Superfund Research Program

Project 1: Biomarkers of Chemical Exposure and Leukemia Risk

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Summary

This project builds upon the existing Northern California Childhood Leukemia Study (NCCLS), a large case-control study with over 1,000 cases. Its overall goal is to determine the role exposure to environmental chemicals plays in the etiology of childhood leukemia. Project investigators are examining the potential role benzene, polycyclic aromatic hydrocarbons (PAH) and other selected Superfund chemicals, such as trichloroethylene (TCE), play in the etiology of childhood leukemia in California. They are using state-of-the-art exposure assessment techniques to accomplish this goal. They are further using gene expression profiling and proteomics to develop new biomarkers that aid in the classification of etiologic subtypes of this disease and help find its cause(s). The hypothesis is that certain subtypes of leukemia will have specific environmental causes. Specifically, Drs. Buffler and Smith are: 1) Extending case ascertainment through 2009, such that biological samples will be available from over 1000 cases; 2) characterizing the childhood leukemia cases by proteomics and gene expression profiling; 3) collaborating with the CDC to measure more than 30 volatile hydrocarbons in the blood of mothers of children with leukemia and control mothers (they are comparing these measures with results from concomitant home air and water sampling and with surrogate markers of past exposures to VOCs using self-reported exposure to tobacco smoke and estimated traffic density); 4) measuring protein adducts of benzene and naphthalene (a representative PAH) in serum from mothers of cases and controls in collaboration with Dr. Rappaport of the University of North Carolina SBRP; and, 5) measuring protein adducts of benzene and naphthalene in the plasma of children with different forms of leukemia and correlate these measurements with the chemical exposure analysis conducted with household samples. The strengths of the study are: a) Large sample size; b) extensive residential exposure assessment; c) measures of current and cumulative exposure to Superfund chemicals in both case and control mothers and children; d) ability to compare exposures to national NHANES data; e) availability of carefully processed biological samples; and, f) application of sophisticated -omic technologies to case characterization. These studies should provide new insights into the role of chemical exposure in the etiology of childhood leukemia and produce new biomarkers of exposure and disease status that can be used in future studies.

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Project Update

The most common mutation in childhood leukemia is a translocation between chromosomes 12 and 21 which fuses the TEL and AML1 genes causing the B cells to grow abnormally as a cancer. Earlier work from this project confirmed that this mutation is a prenatal mutation in most children arising when the child is still a fetus. Other mutations seem to be necessary, however, for the generation of full blown leukemia.  One such frequent mutation in this subtype is partial deletion of the short arm of chromosome 12 called del(12p) which deletes the second copy of the TEL gene. Drs. Patricia Buffler and Martyn Smith sequenced the DNA at nine breakpoints in the chromosome 12 deletions of six childhood leukemia cases to explore the etiology of this genetic event.  The majority of these breakpoints were located in highly repetitive regions of the DNA. This stands in contrast with the TEL-AML1 translocation which infrequently involved breakage in DNA repeats. The two events are therefore quite different and may have different causes. The data are also compatible with a two-stage natural history: TEL-AML1 occurring prenatally, and del(12p) occurring postnatally in more mature cells.  These findings have recently been published in the December 2008 issue of Cancer Research.

The researchers are exploring the causes of the DNA mutations which produce childhood leukemia by asking the parents about their exposures to household chemicals, such as paints and solvents. They recently reported in a paper that is on-line in Environmental Health Perspectives that acute lymphoblastic leukemia (ALL) risk was significantly associated with paint exposure with a higher risk observed when paint was used postnatally, by a person other than the mother, or frequently. Further, the association was restricted to leukemia containing translocations between chromosomes 12 and 21. No significant association was found between solvent use and ALL risk overall but, a second rarer form of childhood leukemia, acute myeloid leukemia (AML) was associated with solvent but not with paint exposure. The association of ALL risk with paint exposure was strong, consistent with a causal relationship, while further studies are needed to confirm the association of AML risk with solvent exposure.

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Publications

• Tang X, Bai Y, Duong A, *Smith** MT*, Li L, Zhang L (2009) Formaldehyde in China: Production, consumption, exposure levels, and health effects. /Environ Int/. Nov;35(8):1210-24. PMID: 19589601. [Abstract] [Full Text]
• Lan, Qing, Luoping Zhang, Min Shen, William J. Jo, Roel Vermeulen, Guilan Li, Christopher Vulpe, Sophia Lim, Xuefeng Ren, Stephen M. Rappaport, Sonja I. Berndt, Meredith Yeager, Jeff Yuenger, Richard B. Hayes, Martha S. Linet, Songnian Yin, Stephen Chanock, Martyn T. Smith, and Nathaniel Rothman. 2009. Large-scale evaluation of candidate genes Identifies associations between DNA repair and genomic maintenance and development of benzene hematotoxicity. Carcinogenesis. (http://carcin.oupjournals.org/) 30(1):50-58. doi:10.1093/carcin/bgn249 (http://dx.doi.org/10.1093/carcin/bgn249)
• Scelo, Ghislaine, Catherine Metayer, L. Zhang, Joseph L. Wiemels, Melinda C. Aldrich, Steve Selvin, Stacy Month, M.T. Smith, and Patricia A. Buffler. 2009. Household exposure to paint and petroleum solvents, chromosomal translocations, and the risk of childhood leukemia. Environmental Health Perspectives. 117(1):133-9. doi:10.1289/ehp.11927 (http://dx.doi.org/10.1289/ehp.11927)
• Colt, Joanne S., Robert B. Gunier, Catherine Metayer, Marcia Nishioka, E.M. Bell, Peggy Reynolds, Patricia A. Buffler, and M.H. Ward. 2008. Household vacuum cleaners vs. the high-volume surface sampler for collection of carpet dust samples In epidemiologic studies of children. Environmental Health: A Global Access Science Source. 7:doi:10.1186/1476-069X-7-6 (http://dx.doi.org/10.1186/1476-069X-7-6)
• Galvan, N., S. Lim, S. Zmugg, Martyn T. Smith, and Luoping Zhang. 2008. Depletion of WRN enhances DNA damage in HeLa cells exposed to the benzene metabolite, hydroquinone. Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 649:54-61.

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