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  • Publication
    Contributions of indoor household activities to inhalation health risks induced by gaseous air pollutants in Hong Kong home
    ( 2023-09-01)
    Zeng, Lewei
    ;
    Li, Kaimin
    ;
    Guo, Hai
    ;
    Zhou, Beining
    ;
    Lyu, Xiaopu
    ;
    Huo, Yunxi
    ;
    Uhde, Erik
    ;
    Jin, Yang
    ;
    Zeren, Yangzong
    ;
    Lu, Haoxian
    ;
    Yao, Dawen
    ;
    Qian, Zhe
    To understand inhalation health risks at home, a comprehensive sampling campaign was conducted in a Hong Kong residential apartment from October to December 2019. Emissions of nine typical household activities, household background release and outdoor pollution were continuously monitored using a suite of the state-of-the-art instruments. Health risks were evaluated in each one-year exposure period. Acrolein and nitrogen dioxide (NO2) likely caused chronic non-carcinogenic risks to residents in all exposure stages. Furthermore, the health risk of the respiratory system was proved in all age groups. For the first time, several household activities were found to cause acute health risks due to exposure to formaldehyde, benzene, NO2 and acrolein in normal urban daily life. The probability distributions of cancer risks from household activities revealed that formaldehyde was the main carcinogen with an average risk of 2.00 × 10–4, followed by benzene, acetaldehyde, ethylbenzene and dichlorobenzene. Among all indoor activities, incense burning was the largest contributor to total cancer risk (46%), as this source was respectively responsible for 47%, 54%, and 39% of cancer risks from formaldehyde, benzene, and acetaldehyde, followed by cooking and smoking. Notably, source-related health risk analysis showed that household background release dominated regardless of cancer risk (35.7–58.5%) or non-carcinogenic risk (57.1%). Further, the cancer risk from birth to 18 years was approximately 1.8–2.7 times that of 18–60 and 60–85 years of age. This study shed light on health risks posed by various household activities and highlighted the importance of indoor activities and household background release on acute and chronic health risks.
  • Publication
    Biologische Wirkungen synthetisch hergestellter Multiwall-Carbon-Nanotubes am Tiermodell und in der Zellkultur
    ( 2015)
    Hackbarth, Anja
    ;
    Steinberg, Pablo
    ;
    Dasenbrock, Clemens
    ;
    Steinberg, Pablo
    ;
    Kietzmann, Manfred
    Ziel dieser Arbeit war es zu klären, ob lange, gerade MWCNT eine asbestartige Wirkung ausüben und ob mögliche kanzerogene und andere adverse Wirkungen in in vitro Screeningtests und in vivo Tests kurzer Dauer nachweisbar sind. Dazu wurde ein Kanzerogenitätstest durchgeführt und ein BrdU Test entwickelt. In lnhalationsversuchen (Kurzzeit und 90 Tage Inhalation) sollten die Migration der MWCNT und die Clearance bestimmt werden. Zusätzlich wurden in vitro Versuche durchgeführt, welche als Screeningtest eine frühzeitige Aussage zur Toxizität bzw. Kanzerogenität liefern sollten. Mit der hier vorliegenden Arbeit konnte gezeigt werden, dass alle vier von uns im Kanzerogenitätstest getesteten MWCNT bei Ratten dosisabhängig zu einer erhöhten Mesotheliombildung und Mortalität führten. Dieses Ergebnis konnte jedoch keinen Aufschluss darüber geben, ob die Länge oder der Durchmesser der MWCNT für die Mesotheliombildung ausschlaggebend sind. Es ergaben sich aber Hinweise, dass eine eher nadelförmige und starre Struktur der MWCNT zu einer höheren Mesotheliombildung führt. Der BrdU Test nach einmaliger i.p. MWCNT Gabe ist zur Früherkennung eines möglichen kanzerogenen Potentials geeignet. Dabei zeigte sich, dass der beste Zeitpunkt für diese Bestimmung drei Monate nach Behandlung mit MWCNT war. Im subchronischen (90 Tage) lnhalationstest konnte kaum Migration der MWCNT festgestellt warden. Es wurden Makrophagenakkumulationen (partikel- bzw. faserbeladen) bei allen Behandlungsgruppen über den gesamten Beobachtungszeitraum festgestellt. Zudem wurden Entzündungsreaktionen (Mikrogranulome und Fibrosen) in den MWCNT, Printex 90 (keine Mikrogranulome) und Amosit exponierten Gruppen beobachtet. Stärker ausgeprägt waren die Befunde bei den Tieren nach Printex 90 und Amosit Inhalation. Diese Effekte waren sowohl in den MWCNT 1 als auch in den Printex 90 bzw. Amosit exponierten Tieren verglichen mit den MWCNT 2 und 3a exponierten Tieren nicht reversibel. Die Retentionsbestimmung konnte darstellen, dass MWCNT 1 und 2 exponierte Tiere eine stark verzögerte Clearance aufwiesen. MWCNT 3a exponierte Tiere zeigten eine aufarbeitungsbedingte, ungewöhnlich kurze Clearance für WHO Fasern (Längen-Durchmesserverhältnis: >= 3/1 , Länge > 5 m und Durchmesser < 3 m) von 38 Tagen. For MWCNT 3 müsste die Hydrolyse der Lungen optimiert werden. In einem Kurzzeit-lnhalationstest mit 60Co aktivierten MWCNT konnte eine Migration von MWCNT aus der Lunge zu den blutreichen Organen gemessen werden. Die starkste Migration zeigte sich nach einem Tag. Jedoch wurde ebenfalls eine hohe 60Co Aktivitat im Magen-Darm-Trakt gemessen, sodass davon ausgegangen werden muss, dass ein Großteil der MWCNT während der Inhalation von den Tieren abgeschluckt wurde. In den in vitro Tests führte besonders eine Behandlung mit MWCNT 3 zu einem erhöhten toxischen Potential im RICC Test LDH Test und Comet Assay. Als Screeningtest für in vivo Versuche scheint sich von den hier untersuchten in vitro Methoden der RICC Test am besten zu eignen, bei dem MWCNT 1, 2 und 3a zu einer Reduktion des Zellwachstums bzw. zu erhöhter Zellsterblichkeit führten. Somit können derzeit in vitro Versuche einen ersten Hinweis auf eine erhöhte Toxizität geben, jedoch sind anschließende in vivo Versuche noch unumgänglich.
  • Publication
    Incorporating potency into EU classification for carcinogenicity and reproductive toxicity
    ( 2014)
    Hennes, C.
    ;
    Batke, Monika
    ;
    Bomann, W.
    ;
    DuHayon, S.
    ;
    Kosemund, K.
    ;
    Politano, V.
    ;
    Stinchcombe, S.
    ;
    Doe, J.
    Although risk assessment, assessing the potential harm of each particular exposure of a substance, is desirable, it is not feasible in many situations. Risk assessment uses a process of hazard identification, hazard characterisation, and exposure assessment as its components. In the absence of risk assessment, the purpose of classification is to give broad guidance (through the label) on the suitability of a chemical in a range of use situations. Hazard classification in the EU is a process involving identification of the hazards of a substance, followed by comparison of those hazards (including degree of hazard) with defined criteria. Classification should therefore give guidance on degree of hazard as well as hazard identification. Potency is the most important indicator of degree of hazard and should therefore be included in classification. This is done for acute lethality and general toxicity by classifying on dose required to cause the effect. The classification in the EU for carcinogenicity and reproductive toxicity does not discriminate across the wide range of potencies seen (6 orders of magnitude) for carcinogenicity and for developmental toxicity and fertility. Therefore potency should be included in the classification process. The methodology in the EU guidelines for classification for deriving specific concentration limits is a rigorous process for assigning substances which cause tumours or developmental toxicity and infertility in experimental animals to high, medium or low degree of hazard categories by incorporating potency. Methods are suggested on how the degree of hazard so derived could be used in the EU classification process to improve hazard communication and in downstream risk management.
  • Publication
    The carcinogenic effect of various multi-walled carbon nanotubes (MWCNTs) after intraperitoneal injection in rats
    ( 2014)
    Rittinghausen, Susanne
    ;
    Hackbarth, Anja
    ;
    Creutzenberg, Otto
    ;
    Ernst, Heinrich
    ;
    Heinrich, Uwe
    ;
    Leonhardt, Albrecht
    ;
    Schaudien, Dirk
    Background: Biological effects of tailor-made multi-walled carbon nanotubes (MWCNTs) without functionalization were investigated in vivo in a two-year carcinogenicity study. In the past, intraperitoneal carcinogenicity studies in rats using biopersistent granular dusts had always been negative, whereas a number of such studies with different asbestos fibers had shown tumor induction. The aim of this study was to identify possible carcinogenic effects of MWCNTs. We compared induced tumors with asbestos-induced mesotheliomas and evaluated their relevance for humans by immunohistochemical methods. Methods: A total of 500 male Wistar rats (50 per group) were treated once by intraperitoneal injection with 109 or 5 × 109 WHO carbon nanotubes of one of four different MWCNTs suspended in artificial lung medium, which was also used as negative control. Amosite asbestos (108 WHO fibers) served as positive control. Morbid rats were sacrificed and necropsy comprising all organs was performed. Histopathological classification of tumors and, additionally, immunohistochemistry were conducted for podoplanin, pan-cytokeratin, and vimentin to compare induced tumors with malignant mesotheliomas occurring in humans. Results: Treatments induced tumors in all dose groups, but incidences and times to tumor differed between groups. Most tumors were histologically and immunohistochemically classified as malignant mesotheliomas, revealing a predominantly superficial spread on the serosal surface of the abdominal cavity. Furthermore, most tumors showed invasion of peritoneal organs, especially the diaphragm. All tested MWCNT types caused mesotheliomas. We observed highest frequencies and earliest appearances after treatment with the rather straight MWCNT types A and B. In the MWCNT C groups, first appearances of morbid mesothelioma-bearing rats were only slightly later. Later during the two-year study, we found mesotheliomas also in rats treated with MWCNT D - the most curved type of nanotubes. Malignant mesotheliomas induced by intraperitoneal injection of different MWCNTs and of asbestos were histopathologically and immunohistochemically similar, also compared with mesotheliomas in man, suggesting similar pathogenesis. Conclusion: We showed a carcinogenic effect for all tested MWCNTs. Besides aspect ratio, curvature seems to be an important parameter influencing the carcinogenicity of MWCNTs.
  • Publication
    The OSIRIS weight of evidence approach: ITS mutagenicity and ITS carcinogenicity
    ( 2013)
    Buist, Harrie
    ;
    Aldenberg, Tom
    ;
    Batke, Monika
    ;
    Escher, Sylvia
    ;
    Klein, Entink R.
    ;
    Kühne, Ralph
    ;
    Marquart, Hans
    ;
    Pauné, Eduard
    ;
    Rorije, Emiel
    ;
    Schüürmann, Gerrit
    ;
    Kroese, Dinant
    Risk assessment of chemicals usually implies data evaluation of in vivo tests in rodents to conclude on their hazards. The FP7 European project OSIRIS has developed integrated testing strategies (ITS) for relevant toxicological endpoints to avoid unnecessary animal testing and thus to reduce time and costs. This paper describes the implementation of ITS mutagenicity and carcinogenicity in the public OSIRIS webtool. The data requirements of REACH formed the basis for these ITS. The main goal was to implement procedures to reach a conclusion on the adequacy and validity of available data. For the mutagenicity ITS a quantitative Weight of Evidence approach based on Bayesian statistics was developed and implemented. The approach allows an overall quality assessment of all available data for the five types of mutagenicity data requirements: in vitro bacterial mutagenicity, in vitro and in vivo chromosome aberration, in vitro and in vivo mammalian mutagenicity. For the carcin ogenicity ITS a tool was developed to evaluate the quality of studies not conforming (entirely) to guidelines. In a tiered approach three quality aspects are assessed: documentation (reliability), study design (adequacy) and scope of examination (validity). The quality assessment is based on expert and data driven quantitative Weight of Evidence.
  • Publication
    PET/CT imaging of c-Myc transgenic mice identifies the genotoxic N-Nitroso-Diethylamine as carcinogen in a Short-Term cancer bioassay
    ( 2012)
    Hueper, K.
    ;
    Elalfy, M.
    ;
    Laenger, F.
    ;
    Halter, R.
    ;
    Rodt, T.
    ;
    Galanski, M.
    ;
    Borlak, J.
    Background: More than 100,000 chemicals are in use but have not been tested for their safety. To overcome limitations in the cancer bioassay several alternative testing strategies are explored. The inability to monitor non-invasively onset and progression of disease limits, however, the value of current testing strategies. Here, we report the application of in vivo imaging to a c-Myc transgenic mouse model of liver cancer for the development of a short-term cancer bioassay. Methodology/Principal Findings: CT and 18F-FDG PET were used to detect and quantify tumor lesions after treatment with the genotoxic carcinogen NDEA, the tumor promoting agent BHT or the hepatotoxin paracetamol. Tumor growth was investigated between the ages of 4 to 8.5 months and contrast-enhanced CT imaging detected liver lesions as well as metastatic spread with high sensitivity and accuracy as confirmed by histopathology. Significant differences in the onset of tumor growth, tumor load and glucose metabolism were observed when the NDEA treatment group was compared with any of the other treatment groups. NDEA treatment of c-Myc transgenic mice significantly accelerated tumor growth and caused metastatic spread of HCC in to lung but this treatment also induced primary lung cancer growth. In contrast, BHT and paracetamol did not promote hepatocarcinogenesis. Conclusions/Significance: The present study evidences the accuracy of in vivo imaging in defining tumor growth, tumor load, lesion number and metastatic spread. Consequently, the application of in vivo imaging techniques to transgenic animal models may possibly enable short-term cancer bioassays to significantly improve hazard identification and follow-up examinations of different organs by non-invasive methods.
  • Publication
    RITA - Registry of Industrial Toxicology Animal data: The application of historical control data for Leydig cell tumors in rats
    ( 2011)
    Nolte, T.
    ;
    Rittinghausen, S.
    ;
    Kellner, R.
    ;
    Karbe, E.
    ;
    Kittel, B.
    ;
    Rinke, M.
    ;
    Deschl, U.
    Historical data for Leydig cell tumors from untreated or vehicle treated rats from carcinogenicity studies collected in the RITA database are presented. Examples are given for analyses of these data for dependency on variables considered to be of possible influence on the spontaneous incidence of Leydig cell tumors. In the 7453 male rats available for analysis, only one case of a Leydig cell carcinoma was identified. The incidence of Leydig cell adenomas differed markedly between strains. High incidences of close to 100% have been found in F344 rats, while the mean incidence was 4.2% in Sprague-Dawley rats and 13.7% in Wistar rats. Incidences in Wistar rats were highly variable, primarily caused by different sources of animals. Mean incidences per breeder varied from 2.8 to 39.9%. Analyses for the dependency on further parameters have been performed in Wistar rats. In breeders G and I, the Leydig cell tumor incidence decreased over the observation period and with increasing mean terminal body weight. The incidence of Leydig cell tumors increased with mean age at necropsy and was higher in studies with dietary admixture compared to gavage studies. These parameters had no effect on Leydig cell tumor incidence in breeders A and B. Animals from almost all breeders had a considerably higher mean age at necropsy when bearing a Leydig cell adenoma than animals without a Leydig cell adenoma. Studies with longitudinal trimming of the testes had a higher incidence than studies with transverse trimming. The observed dependencies and breeder differences are discussed and explanations are given. Consequences for the use of historical control data are outlined. With the retrospective analyses presented here we were able to confirm the published features of Leydig cell adenomas and carcinomas. This indicates that the RITA database is a valuable tool for analyses of tumors for their biological features. Furthermore, it demonstrates that the RITA database is highly beneficial for the definition of reliable historical control data for carcinogenicity studies on a scientifically solid basis.
  • Publication
    Research recommendations for selected IARC-classified agents. Review
    ( 2010)
    Ward, E.M.
    ;
    Schulte, P.A.
    ;
    Straif, K.
    ;
    Hopf, N.B.
    ;
    Caldwell, J.C.
    ;
    Carreon, T.
    ;
    DeMarini, D.M.
    ;
    Fowler, B.A.
    ;
    Goldstein, B.D.
    ;
    Hemminki, K.
    ;
    Hines, C.J.
    ;
    Pursiainen, K.H.
    ;
    Kuempel, E.
    ;
    Lewtas, J.
    ;
    Lunn, R.M.
    ;
    Lynge, E.
    ;
    McElvenny, D.M.
    ;
    Muhle, H.
    ;
    Nakajima, T.
    ;
    Robertson, L.W.
    ;
    Rothman, N.
    ;
    Ruder, A.M.
    ;
    Schubauer-Berigan, M.K.
    ;
    Siemiatycki, J.
    ;
    Silverman, D.
    ;
    Smith, M.T.
    ;
    Sorahan, T.
    ;
    Steenland, K.
    ;
    Stevens, R.G.
    ;
    Vineis, P.
    ;
    Zahm, S.H.
    ;
    Zeise, L.
    ;
    Cogliano, V.J.
    OBJECTIVES: There are some common occupational agents and exposure circumstances for which evidence of carcinogenicity is substantial but not yet conclusive for humans. Our objectives were to identify research gaps and needs for 20 agents prioritized for review based on evidence of widespread human exposures and potential carcinogenicity in animals or humans. DATA SOURCES: For each chemical agent (or category of agents), a systematic review was conducted of new data published since the most recent pertinent International Agency for Research on Cancer (IARC) Monograph meeting on that agent. DATA EXTRACTION: Reviewers were charged with identifying data gaps and general and specific approaches to address them, focusing on research that would be important in resolving classification uncertainties. An expert meeting brought reviewers together to discuss each agent and the identified data gaps and approaches. DATA SYNTHESIS: Several overarching issues were identified that pertained to multiple agents; these included the importance of recognizing that carcinogenic agents can act through multiple toxicity pathways and mechanisms, including epigenetic mechanisms, oxidative stress, and immuno- and hormonal modulation. CONCLUSIONS: Studies in occupational populations provide important opportunities to understand the mechanisms through which exogenous agents cause cancer and intervene to prevent human exposure and/or prevent or detect cancer among those already exposed. Scientific developments are likely to increase the challenges and complexities of carcinogen testing and evaluation in the future, and epidemiologic studies will be particularly critical to inform carcinogen classification and risk assessment processes.
  • Publication
    No effects of radiofrequency radiation on 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone-induced tumorigenesis in female Wistar rats
    ( 2006)
    Heikkinen, P.
    ;
    Ernst, H.
    ;
    Huuskonen, H.
    ;
    Komulainen, H.
    ;
    Kumlin, T.
    ;
    Mäki-Paakkanen, J.
    ;
    Puranen, L.
    ;
    Juutilainen, J.
    This study evaluated possible effects of radiofrequency (RF) radiation on tumorigenesis induced by the mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) given in drinking water. Female Wistar rats aged 7 weeks at the beginning of the experiments were randomly divided into four groups of 72 animals: a cage-control group and three MX-exposed groups (a daily average dose of 1.7 mg MX/kg body weight for 104 weeks), of which two were exposed to 900 MHz pulsed RF radiation and the third served as a sham-RF-radiation group. The RF-radiation groups were exposed 2 h per day, 5 days per week for 104 weeks at nominal whole-body average SARs of 0.3 W/kg and 0.9 W/kg. Complete histopathology was performed on the rats of the three MX-exposed groups. The tumor types and incidences observed in the MX-exposed animals were similar to those reported earlier in MX-exposed female Wistar rats. RF radiation did not statistically significantly affect mortality or organ-specific incidence of any tumor type. The only statistically significant difference was an increase in the combined frequency of vascular tumors of the mesenteric lymph nodes in the high-RF-radiation group compared to the sham-RF-radiation group. However, additional histopathological analysis of the cage-control animals suggested that this difference was due to unusually low frequency of this type of tumor in the sham-RF-radiation group rather than a high frequency in the high-RF-radiation group. With respect to non-neoplastic findings, statistically significant differences between the RF-radiation groups and the sham-RF-radiation group were observed only for single findings in the lacrimal glands, lungs, liver and skin. Such changes are commonly seen in aged rats and were considered to be unrelated to RF radiation. The results of the present study do not support co-carcinogenic effects of low-level long-term RF-radiation exposure in rats.
  • Publication
    Testing of fibrous particles: Short-term assays and strategies
    ( 2005)
    Bernstein, D.
    ;
    Castranova, V.
    ;
    Donaldson, K.
    ;
    Fubini, B.
    ;
    Hadley, J.
    ;
    Hesterberg, T.
    ;
    Kane, A.
    ;
    Lai, D.
    ;
    McConnell, E.E.
    ;
    Muhle, H.
    ;
    Oberdörster, G.
    ;
    Olin, S.
    ;
    Warheit, D.B.
    This working group report is the product of the joint efforts of the members of an expert working group organized and convened by the International Life Sciences Institute Risk Science Institute. All members of the working group contributed by drafting various sections of the report. The final report emerged from extensive discussions and revisions by the working group and represents the consensus of the group on current utility and applicability of short-term assays and testing methods in screening fibers for potential toxicity. The screening strategy proposed by the working group is intended to distinguish between fibers that are unlikely to present a hazard and those that may require further testing for regulatory evaluation. The ILSI Risk Science Institute expresses it sincere thanks to the members of this working group for their tireless efforts over many months and their collegial spirit in developing this report. Financial support for this project through a cooperative agreement between the ILSI Risk Science Institute and the U. S. Environmental Protection Agency Office of Pollution Prevention and Toxics is gratefully acknowledged. The International Life Sciences Institute ( ILSI) is a nonprofit, worldwide foundation established in 1978 to advance the understanding of scientific issues relating to nutrition, food safety, toxicology, risk assessment, and the environment for the well being of the general public. ILSI receives financial support from industry, government, and foundations. The Risk Science Institute (RSI) was established in 1985 as part of the ILSI Research Foundation (RF) to improve the scientific basis of risk assessment. ILSI RF/RSI works toward this goal through an international program of scientific working groups, conferences and workshops, publications, and seminars. ILSI RF/RSI sponsors and participates in a wide range of activities to develop and disseminate new scientific knowledge, encourage exchange of ideas, and build consensus among scientists from academia, industry, government, and public interest/public health groups. ILSI RF/RSI and its programs are supported by government grants, cooperative agreements, and contracts, as well as by contributions from the ILSI Research Foundation and ILSI branches. For further information on ILSI, RF, and RSI, see the ILSI web site: www.ilsi.org.