Center for Environmental Oncology

Selected Publications by Center Researchers

Devra L Davis, PhD, MPH - BIO

Ancillary human health benefits of improved air quality resulting from climate change mitigation - Read abstract >

Declines in Sex Ratio At Birth and Fetal Deaths in Japan, and in U.S. Whites But Not African Americans - Read abstract >

The limits of 2-Year Bioassay Exposure Regimens for Identifying Chemical Carcinogens - Read abstract >

Natural and other experiments: the secret history of the war on cancer - Website (Full text articles not currently available online)

The Need to Develop Centers for Environmental Oncology - Read abstract >

Redefining normal age of breast growth obscures potential environmental causes - Read more >

Personal care products that contain estrogens or xenoestrogens may increase breast cancer risk - Read abstract >

Aspartame and Incidence of Brain Malignancies - Read more >

Evelyn Talbott, DrPH - BIO

Association between biomarkers of environmental exposure and increased risk of breast cancer - Read more >

Connecting environmental health data to people and policy: integrating information and mobilizing communities for environmental public health tracking - Read abstract >

Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome - Read abstract >

Polycystic ovarian syndrome (PCOS): a significant contributor to the overall burden of type 2 diabetes in women - Read abstract >

Jean Latimer, PhD

Association between biomarkers of environmental exposure and increased risk of breast cancer - Read more >

Jonathan Weinkle, MD

Aspartame and Incidence of Brain Malignancies - Read more >

Index of Suspicion in the Nursery - Read abstract >

Maryann Donovan, PhD, MPH - BIO

Association between biomarkers of environmental exposure and increased risk of breast cancer - Read more >

The Need to Develop Centers for Environmental Oncology - Read abstract >

Personal care products that contain estrogens or xenoestrogens may increase breast cancer risk - Read abstract >

Redefining normal age of breast growth obscures potential environmental causes - Read more >

Talal El-Hefnawy, MD, PhD

Autoantibody profiles reveal ubiquilin 1 as a humoral immune response target in lung adenocarcinoma - Read abstract >

Cross-reactive CD4+ T cells against one immunodominant tumor-derived epitope in melanoma patients - Read abstract >

Optimal markers for real-time quantitative reverse transcription PCR detection of circulating tumor cells from melanoma, breast, colon, esophageal, head and neck, and lung cancers - Read abstract >

Non-Center Researchers - Related Publications

Blum A. 2007. The fire retardant dilemma. Science 318(5848):194b-195.

Burger J, Gochfeld M, Jeitner C, Snigaroff D, Snigaroff R, Stamm T, Volz C. Assessment of metals in down feathers of female common eiders and their eggs from the Aleutians: arsenic, cadmium, chromium, lead, manganese, mercury, and selenium. Environ Monit Assess (2007) Oct 13.

Burger J, Gochfeld M, Kosson D, Powers CW, Friedlander B, Stabin M, Favret D, Jewett S, Snigaroff D, Snigaroff R, Stamm T, Weston J, Jeitner C, Volz C. Radionuclides in marine fishes and birds from Amchitka and Kiska Islands in the Aleutians: establishing a baseline. Health Phys. 2007 Mar; 92(3):265-79.

Burger J, Gochfeld M, Shukla T, Jeitner C, Burke S, Donio M, Shukla S, Snigaroff R, Snigaroff D, Stamm T, Volz C. Heavy metals in Pacific cod (Gadus macrocephalus) from the Aleutians: location, age, size, and risk. J Toxicol Environ Health A. 2007 Nov; 70(22):1897-911.

Clapp R, Howe G, Jacobs Lefevre M. Environmental and occupational causes of cancer: A review of recent scientific literature. Lowell, MA: Lowell Center for Sustainable Production, University of Massachusetts Lowell; 2005.

Kunz G, Klein K, Clemons R, Gottschalk M, Jones K. Virilization of young children after topical androgen use by their parents. Pediatrics 2004; 114: 282-4.

Li S, Lozano P, Grossman D, Graham E. Hormone-containing hair product use in prepubertal children. Archives of Pediatric & Adolescent Medicine 2002; 156: 85-6.

Volz, CD, 2008. Southwestern Pennsylvania's Water Quality Problems and How to Address Them Regionally. Eds Miller, T, Gorley, T, and Barron, B, Institute of Politics, University of Pittsburgh. [PDF]

Ancillary human health benefits of improved air quality resulting from climate change mitigation

Greenhouse gas (GHG) mitigation policies can provide ancillary benefits in terms of short-term improvements in air quality and associated health benefits. Several studies have analyzed the ancillary impacts of GHG policies for a variety of locations, pollutants, and policies. In this paper we review the existing evidence on ancillary health benefits relating to air pollution from various GHG strategies and provide a framework for such analysis.

We evaluate techniques used in different stages of such research for estimation of: (1) changes in air pollutant concentrations; (2) avoided adverse health endpoints; and (3) economic valuation of health consequences. The limitations and merits of various methods are examined. Finally, we conclude with recommendations for ancillary benefits analysis and related research gaps in the relevant disciplines.

We found that to date most assessments have focused their analysis more heavily on one aspect of the framework (e.g., economic analysis). While a wide range of methods was applied to various policies and regions, results from multiple studies provide strong evidence that the short-term public health and economic benefits of ancillary benefits related to GHG mitigation strategies are substantial. Further, results of these analyses are likely to be underestimates because there are a number of important unquantified health and economic endpoints.

Remaining challenges include integrating the understanding of the relative toxicity of particulate matter by components or sources, developing better estimates of public health and environmental impacts on selected sub-populations, and devising new methods for evaluating heretofore unquantified and non-monetized benefits.

Bell ML, Davis DL, Cifuentes LA, Krupnick AJ, Morgenstern RD, and Thurston GD. Ancillary human health benefits of improved air quality resulting from climate change mitigation. Environmental Health 2008, 7:41.

Aspartame and Incidence of Brain Malignancies

Davis D, Ganter L, Weinkle J. Aspartame and Incidence of Brain Malignancies. Cancer Epidemiol Biomarkers Prev. 2008 17:1295-1296. [Full Text] [PDF]

Association between biomarkers of environmental exposure and increased risk of breast cancer

Donovan M, Miles T, Latimer J, Grant S, Talbott E, Sasco A, et al. Association between biomarkers of environmental exposure and increased risk of breast cancer. Nature Review Cancer. 6(8), Correspondence.

The article was a response to: Winn, D. The Long Island Breast Cancer Study Project. Nature Rev. Cancer 5, 986-994 (2005).
The original author replied: Winn, D. Association between biomarkers of environmental exposure and increased risk of breast cancer. Nat Rev Cancer. 6(8), Correspondence.

Autoantibody profiles reveal ubiquilin 1 as a humoral immune response target in lung adenocarcinoma

There is considerable evidence that the presence of cancer can elicit a humoral immune response to specific proteins in the host, and these resulting autoantibodies may have potential as noninvasive biomarkers. To characterize the autoantibody repertoire present in the sera of patients with lung adenocarcinoma, we developed a high-density peptide microarray derived from biopanning a lung cancer phage display library. Using a 2,304-element microarray, we interrogated a total of 250 sera from Michigan lung cancer patients and noncancer controls to develop an "autoantibody profile" of lung adenocarcinoma. A set of 22 discriminating peptides derived from a training set of 125 serum samples from lung adenocarcinoma patients and control subjects was found to predict cancer status with 85% sensitivity and 86% specificity in an independent test set of 125 sera. Sequencing of the immunoreactive phage-peptide clones identified candidate humoral immune response targets in lung adenocarcinoma, including ubiquilin 1, a protein that regulates the degradation of several ubiquitin-dependent proteasome substrates. An independent validation set of 122 serum samples from Pittsburgh was examined using two overlapping clones of ubiquilin 1 that showed 0.79 and 0.74 of the area under the receiver operating characteristics curve, respectively. Significantly increased levels of both ubiquilin 1 mRNA and protein, as well as reduced levels of the phosphorylated form of this protein, were detected in lung tumors. Immunofluorescence using anti-ubiquilin 1 antibodies confirmed intracellular expression within tumors cells. These studies indicate that autoantibody profiles, as well as individual candidates, may be useful for the noninvasive detection of lung adenocarcinoma.

Chen G, Wang X, Yu J, Varambally S, Yu J, Thomas DG, Lin MY, Vishnu P, Wang Z, Wang R, Fielhauer J, Ghosh D, Giordano TJ, Giacherio D, Chang AC, Orringer MB, El-Hefnawy T, Bigbee WL, Beer DG, Chinnaiyan AM. Autoantibody profiles reveal ubiquilin 1 as a humoral immune response target in lung adenocarcinoma. Cancer Res. 2007 Apr 1;67(7):3461-7.

Connecting environmental health data to people and policy: integrating information and mobilizing communities for environmental public health tracking

Evaluation of available data is a critical preliminary step in the assessment of local environmental health. As part of a multi-organizational initiative to improve environmental health in the Pittsburgh, Pennsylvania region, the University of Pittsburgh Center for Healthy Environments and Communities (CHEC) interviewed 70 experts in the academic, government, non-profit, and private sectors and reviewed print and electronic resources to characterize environmental and public health data available in the region. The objectives of this undertaking were: to provide a conceptual framework for categorizing data locally on environmental hazards, exposures and health endpoints, to describe and evaluate the types of environmental public health data available nationally and locally, to identify existing endeavors to gather and categorize such data, and to present case studies on the real-life relevance of the availability or lack of availability of environmental health data. The purpose and relevance of this project, the evolution of the methodology, successes and challenges met, and anticipated next steps are presented. This process description and resulting comprehensive report is available to communities, at both the state and local health department level as well as lay community members, engaged in similar endeavors, to characterize their local and regional environmental health landscape. The framework outlined serves as background for a related statewide environmental health project sponsored by the Pennsylvania Department of Health through the Pennsylvania Consortium on Interdisciplinary Environmental Policy (PCIEP) and potentially as a foundation for community-based data evaluation for the National Environmental Public Health Tracking Program.

Ali R, Wheitner D, Talbott EO, Zborowski JV. Connecting environmental health data to people and policy: integrating information and mobilizing communities for environmental public health tracking. J Community Health. 2007 Oct;32(5):357-74.

Cross-reactive CD4+ T cells against one immunodominant tumor-derived epitope in melanoma patients

TCRs exhibit a high degree of specificity but may also recognize multiple and distinct peptide-MHC complexes, illustrating the so-called cross-reactivity of TCR-peptide-MHC recognition. In this study, we report the first evidence of CD4(+) T cells recognizing the same tumor peptide-epitope from NY-ESO-1, in the context of multiple HLA-DR and HLA-DP molecules. These cross-reactive CD4(+) T cells recognized not only autologous but also allogenic dendritic cells previously loaded with the relevant protein (i.e., the normally processed and presented epitope). Using clonotypic real-time RT-PCR, we have detected low frequencies of CD4(+) T cells expressing one cross-reactive TCR from circulating CD4(+) T cells of patients with stage IV melanoma either spontaneously or after immunization but not in normal donors. The maintenance of cross-reactive tumor Ag-specific CD4(+) T cells in PBLs of cancer patients required the presence of tumor Ag/epitope in the context of the MHC molecule used to prime the Ag-specific CD4(+) T cells. Our findings have significant implications for the optimization of TCR gene transfer immunotherapies widely applicable to cancer patients.

Kudela P, Janjic B, Fourcade J, Castelli F, Andrade P, Kirkwood JM, El-Hefnawy T, Amicosante M, Maillere B, Zarour HM. Cross-reactive CD4+ T cells against one immunodominant tumor-derived epitope in melanoma patients. J Immunol. 2007 Dec 1;179(11):7932-40.

Declines in Sex Ratio At Birth and Fetal Deaths in Japan, and in U.S. Whites But Not African Americans

Background: The expected ratio of male to female births is generally believed to be 1.05, also described as the male proportion of 0.515.

Objectives: We describe trends in sex ratio at birth and in fetal deaths in the United States, in African Americans and in whites, and in Japan, two industrial countries with well-characterized health data infrastructures, and we speculate about possible explanations.

Methods: Public health records from national statistical agencies were assembled to create information on sex ratio at birth and in fetal deaths in the United States (1970-2002) and Japan (1970-1999) , using SPSS.

Results: Sex ratio at birth has declined significantly in Japan and in U.S. whites, but not for African Americans, for whom sex ratio remains significantly lower than that of whites. The male proportion of fetal death has increased overall in Japan and in the United States.

Conclusions: Sex ratio declines are equivalent to a shift from male to female births of 135,000 white males in the United States and 127,000 males in Japan. Known and hypothesized risk factors for reduced sex ratio at birth and in fetal deaths cannot account fully for recent trends or racial or national differences. Whether avoidable environmental or other factors-such as widespread exposure to metalloestrogens or other known or suspected endocrine-disrupting materials, changes in parental age, obesity, assisted reproduction, or nutrition-may account for some of these patterns is a matter that merits serious concern.

Davis, D, Webster P, Stainthorpe H, Chilton J, Jones L, Doi R. Declines in Sex Ratio At Birth and Fetal Deaths in Japan, and in U.S. Whites But Not African Americans. Environmental Health Perspectives 115 (2007): 941-946.

Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) exhibit an adverse cardiovascular risk profile, characteristic of the metabolic cardiovascular syndrome (MCS). The aim of this study was to determine the prevalence of coronary artery (CAC) and aortic (AC) calcification among middle-aged PCOS cases and controls and to explore the relationship among calcification, MCS, and other cardiovascular risk factors assessed 9 yr earlier. This was a prospective study of 61 PCOS cases and 85 similarly aged controls screened in 1993-1994 for risk factors and reevaluated in 2001-2002. The main outcome measures were CAC and AC, measured by electron beam tomography. Women with PCOS had a higher prevalence of CAC (45.9% vs. 30.6%) and AC (68.9% vs. 55.3%) than controls. After adjustment for age and body mass index, PCOS was a significant predictor of CAC (odds ratio = 2.31; P = 0.049). PCOS subjects were also 4.4 times more likely to meet the criteria for MCS than controls. High-density lipoprotein cholesterol and insulin appeared to mediate the PCOS influence on CAC. Interestingly, total testosterone was an independent risk factor for AC in all subjects after controlling for PCOS, age, and body mass index (P = 0.034). We conclude that women with PCOS are at increased risk of MCS and demonstrate increased CAC and AC compared with controls. Components of MCS mediate the association between PCOS and CAC, independently of obesity.

Talbott EO, Zborowski JV, Rager JR, Boudreaux MY, Edmundowicz DA, Guzick DS. Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2004 Nov;89(11):5454-61.

Index of Suspicion in the Nursery

Weinkle J, Compomizzi M, Kloesz M. Index of Suspicion in the Nursery. NeoReviews Vol.7 No.8 2006 e440.

Optimal markers for real-time quantitative reverse transcription PCR detection of circulating tumor cells from melanoma, breast, colon, esophageal, head and neck, and lung cancers

BACKGROUND: The detection of circulating tumor cells (CTCs) may prove useful for screening, prognostication, and monitoring of response to therapy. However, given the large background of circulating cells, it is probably necessary to detect 1 cancer cell in >10(6) leukocytes. Although reverse transcription (RT)-PCR is potentially sensitive and specific enough to achieve this goal, success will require the use of appropriate mRNA markers. The goal of this study was to identify optimal marker combinations for detection of CTCs. METHODS: An extensive literature and internet database survey was conducted to identify potential markers. We then used real-time quantitative RT-PCR to test for expression of selected potential markers in tissue samples from primary tumors of breast, colon, esophagus, head and neck, lung, and melanoma and normal blood samples. Markers with high expression in tumors and a median 1000-fold lower expression in normal blood were considered potentially useful for CTC detection and were tested further in an expanded sample set. RESULTS: A total of 52 potential markers were screened, and 3-8 potentially useful markers were identified for each tumor type. The mRNAs for all but 2 markers were found in normal blood. Marker combinations were identified for each tumor type that had a minimum 1000-fold higher expression in tumors than in normal blood. CONCLUSIONS: Several mRNA markers may be useful for RT-PCR-based detection of CTCs from each of 6 cancer types. Quantification of these mRNAs is essential to distinguish normal expression in blood from that due to the presence of CTCs. Few markers provide adequate sensitivity individually, but combinations of markers may produce good sensitivity for detection of the presence of these 6 neoplasms.

Xi L, Nicastri DG, El-Hefnawy T, Hughes SJ, Luketich JD, Godfrey TE. Optimal markers for real-time quantitative reverse transcription PCR detection of circulating tumor cells from melanoma, breast, colon, esophageal, head and neck, and lung cancers. Clin Chem. 2007 Jul;53(7):1206-15. Epub 2007 May 24.

Personal care products that contain estrogens or xenoestrogens may increase breast cancer risk

Established models of breast cancer risk, such as the Gail model, do not account for patterns of the disease in women under the age of 35, especially in African Americans. With the possible exceptions of ionizing radiation or inheriting a known genetic mutation, most of the known risk factors for breast cancer are related to cumulative lifetime exposure to estrogens. Increased risk of breast cancer has been associated with earlier onset of menses or later age at menopause, nulliparity or late first parity, use of hormonal contraceptives or hormone replacement therapy, shorter lactation history, exposure to light at night, obesity, and regular ingestion of alcohol, all of which increase circulating levels of unbound estradiol. Among African Americans at all ages, use of hormone-containing personal care products (PCPs) is more common than among whites, as is premature appearance of secondary sexual characteristics among infants and toddlers. We hypothesize that the use of estrogen and other hormone-containing PCPs in young African American women accounts, in part, for their increased risk of breast cancer prior to menopause, by subjecting breast buds to elevated estrogen exposure during critical windows of vulnerability in utero and in early life. These early life and continuing exposures to estrogenic and xenoestrogenic agents may also contribute to the increased lethality of breast cancer in young women in general and in African American women of all ages. Public disclosure by manufacturers of proprietary hormonally active ingredients is required for this research to move forward.

Donovan M, Tiwary C, Axelrod D, Sasco A, Jones L, Hajek R, Sauber E, Kuo J, Davis D. Medical Hypothesis: Personal care products that contain estrogens or xenoestrogens may increase breast cancer risk. Med Hypotheses 2007;68(4):756-66. [PDF]

Polycystic ovarian syndrome (PCOS): a significant contributor to the overall burden of type 2 diabetes in women

BACKGROUND: Given the high prevalence of polycystic ovarian syndrome (PCOS) in the population, the increased risk for the development of type 2 diabetes in these women, and the role of type 2 diabetes in mediating adverse long-term sequelae, the objective of this analysis was to quantify the contribution of this early-life exposure (e.g., PCOS) to the burden of type 2 diabetes in the total population of middle-aged women. METHODS: The cumulative incidence and relative risk (RR) of type 2 diabetes were examined in a group of women with PCOS (n = 149) and unaffected women (n = 166), aged 35-64, who were part of an ongoing investigation of cardiovascular risk factors in women with PCOS. The population attributable risk percent (PAR%) was calculated using Levin's formula to estimate the percentage of type 2 diabetes in the total population among middle-aged women that can be attributed to the presence of PCOS at young adulthood. RESULTS: When the RR of type 2 diabetes among women with PCOS observed in our current study and others (4.0-6.0) was applied to an estimated 6%-10% prevalence of PCOS in the female population, 15.0%-35.6% of all incident cases of type 2 diabetes in white women were estimated to be attributable to PCOS. Moreover, other investigators have noted this proportion of undiagnosed PCOS in populations of women with type 2 diabetes. CONCLUSIONS: These results support the recommendation that all women with PCOS should be periodically rescreened for diabetes and underscores the importance of the early identification of young women with PCOS and the need for early lifestyle intervention.

Talbott EO, Zborowski JV, Rager JR, Kip KE, Xu X, Orchard TJ. Polycystic ovarian syndrome (PCOS): a significant contributor to the overall burden of type 2 diabetes in women. J Womens Health (Larchmt). 2007 Mar;16(2):191-7.

Redefining normal age of breast growth obscures potential environmental causes

February 8, 2007, we've heard that private laboratory tests reveal that popular children's shampoos and soaps can contain a known carcinogen, at levels above those allowed by the FDA. What does this mean? Fortunately, childhood cancer is rare. Unfortunately, the National Cancer Institute reports that it is less rare today than in years past. Lance Armstrong sends an incredibly inspiring message about the ability of young men to survive testicular cancer, but he also reflects a worrisome trend-Rates of this most common cancer in young men are rising throughout the industrial world. NCI reports that inherited germ line defects that are passed on from our parents, explain less than one in ten cases of cancer in young persons today. As was the case with Mr. Armstrong, we can't explain why most cancer in young persons occurs.

Davis D, Tiwary C, Donovan M, Axelrod D, Sasco A. Redefining normal age of breast growth obscures potential environmental causes. Post-publication Peer Review of L. Kurt Midyett, Wayne V. Moore, and Jill D. Jacobson, Are Pubertal Changes in Girls Before Age 8 Benign? Pediatrics 111 (2003): 47-51.

The limits of 2-Year Bioassay Exposure Regimens for Identifying Chemical Carcinogens

Background: Chemical carcinogenesis bioassays in animals have long been recognized and accepted as valid predictors of potential cancer hazards to humans. Most rodent bioassays begin several weeks after birth and expose animals to chemicals or other substances including workplace and environmental pollutants for 2 years. New findings indicate the need to extend the timing and duration of exposures used in the rodent bioassay.

Objectives: This Commentary proposes that the sensitivity of chemical carcinogenesis bioassays would be enhanced by exposing rodents beginning in utero and continuing for 30 months (130 weeks) or until their natural deaths at up to about 3 years.

Discussion: Studies of three chemicals of different structures and uses – aspartame, cadmium, and toluene -- suggest that exposing experimental animals in utero and for 30 months or until their natural deaths increases the sensitivity of bioassays, avoids false negative results, and strengthens the value and validity of results for regulatory agencies.

Conclusions: Government agencies, drug companies, and the chemical industry should conduct and compare the results of 2-year bioassays of known carcinogens or chemicals for which there is equivocal evidence of carcinogenicity with longer-term studies, with and without in utero exposure. If studies longer than 2 years or/and with in utero exposure are shown to be better able to identify potential human carcinogens, then regulatory agencies should promptly revise their testing guidelines, which were established in the 1960s and early 1970s. Changing the timing and dosing of the animal bioassay would enhance protection of workers and consumers who are exposed to potentially dangerous workplaces or home contaminants, pollutants, drugs, food additives, and other chemicals throughout their lives.

Huff J, Jacobson MF, Davis DL. The limits of 2-Year Bioassay Exposure Regimens for Identifying Chemical Carcinogens. EHP June 30, 2008 Available free online.

The Need to Develop Centers for Environmental Oncology

The scale and scope of the cancer problem in the United States today is much greater than four decades ago when the formal war against the disease was first announced. Patterns of the disease are not fully explained by known risk factors. Much progress has been made in understanding the molecular basis of carcinogenesis, particularly the near consensus (realization) that virtually all cancers arise from an accumulation of genetic mutations and the more recent recognition of the role of inflammation and the tissue microenvironment, in particular for hormone-dependant cancers. However, most genetic mutations that contribute to cancer are not inherited, and thus must be attributable to accumulation of somatic mutations and epigenetic changes, from as yet poorly understood environmental factors, that certainly cannot be explained entirely by tobacco, use and arise over the course of a lifetime. Much of the national effort to control cancer has focused on detecting and treating the disease-not on seeking approaches to prevent cases from arising. Given this reality, we present a cross-disciplinary framework for establishing comprehensive research and policy centers focused on environmental oncology to be based at selected academic cancer centers across the country. The principal goal of such centers is to improve the ability to prevent cancer, by developing effective interventions based on insights obtained from epidemiology, including molecular epidemiology and basic scientific research on genomic, metabolomic, and other biomarkers of exposure, susceptibility, and disease. As the needed scientific evidence for environmental factors contributing to cancer is revealed, these academic centers will develop specific interventions and/or policy recommendations regarding ways to lower the burden of cancer, based on existing information about cancer hazards in the personal, occupational, and general environment. Ultimately the centers will improve the ability to identify and control the underlying causes of the occurrence of cancer and its progression.

Davis D, Donovan M, Herberman R, Gaynor M, Axelrod D, van Larebeke N, Sasco A. The Need to Develop Centers for Environmental Oncology. Biomedicine & Pharmacotherapy. 2007 Dec; 61(10): 614-622.