-2888
SECTION & PARAGRAPH                                        COMMENT
                   V
                                                       See examples be/ow.
General Comments                Adriamycin is another name for “Doxorubicin” which
                                is also commonly used.
                                The provided document gives general information on
                          .     Adriamycin and its toxic effects with key published in
                                vitro/in vivo/human study data. Additional studies are
                                cited below for consideration.
Specific Comments
Section 2                       Reference 9 contairis more information than indicated
                                “the identity and some physicochemical properties of
                                Adriamycin are given ”     710 (page 7). It should
                                                           5
                                                           ’
                                                           4
                                                           below
                                be also cited at 2.2, Le., “Evidence for
                                carcinogenicity.  . . “, “ Adriamycin (Doxorubicin
                                hydrochioride): reasonably anticipated to be a human
                                carcinogen...”. http://toxnet.nlm .nih .goyLcgi
                                bin/sis/search2/f?./temp/yTxRkW: 1
                                A recent animal study showed that Adriamycin induces
                                cardiac fibrosis: Protective effect ofresveratrol against
                                doxorubicin-induced cardiac toxicity andfibrosis in
                                male experirnental rats. Arafa MH, Mohammad NS,
                                Atteia HH, Abd-Elaziz HR. 1 Physiol Biochem 2014
                                Jun 18. [Epub ahead’ of print].
                                http://link.springer.com/article/l 0.1 007%2Fs.1 3105-
                                Ol4-0339-y [ABSTRACT ONLY].
                                The inciusion of some occupational exposure studies
                                should be inciuded even though no regulatory exposure
                                limit is available.
                                Occupational exposure to carcinogens in the European
                                Union. Timo Kauppinen, Jouni Toikkanen, David
                                Pedersen, Randy Young,Wolfgang Abrens, Paolo
                                Boffetta, Johnni Hansen, Hans Kromhout, Jeronimo
                                Maqueda Blasco, Dario Mirabelli, Victoria de la
                                Orden-Rivera, Brian Pannefl, Nils Plato, Anja Savela,
                                Raymond Vincent, Manolis Kogevinas Occup Environ
                                Med 2000;57:10—18
                                http://oem.bmj.com/contentJ57/1/10.1ong
                                       1
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<pre>Section 2 (con’t) Biological inonitoring ofnurses exposed to doxorubicin
                  and epirubicin by a validated liquid
                  chroinatography/Jluorescence detection method.
                  Pieri M, Castiglia L, Basilicata P, Sannolo N,
                  Acampora A, Miraglia N. Ann. Occup. Hyg,
                  54(4):368-76 (2010)
                  http://annhyg.oxfordjouma1s.org/content/54/4/368
Section 2.3       An additional article on the mutagenicity of
                  Adriamycin was located: Matney, T.S., T.V. Nguyen,
                  T.H. Connor, W.J. Dana and J.C. Theiss. Genotoxic
                  classijication ofanticancer drugs. Teratogenesis,
                  Carcinogenesis, and Mutagenesis 5:319-328, (1985)
Section 2.5       Could not locate any reference to an OEL.
Section 3         Carcinogenicity studies the following references
                                             -
                  should be considered:
                  Doxorubicin and metastasis: Chemotherapy
                  enhanced infiammation may lead to the failure of
                  therapy and metastasis. Dinesh Vyas, Gieric Laput,
                  Arpitak K Vyas. OncoTargets Ther 12(7):1015-23,
                  2014
                  http://www.ncbi.nlm .nih.ov/imc/articIes/PMC406 116
                  4/
                  “Doxorubicin treatment alone potentially enhanced
                  metastasis to lung in the human breast cancer MDA
                  MB-231 orthotopic xenograft model and metastasis to
                  bone in the 4T1 orthotopic xenograft model,     ...“.
                  Doxorubicin in combination with a small TGFbeta
                  inhibitor: apotential novel therapyfor metastatic
                  breast cancer in mouse models. Bandyopadhyay Al,
                  Wang L, Agyin J, Tang Y, Lin S, Yeh IT, De K, Sun
                  LZ. PLoS One 2010 Apr 28;5(4):e10365
                  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC286098
            :     9/pdf/pone.00 10365 .pdf
Section F         Animal studies: A report showed that high-dose (10
                   mg/kg bw) Adriamycin treatment induces tumor in SD
                   rats while other studies provided here showed its lethal
                   toxicity. This paper describes the difference in tumor
                   biodistribution compared to other studies in SD rats.
                  Mamnmamy tumor induclion in male andfemnale
                   Sprague-Dawley rots by Adriamycin and Daunomycin.
                   Emilio Bucciarelli. JNCI, 66(1): January 1981.
                   http://inci.oxfordiouma1s.org/content/66/1/81.fuLI.pdf
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<pre>Section F (con’t) Genotoxicity and Mechanism of genotoxicity:
                  Studies provided here are before 1984. Below reference
                  provides relevant publications on genotoxicity of
                  Doxorubicin after 1984.
                  “The anthracycline antibiotic Doxorubicin (DXR), a
                  drug that targets topoisomerase 11 (Top2) (Islaih et al.,
                  2005), is one of the most effective anticancer drugs
                  used in the clinic (Lyu et al., 2007). This drug may
                  induce mutations by intercalating formaldehyde
                  adducts in the DNA (Spencer et al., 2008) or by
                  inducing the formation of oxygen free radicals
                  (Navarro et al., 2006), single- and double-strand DNA
                  breaks (Lyu et al., 2007) and somatic recombination
                  (Lehmann et al., 2003, Valadares et al., 2008, de
                  Rezende et al., 2009 and Sousa et al., 2009)»’.
                  The effect of the dibenzylbutyrolactolic lignan (-)-
                  cubebin on doxorubicin mutagenicity and
                  recoinbinogenicity in wing somafic cel/s ofDrosophila
                  melanogaster. Rezende AA, Silva ML, Tavares DC.
                  Cunha WR, Rezende KC, Bastos JK, Lehmann M, de
                  Andrade [-1H, Guterres ZR, Silva LP, Spanô MA. Food
                  Chern Toxicol. 2011 Jun;49(6):1235-41
                  http://www.sciencedirect.com/science/article/pii/S0278
                  691511000706
Other Information Recent clinical trials and applied research
                  investigate pulmonary administration and
                  nanoassembly of Adriamycin, albeit their toxicities
                  have not been well studied and need further
                  investigation.
                  Pulmonary admjnjstratjon of a doxorubicin -conjugated
                  dendri,ner enhances drug expos ure to lung metaslases
                  and improves cancer therapy. Kaminskas LM, McLeod
                  VM, Ryan GM, Kelly BD, Haynes JM, Williajnson M,
                  Thienthong N, Owen DJ, Porter CJ. J Control Release.
                  2014 Jun 10; 183 : 18-26
                  http://www.sciencedirect.com/science/article/pii/S0168
                  365914001461 [ABSTRACT ONLY]
                        3
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<pre>Other Information (con’t) Phase 1 study of inhaled Doxorubicin for patients with  -
                          inetastatic turnors to the lungs. Otterson GA, Villatona
                          Calero MA, Sharma S, Kris MG, Imondi A, Gerber M,
                          White DA, Ratain MJ, Schiller JH, Sandler A, Kraut
                          M, Mani S, Murren JR. Clin Cancer Res. 2007 Feb
                           15; 13(4): 1246-52
                          http://clincancerres.aacrjoumals.org/contentl 13/4/1246.
                          full.pdf+html
                          A unique squalenoylated and nonpegylated doxorubicin
                          nanoinedicine with systernic Zong-circulating properties
                          and anticancer activity. Maksimenko A, Dosio F,
                          Mougin J, Ferrero A, Wack S, Redcly LH, Weyn AA,
                          Lepeltier E, Bourgaux C, Stella B, Cattel L, Couvreur
                          P. Proc Nati Acad Sci 2014; 1 1(2):E217-26
                          http://www.ncbi .nlm.nih.gov/pmc/articlesfPMC3 89618
                          9/
Recommendations           1 concur with the recommendations for a 1B category.
                                4
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