IARC Monographs: 40 Years of Evaluating Carcinogenic Hazards to Humans

Pearce, Neil,Blair, Aaron,Vineis, Paolo,Ahrens, Wolfgang,Andersen, Aage,Anto, Josep M.,Armstrong, Bruce K.,Baccarelli, Andrea A.,Beland, Frederick A.,Berrington, Amy,Bertazzi, Pier Alberto,Birnbaum, L U.S. Dept. of Health, Education, and Welfare, Publ 2015 Environmental health perspectives Vol.123 No.6

<P>Background: Recently, the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also for the approach used to perform these evaluations. Some critics have claimed that failures of IARC Working Groups to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans.</P><P>Objectives: The authors of this Commentary are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We examined criticisms of the IARC classification process to determine the validity of these concerns. Here, we present the results of that examination, review the history of IARC evaluations, and describe how the IARC evaluations are performed.</P><P>Discussion: We concluded that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various disciplines and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed.</P><P>Conclusions: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public’s health.</P><P>Citation: Pearce N, Blair A, Vineis P, Ahrens W, Andersen A, Anto JM, Armstrong BK, Baccarelli AA, Beland FA, Berrington A, Bertazzi PA, Birnbaum LS, Brownson RC, Bucher JR, Cantor KP, Cardis E, Cherrie JW, Christiani DC, Cocco P, Coggon D, Comba P, Demers PA, Dement JM, Douwes J, Eisen EA, Engel LS, Fenske RA, Fleming LE, Fletcher T, Fontham E, Forastiere F, Frentzel-Beyme R, Fritschi L, Gerin M, Goldberg M, Grandjean P, Grimsrud TK, Gustavsson P, Haines A, Hartge P, Hansen J, Hauptmann M, Heederik D, Hemminki K, Hemon D, Hertz-Picciotto I, Hoppin JA, Huff J, Jarvholm B, Kang D, Karagas MR, Kjaerheim K, Kjuus H, Kogevinas M, Kriebel D, Kristensen P, Kromhout H, Laden F, Lebailly P, LeMasters G, Lubin JH, Lynch CF, Lynge E, ‘t Mannetje A, McMichael AJ, McLaughlin JR, Marrett L, Martuzzi M, Merchant JA, Merler E, Merletti F, Miller A, Mirer FE, Monson R, Nordby KC, Olshan AF, Parent ME, Perera FP, Perry MJ, Pesatori AC, Pirastu R, Porta M, Pukkala E, Rice C, Richardson DB, Ritter L, Ritz B, Ronckers CM, Rushton L, Rusiecki JA, Rusyn I, Samet JM, Sandler DP, de Sanjose S, Schernhammer E, Seniori Costantini A, Seixas N, Shy C, Siemiatycki J, Silverman DT, Simonato L, Smith AH, Smith MT, Spinelli JJ, Spitz MR, Stallones L, Stayner LT, Steenland K, Stenzel M, Stewart BW, Stewart PA, Symanski E, Terracini B, Tolbert PE, Vainio H, Vena J, Vermeulen R, Victora CG, Ward EM, Weinberg CR, Weisenburger D, Wesseling C, Weiderpass E, Zahm SH. 2015. IARC Monographs: 40 years of evaluating carcinogenic hazards to humans. Environ Health Perspect 123:507–514; http://dx.doi.org/10.1289/ehp.1409149</P>

Combining PM _2.5 Component Data from Multiple Sources: Data Consistency and Characteristics Relevant to Epidemiological Analyses of Predicted Long-Term Exposures

Kim, Sun-Young,Sheppard, Lianne,Larson, Timothy V.,Kaufman, Joel D.,Vedal, Sverre U.S. Dept. of Health, Education, and Welfare, Publ 2015 Environmental health perspectives Vol.123 No.7

<P><B>Background</B></P><P>Regulatory monitoring data have been the exposure data resource most commonly applied to studies of the association between long-term PM<SUB>2.5</SUB> components and health. However, data collected for regulatory purposes may not be compatible with epidemiological studies.</P><P><B>Objectives</B></P><P>We studied three important features of the PM<SUB>2.5</SUB> component monitoring data to determine whether it would be appropriate to combine all available data from multiple sources for developing spatiotemporal prediction models in the National Particle Component and Toxicity (NPACT) study.</P><P><B>Methods</B></P><P>The NPACT monitoring data were collected in an extensive monitoring campaign targeting cohort participant residences. The regulatory monitoring data were obtained from the Chemical Speciation Network (CSN) and the Interagency Monitoring of Protected Visual Environments (IMPROVE). We performed exploratory analyses to examine features that could affect our approach to combining data: comprehensiveness of spatial coverage, comparability of analysis methods, and consistency in sampling protocols. In addition, we considered the viability of developing spatiotemporal prediction models given <I>a</I>) all available data, <I>b</I>) NPACT data only, and <I>c</I>) NPACT data with temporal trends estimated from other pollutants.</P><P><B>Results</B></P><P>The number of CSN/IMPROVE monitors was limited in all study areas. The different laboratory analysis methods and sampling protocols resulted in incompatible measurements between networks. Given these features we determined that it was preferable to develop our spatiotemporal models using only the NPACT data and under simplifying assumptions.</P><P><B>Conclusions</B></P><P>Investigators conducting epidemiological studies of long-term PM<SUB>2.5</SUB> components need to be mindful of the features of the monitoring data and incorporate this understanding into the design of their monitoring campaigns and the development of their exposure prediction models.</P><P><B>Citation</B></P><P>Kim SY, Sheppard L, Larson TV, Kaufman JD, Vedal S. 2015. Combining PM<SUB>2.5</SUB> component data from multiple sources: data consistency and characteristics relevant to epidemiological analyses of predicted long-term exposures. Environ Health Perspect 123:651–658; http://dx.doi.org/10.1289/ehp.1307744</P>

Structural Basis for Depletion of Heat Shock Protein 90 Client Proteins by Deguelin

Oh, S. H.,Woo, J. K.,Yazici, Y. D.,Myers, J. N.,Kim, W.-Y.,Jin, Q.,Hong, S. S.,Park, H.-J.,Suh, Y.-G.,Kim, K.-W.,Hong, W. K.,Lee, H.-Y. U.S. Dept. of Health, Education, and Welfare, Publ 2007 Journal of the National Cancer Institute Vol.99 No.12

Induced Phenotype Targeted Therapy: Radiation-Induced Apoptosis-Targeted Chemotherapy

Lee, Beom Suk,Cho, Yong Woo,Kim, Gui Chul,Lee, Do Hee,Kim, Chang Jin,Kil, Hee Seup,Chi, Dae Yoon,Byun, Youngro,Yuk, Soon Hong,Kim, Kwangmeyung,Kim, In-San,Kwon, Ick Chan,Kim, Sang Yoon U.S. Dept. of Health, Education, and Welfare, Publ 2015 Journal of the National Cancer Institute Vol.107 No.2

<P><B>Background:</B></P><P>Tumor heterogeneity and evolutionary complexity may underlie treatment failure in spite of the development of many targeted agents. We suggest a novel strategy termed induced phenotype targeted therapy (IPTT) to simplify complicated targets because of tumor heterogeneity and overcome tumor evolutionary complexity.</P><P><B>Methods:</B></P><P>We designed a caspase-3 specific activatable prodrug, DEVD-S-DOX, containing doxorubicin linked to a peptide moiety (DEVD) cleavable by caspase-3 upon apoptosis. To induce apoptosis locally in the tumor, we used a gamma knife, which can irradiate a very small, defined target area. The in vivo antitumor activity of the caspase-3–specific activatable prodrug combined with radiation was investigated in C3H/HeN tumor-bearing mice (n = 5 per group) and analyzed with the Student’s <I>t</I> test or Mann-Whitney U test. All statistical tests were two-sided. We confirmed the basic principle using a caspase-sensitive nanoprobe (Apo-NP).</P><P><B>Results:</B></P><P>A single exposure of radiation was able to induce apoptosis in a small, defined region of the tumor, resulting in expression of caspase-3. Caspase-3 cleaved DEVD and activated the prodrug. The released free DOX further activated DEVD-S-DOX by exerting cytotoxic effects on neighboring tumor or supporting cells, which repetitively induced the expression of caspase-3 and the activation of DEVD-S-DOX. This sequential and repetitive process propagated the induction of apoptosis. This novel therapeutic strategy showed not only high efficacy in inhibiting tumor growth (14-day tumor volume [mm<SUP>3</SUP>] vs radiation alone: 848.21±143.24 vs 2511.50±441.89, <I>P</I> < .01) but also low toxicity to normal cells and tissues.</P><P><B>Conclusion:</B></P><P>Such a phenotype induction strategy represents a conceptually novel approach to overcome tumor heterogeneity and complexity as well as to substantially improve current conventional chemoradiotherapy with fewer sequelae and side effects.</P>

Mortality among Pesticide Applicators Exposed to Chlorpyrifos in the Agricultural Health Study

Lee, Won Jin,Alavanja, Michael C.R.,Hoppin, Jane A.,Rusiecki, Jennifer A.,Kamel, Freya,Blair, Aaron,Sandler, Dale P. U.S. Dept. of Health, Education, and Welfare, Publ 2007 Environmental health perspectives Vol. No.

<P><B>Background</B></P><P>Chlorpyrifos is one of the most widely used organophosphate insecticides in the United States. Although the toxicity of chlorpyrifos has been extensively studied in animals, the epidemiologic data are limited.</P><P><B>Objective</B></P><P>To evaluate whether agricultural chlorpyrifos exposure was associated with mortality, we examined deaths among pesticide applicators in the Agricultural Health Study, a prospective study of licensed pesticide applicators in Iowa and North Carolina.</P><P><B>Methods</B></P><P>A total of 55,071 pesticide applicators were included in this analysis. Detailed pesticide exposure data and other information were obtained from self-administered questionnaires completed at the time of enrollment (1993–1997). Lifetime chlorpyrifos use was divided into tertiles. Poisson regression analysis was used to evaluate the exposure–response relationships between chlorpyrifos use and causes of death after adjustment for potential confounders.</P><P><B>Results</B></P><P>A total of 1,851 deaths (588 among chlorpyrifos users) were observed during the study period, 1993–2001. The relative risk (RR) of death from all causes combined among applicators exposed to chlorpyrifos was slightly lower than that for nonexposed applicators (RR = 0.90; 95% confidence interval, 0.81–1.01). For most causes of death analyzed, there was no evidence of an exposure–response relationship. However, the relative risks for mortality from suicide and non-motor-vehicle accidents were increased 2-fold in the highest category of chlorpyrifos exposure days.</P><P><B>Conclusions</B></P><P>Our findings of a possible association between chlorpyrifos use and external causes of death were based on small numbers. However, the findings may reflect a link between chlorpyrifos and depression or other neurobehavioral symptoms that deserves further evaluation.</P>

Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases

Jeong, Han-Sin,Jones, Dennis,Liao, Shan,Wattson, Daniel A.,Cui, Cheryl H.,Duda, Dan G.,Willett, Christopher G.,Jain, Rakesh K.,Padera, Timothy P. U.S. Dept. of Health, Education, and Welfare, Publ 2015 Journal of the National Cancer Institute Vol.107 No.9

<P><B>Background:</B></P><P>To date, antiangiogenic therapy has failed to improve overall survival in cancer patients when used in the adjuvant setting (local-regional disease with no detectable systemic metastasis). The presence of lymph node metastases worsens prognosis, however their reliance on angiogenesis for growth has not been reported.</P><P><B>Methods:</B></P><P>Here, we introduce a novel chronic lymph node window (CLNW) model to facilitate new discoveries in the growth and spread of lymph node metastases. We use the CLNW in multiple models of spontaneous lymphatic metastases in mice to study the vasculature of metastatic lymph nodes (n = 9–12). We further test our results in patient samples (n = 20 colon cancer patients; n = 20 head and neck cancer patients). Finally, we test the ability of antiangiogenic therapy to inhibit metastatic growth in the CLNW. All statistical tests were two-sided.</P><P><B>Results:</B></P><P>Using the CLNW, we reveal the surprising lack of sprouting angiogenesis during metastatic growth, despite the presence of hypoxia in some lesions. Treatment with two different antiangiogenic therapies showed no effect on the growth or vascular density of lymph node metastases (day 10: untreated mean = 1.2%, 95% confidence interval [CI] = 0.7% to 1.7%; control mean = 0.7%, 95% CI = 0.1% to 1.3%; DC101 mean = 0.4%, 95% CI = 0.0% to 3.3%; sunitinib mean = 0.5%, 95% CI = 0.0% to 1.0%, analysis of variance <I>P</I> = .34). We confirmed these findings in clinical specimens, including the lack of reduction in blood vessel density in lymph node metastases in patients treated with bevacizumab (no bevacizumab group mean = 257 vessels/mm<SUP>2</SUP>, 95% CI = 149 to 365 vessels/mm<SUP>2</SUP>; bevacizumab group mean = 327 vessels/mm<SUP>2</SUP>, 95% CI = 140 to 514 vessels/mm<SUP>2</SUP>, <I>P</I> = .78).</P><P><B>Conclusion:</B></P><P>We provide preclinical and clinical evidence that sprouting angiogenesis does not occur during the growth of lymph node metastases, and thus reveals a new mechanism of treatment resistance to antiangiogenic therapy in adjuvant settings. The targets of clinically approved angiogenesis inhibitors are not active during early cancer progression in the lymph node, suggesting that inhibitors of sprouting angiogenesis as a class will not be effective in treating lymph node metastases.</P>

EphA2 immunoconjugate as molecularly targeted chemotherapy for ovarian carcinoma.

Lee, Jeong-Won,Han, Hee Dong,Shahzad, Mian M K,Kim, Seung Wook,Mangala, Lingegowda S,Nick, Alpa M,Lu, Chunhua,Langley, Robert R,Schmandt, Rosemarie,Kim, Hye-Sun,Mao, Shenlan,Gooya, John,Fazenbaker, Ch U.S. Dept. of Health, Education, and Welfare, Publ 2009 Journal of the National Cancer Institute Vol.101 No.17

<P>EphA2 is overexpressed in many types of human cancer but is absent or expressed at low levels in normal epithelial tissues. We investigated whether a novel immunoconjugate containing an anti-EphA2 monoclonal antibody (1C1) linked to a chemotherapeutic agent (monomethyl auristatin phenylalanine [MMAF]) through a noncleavable linker maleimidocaproyl (mc) had antitumor activity against ovarian cancer cell lines and tumor models.</P>

Female Breast Cancer Incidence Among Asian and Western Populations: More Similar Than Expected

Sung, Hyuna,Rosenberg, Philip S.,Chen, Wan-Qing,Hartman, Mikael,Lim, Wei-yen,Chia, Kee Seng,Wai-Kong Mang, Oscar,Chiang, Chun-Ju,Kang, Daehee,Ngan, Roger Kai-Cheong,Tse, Lap Ah,Anderson, William F.,Ya U.S. Dept. of Health, Education, and Welfare, Publ 2015 Journal of the National Cancer Institute Vol.107 No.7

<P><B>Background:</B></P><P>Previous reports suggested that female breast cancer is associated with earlier ages at onset among Asian than Western populations. However, most studies utilized cross-sectional analyses that may be confounded by calendar-period and/or birth cohort effects. We, therefore, considered a longitudinal (forward-looking) approach adjusted for calendar-period changes and conditioned upon birth cohort.</P><P><B>Methods:</B></P><P>Invasive female breast cancer data (1988–2009) were obtained from cancer registries in China, Hong Kong, South Korea, Taiwan, Singapore, and the United States. Age-period-cohort models were used to extrapolate longitudinal age-specific incidence rates for the 1920, 1944, and 1970 birth cohorts.</P><P><B>Results:</B></P><P>Cross-sectional age-specific incidence rates rose continuously until age 80 years among US white women, but plateaued or decreased after age 50 years among Asian women. In contrast, longitudinal age-specific rates were proportional (similar) among all Asian countries and the United States with incidence rates rising continuously until age 80 years. The extrapolated estimates for the most recent cohorts in some Asian countries actually showed later ages at onset than in the United States. Additionally, over successive birth cohorts, the incidence rate ratios (IRRs) for the longitudinal curves converged (narrowed) between Asian and US white women.</P><P><B>Conclusions:</B></P><P>Similar longitudinal age-specific incidence rates along with converging IRRs indicate that the age effects for invasive breast cancer are more similar among Asian and Western populations than might be expected from a solely cross-sectional analysis. Indeed, the Asian breast cancer rates in recent generations are even surpassing the historically high rates in the United States, highlighting an urgent need for efficient prevention and treatment strategies among Asian populations.</P>

Longer-Term Impact of High and Low Temperature on Mortality: An International Study to Clarify Length of Mortality Displacement

Armstrong, Ben,Bell, Michelle L.,de Sousa Zanotti Stagliorio Coelho, Micheline,Leon Guo, Yue-Liang,Guo, Yuming,Goodman, Patrick,Hashizume, Masahiro,Honda, Yasushi,Kim, Ho,Lavigne, Eric,Michelozzi, Pao U.S. Dept. of Health, Education, and Welfare, Publ 2017 Environmental health perspectives Vol.125 No.10

<P><B>Background:</B></P><P>In many places, daily mortality has been shown to increase after days with particularly high or low temperatures, but such daily time-series studies cannot identify whether such increases reflect substantial life shortening or short-term displacement of deaths (harvesting).</P><P><B>Objectives:</B></P><P>To clarify this issue, we estimated the association between annual mortality and annual summaries of heat and cold in 278 locations from 12 countries.</P><P><B>Methods:</B></P><P>Indices of annual heat and cold were used as predictors in regressions of annual mortality in each location, allowing for trends over time and clustering of annual count anomalies by country and pooling estimates using meta-regression. We used two indices of annual heat and cold based on preliminary standard daily analyses: <I>a</I>) mean annual degrees above/below minimum mortality temperature (MMT), and <I>b</I>) estimated fractions of deaths attributed to heat and cold. The first index was simpler and matched previous related research; the second was added because it allowed the interpretation that coefficients equal to 0 and 1 are consistent with none (0) or all (1) of the deaths attributable in daily analyses being displaced by at least 1 y.</P><P><B>Results:</B></P><P>On average, regression coefficients of annual mortality on heat and cold mean degrees were 1.7% [95% confidence interval (CI): 0.3, 3.1] and 1.1% (95% CI: 0.6, 1.6) per degree, respectively, and daily attributable fractions were 0.8 (95% CI: 0.2, 1.3) and 1.1 (95% CI: 0.9, 1.4). The proximity of the latter coefficients to 1.0 provides evidence that most deaths found attributable to heat and cold in daily analyses were brought forward by at least 1 y. Estimates were broadly robust to alternative model assumptions.</P><P><B>Conclusions:</B></P><P>These results provide strong evidence that most deaths associated in daily analyses with heat and cold are displaced by at least 1 y. https://doi.org/10.1289/EHP1756</P>

Serum Levels of Persistent Organic Pollutants and Insulin Secretion among Children Age 7–9 Years: A Prospective Cohort Study

Park, Su Hyun,Ha, Eunhee,Hong, Young Sun,Park, Hyesook U.S. Dept. of Health, Education, and Welfare, Publ 2016 Environmental health perspectives Vol.124 No.12

<P><B>Background:</B></P><P>Persistent organic pollutants (POPs) are endocrine disruptors and have been suggested as possible risk factors for diabetes. Few studies have been performed to investigate this association among children.</P><P><B>Objectives:</B></P><P>In this study, we prospectively examined the relationship between the serum concentration of POPs and glucose metabolism in children.</P><P><B>Methods:</B></P><P>Data were collected from the Ewha Birth & Growth Cohort Study, an ongoing birth cohort study initially constructed between 2001 and 2006. In 2010–2012, the POP concentration was measured in serum from a total of 214 children, 7–9 years of age. Using fasting glucose and insulin measurements at both baseline and the second year of follow-up, the homeostatic model assessment of beta-cell function (HOMA-β) and homeostatic model assessment of insulin resistance (HOMA-IR) were calculated. Multiple linear regression analysis and a linear mixed-effects model were used to determine the relationship between POP tertiles and metabolic biomarkers.</P><P><B>Results:</B></P><P>Compared with the lowest tertile of total marker PCBs, participants in the third tertile had decreased HOMA-β values, after adjustment for age, sex, body mass index z-score, mother’s education, ponderal index, and history of breastfeeding (–18.94%; 95% CI: –32.97%, –1.98%). In a linear mixed model, the HOMA-β values were still lower in subjects in the highest compared with the lowest tertile of total PCBs at the 2-year follow-up period (108.3 vs. 135.0, respectively).</P><P><B>Conclusion:</B></P><P>The results of the study suggested that exposure to POPs among children might affect insulin secretory function, which could lead to an increased risk of developing diabetes.</P><P><B>Citation:</B></P><P>Park SH, Ha EH, Hong YS, Park H. 2016. Serum levels of persistent organic pollutants and insulin secretion among children age 7–9 years: a prospective cohort study. Environ Health Perspect 124:1924–1930; http://dx.doi.org/10.1289/EHP147</P>