Environmental Factor, January 2011, National Institute of Environmental Health Sciences
2010 Papers of the Year
By Matt Goad
- Prenatal exposure to phthalates is associated with reduced masculine behavior in boys
- Obesity is a tumor promoter
- Fetal and early life exposures to BPA may increase the risk of cancer
- Mother's exposure to urban air pollutants affects children's cognitive abilities
- Researchers map the first human epigenome
- Living, breathing lung-on-a-chip
- Flame retardants linked to reduced human fertility
- Arsenic-related mortality in Bangladesh
- Genetic studies identify DNA sequences associated with lung function
- Acetaminophen-induced transcriptional changes predict liver injury
- Early-life exposures are linked to development of uterine fibroids
- Stem cell survival advantage toward arsenic drives malignant transformation
- Cholesterol trafficking linked to inflammatory response
- Genome instability due to ribonucleotide incorporation into DNA
- Gender differences in glucocorticoid-mediated inflammation
- Paused Pol II regulates gene activity
- Effects of low dose atrazine on pubertal timing and prostate development of male rats
- Genetic and epigenetic mechanisms in liver tumors of oxazepam-exposed mice
- Useful immunohistochemical markers of tumor differentiation
- Arsenic, stem cells and the developmental basis of adult cancer
- Cancer in experimental animals exposed to arsenic and arsenic compounds
Prenatal exposure to phthalates is associated with reduced masculine behavior in boys
University of Rochester researchers and NIEHS grantees Shanna Swan, Ph.D., and Bernard Weiss, Ph.D., reported for the first time that prenatal exposure to phthalates causes reduced masculine behavior in boys.
Mothers, whose urine had been analyzed for phthalates in mid-pregnancy, completed a questionnaire, including the Pre-School Activities Inventory used to assess gender differences in play behavior. The results showed that concentrations of dibutyl phthalate and diethylhexyl phthalate metabolites in the mothers' urine samples were statistically associated with decreased masculine play behavior in boys who were an average of five years old at the time of the assessment.
Citation: Swan SH, Liu F, Hines M, Kruse RL, Wang C, Redmon JB, Sparks A, Weiss B. 2010. Prenatal phthalate exposure and reduced masculine play in boys. Int J Androl 33(2):259-269. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/19919614) ] [synopsis(https://factor.niehs.nih.gov/2010/june/science-extramural.cfm#three)]
Obesity is a tumor promoter
Scientists at the University of California, San Diego reported the confirmation that obesity acts as a tumor promoter, in a January 2010 publication in the prestigious journal Cell. The findings suggest that anti-inflammatory drugs taken routinely by millions of people may also reduce the risk of cancer in those at high risk due to obesity and other factors. The research was jointly supported by an NIEHS grant and the Superfund Research Program.
The research team led by Michael Karin, Ph.D., found that liver cancer is promoted by a chronic inflammatory state that coincides with obesity. Liver cancer development was dependent on two well-known inflammatory factors, IL-6 and tumor necrosis factor. These inflammatory cytokines caused liver inflammation and activation of an oncogenic transcription factor known as STAT3.
Citation: Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Osterreicher CH, Takahashi H, Karin M. 2010. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140(2):197-208. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/20141834?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1) ] [synopsis(https://factor.niehs.nih.gov/2010/march/science-extramural.cfm#obesity)]
Fetal and early life exposures to BPA may increase the risk of cancer
NIEHS-funded researchers, using an American Recovery and Reinvestment Act (ARRA) supplement, demonstrated that regardless of route of exposure to bisphenol A (BPA), the effect on rats' prostates is the same. This has been a critical point of contention.
Serum BPA was delivered by injection and by oral exposure to neonatal rats. No matter the method of exposure, prostates from the aged rats exhibited nearly identical, heightened susceptibility to prostate intraepithelial neoplasia, thought to be a precursor to cancer.
Citation: Prins GS, Ye SH, Birch L, Ho SM, Kannan K. 2010. Serum bisphenol A pharmacokinetics and prostate neoplastic responses following oral and subcutaneous exposures in neonatal Sprague-Dawley rats. Reprod Toxicol; doi:10.1016/j.reprotox.2010.09.009 [Online 8 October 2010] [abstract(https://www.ncbi.nlm.nih.gov/pubmed/20887781) ]
Mother's exposure to urban air pollutants affects children's cognitive abilities
An NIEHS-supported study carried out in Krakow, Poland, reported prenatal exposure to air pollutants adversely affected the cognitive development of children at age 5. These findings confirmed a similar study conducted earlier in New York City.
The study was conducted in a cohort of 214 children born to healthy non-smoking women in Krakow, Poland, between 2001 and 2006. During pregnancy, the mothers wore small backpack-mounted personal air monitors to estimate their babies' exposures to polycyclic aromatic hydrocarbons (PAHs). PAHs are released into the air when fossil fuels are burned for purposes such as transportation, heating, and energy production.
At age 5, the children took a standard intelligence examination. Children in the high exposure group scored lower on the intelligence exam by about four IQ points.
Citation: Edwards SC, Jedrychowski W, Butscher M, Camann D, Kieltyka A, Mroz E, Flak E, Li Z, Wang S, Rauh V, Perera F. 2010. Prenatal exposure to airborne polycyclic aromatic hydrocarbons and children's intelligence at 5 years of age in a prospective cohort study in Poland. Environ Health Perspect 118(9):1326-1331. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/20406721) ] [synopsis(https://factor.niehs.nih.gov/2010/may/science-extramural.cfm#mother)]
Researchers map the first human epigenome
A comparison of the epigenomes of embryonic stem cells and fibroblasts shows a pattern of methylation unique to stem cells, according to a study supported by NIEHS. The novel methylation pattern may help to explain how stem cells maintain their pluripotent state.
The research team developed a high-throughput method to determine the methylation status of every cytosine molecule in the genome and to layer the resulting epigenomic map onto the genome it regulates. The technique was then applied to human fibroblasts and embryonic stem cells to determine if the epigenomes differed between differentiated cells that perform a specific job and cells that have the potential to become any cell type.
This study provides the first complete high-resolution map of an epigenome superimposed on the human genome. This knowledge could be extremely valuable for understanding and developing treatments for diseases.
Citation: Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR. 2009. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462(7271):315-322. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/19829295) ] [synopsis(https://factor.niehs.nih.gov/2010/january/extramural-papers.cfm#researchers)]
Living, breathing lung-on-a-chip
NIEHS-supported researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University developed a device that mimics a living and breathing human lung on a microchip roughly the size of a quarter.
The lung-on-a-chip device uses a new approach to tissue engineering that places tissue, from the lining of the alveoli and blood vessels that surround them, across a porous membrane. Air flows across the lung cells while culture medium, mimicking blood, is pumped through the capillaries. Mechanical stretching of the device mimics the expansion and contraction of the lungs during breathing.
The device has the potential to be a valuable research tool for testing the effects of environmental agents, and the absorption, safety, and efficacy of drug candidates.
Citation: Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE. 2010. Reconstituting organ-level lung functions on a chip. Science 328(5986):1662-1668. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/20576885) ] [synopsis(https://factor.niehs.nih.gov/2010/august/science-extramural.cfm#two)]
Flame retardants linked to reduced human fertility
Women exposed to high levels of flame retardants take longer to become pregnant, according to an NIEHS-funded study at the University of California, Berkeley. This is the first study to show decreases in human fertility related to the chemicals.
Polybrominated diphenyl ethers, or PBDEs, are a class of flame retardants found in many consumer products, such as foam cushions in furniture, carpet padding, clothing, and electronics. The compounds accumulate in fatty tissue and laboratory animal studies have identified them as endocrine disruptors.
More than 97 percent of the women participating in the study had measureable levels of PBDEs in their blood. With each tenfold increase in the blood level, the odds of becoming pregnant reduced by 30 percent.
Citation: Harley KG, Marks AR, Chevrier J, Bradman A, Sjodin A, Eskenazi B. 2010. PBDE concentrations in women's serum and fecundability. Environ Health Perspect 118(5):699-704. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/20103495) ] [synopsis(https://factor.niehs.nih.gov/2010/may/science-extramural.cfm#flame)]
Arsenic-related mortality in Bangladesh
NIEHS-supported researchers reported that 21.4 percent of all deaths in the Araihazar region of Bangladesh can be attributed to well water arsenic concentrations greater than 10 micrograms per liter. Their findings are from the first prospective study to investigate the link between arsenic exposure and mortality, and are published online in The Lancet.
A unique feature of this study is that it includes participants at both the low and high ends of the dose-response curve. For people exposed to the highest doses of arsenic, all-cause mortality was nearly 70 percent higher, relative to those exposed to less than the World Health Organization standard of 10 micrograms per liter.
Citation: Argos M, Kalra T, Rathouz PJ, Chen Y, Pierce B, Parvez F, Islam T, Ahmed A, Rakibuz-Zaman M, Hasan R, Sarwar G, Slavkovich V, van Geen A, Graziano J, Ahsan H. 2010. Arsenic exposure from drinking water, and all-cause and chronic-disease mortalities in Bangladesh (HEALS): a prospective cohort study. Lancet 376(9737):252-258. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/20646756) ] [synopsis(https://factor.niehs.nih.gov/2010/july/science-extramural.cfm#one)] [newsletter article(https://factor.niehs.nih.gov/2010/july/science-arsenic.cfm)]
Genetic studies identify DNA sequences associated with lung function
A collaborative research effort, led by NIEHS scientists, identified genetic factors that increase the risk of impaired lung function. The study provides insight into the biological mechanisms that contribute to pulmonary function and possibly to the pathogenesis of chronic lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD).
Stephanie London, M.D., Dr.P.H., and colleagues conducted analyses of data generated from several studies that involved more than 20,000 participants. Using this data, the authors identified genetic variations in eight previously unrecognized DNA regions that alter lung function.
The investigators determined that individuals carrying the identified genetic variations have lower pulmonary function and are at greater risk for developing COPD. Moreover, predictions involving these genetic alterations were consistent with those for known risk factors associated with decreased lung function, such as smoking and increasing age.
Citation: Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, Franceschini N, van Durme YM, Chen TH, Barr RG, Schabath MB, Couper DJ, Brusselle GG, Psaty BM, van Duijn CM, Rotter JI, Uitterlinden AG, Hofman A, Punjabi NM, Rivadeneira F, Morrison AC, Enright PL, North KE, Heckbert SR, Lumley T, Stricker BH, O'Connor GT, London SJ. 2010. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat Genet 42(1):45-52. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/20010835?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=2) ] [synopsis(https://factor.niehs.nih.gov/2010/february/science-intramural.cfm#four)] [newsletter article(https://factor.niehs.nih.gov/2010/january/science-genetic.cfm)] [press release(https://www.niehs.nih.gov/news/newsroom/releases/2009/december14/index.cfm)]
Acetaminophen-induced transcriptional changes predict liver injury
A collaborative research effort led by NIEHS scientists demonstrated that nontoxic doses of acetaminophen induce transcriptional changes in humans similar to those observed in overdose patients and rats exposed to toxic doses of the drug. These findings reveal potential biomarkers that may indicate early signs of drug-induced liver injury (DILI).
The authors examined changes in human peripheral blood (PB) gene expression in response to a dose of acetaminophen that did not induce detectable levels of liver injury. They observed a distinct transcriptional signature, including downregulation of genes associated with oxidative phosphorylation, and metabolic changes that led to increased serum lactate levels.
The identification of acetaminophen-induced transcriptional and metabolic signatures in human PB may address the need for better biomarkers of DILI. These expression profiles may assist clinicians and provide more meaningful liver safety data in clinical trials of new drugs.
Citation: Fannin RD, Russo M, O'Connell TM, Gerrish K, Winnike JH, Macdonald J, Newton J, Malik S, Sieber SO, Parker J, Shah R, Zhou T, Watkins PB, Paules RS. 2010. Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation. Hepatology 51(1):227-236. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/19918972?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=2) ] [synopsis(https://factor.niehs.nih.gov/2010/march/science-intramural.cfm#acetaminophen)]
Early-life exposures are linked to development of uterine fibroids
Epidemiologists at NIEHS, for the first time, linked soy formula during infancy, maternal prepregnancy diabetes, low childhood socioeconomic status, and early gestational age at birth to greater risk of early diagnosis of uterine leiomyomata (fibroids) in women.
Fibroids, the most common indication for hysterectomies in the United States, are benign smooth-muscle tumors, associated with pelvic pain, heavy bleeding, and reproductive problems. This study associated increased risk of fibroids diagnosed by age 35 with several factors, including being fed soy formula during infancy.
Citation: D'Aloisio AA, Baird DD, DeRoo LA, Sandler DP. 2010. Association of intrauterine and early-life exposures with diagnosis of uterine leiomyomata by 35 years of age in the sister study. Environ Health Perspect 118(3):375-381. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/20194067) ] [synopsis(https://factor.niehs.nih.gov/2010/may/science-intramural.cfm#early)]
Stem cell survival advantage toward arsenic drives malignant transformation
Researchers from the National Cancer Institute at NIEHS, now with National Toxicology Program, reported that the carcinogen arsenic targets stem cells for transformation, eventually producing cancers enriched in cancer stem cells. This is facilitated by a stem cell survival advantage toward arsenic during malignant transformation.
These observations further strengthen the argument that arsenic most likely targets cells that have either a stem or progenitor phenotype and undergo survival selection during arsenic-induced malignant transformation.
Citation: Tokar EJ, Qu W, Liu J, Liu W, Webber MM, Phang JM, Waalkes MP. 2010. Arsenic-specific stem cell selection during malignant transformation. J Natl Cancer Inst. 102(9):638-649. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/20339138) ] [synopsis(https://factor.niehs.nih.gov/2010/july/science-intramural.cfm#four)]
Cholesterol trafficking linked to inflammatory response
Investigators from the NIEHS Laboratory of Respiratory Biology report that Myeloid differentiation primary response protein 88 (MyD88), an adaptor protein in innate immunity signaling pathways, is required for cholesterol export from cells and couples cholesterol export to inflammation. They found that apolipoprotein A-I (apoA-I), the major protein component of high-density lipoprotein (HDL) particles, elicits MyD88-dependent inflammatory signals in macrophages.
This work supports a new paradigm in which the innate immune response acts as a physiologic signal in cholesterol homeostasis. Whereas inflammation is generally thought to promote atherosclerosis, the authors provide evidence that immune pathways may also be required for removal of cholesterol from vessel walls.
Citation: Smoak KA, Aloor JJ, Madenspacher J, Merrick BA, Collins JB, Zhu X, Cavigiolio G, Oda MN, Parks JS, Fessler MB. 2010. Myeloid differentiation primary response protein 88 couples reverse cholesterol transport to inflammation. Cell Metab 11(6):493-502. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/20519121) ] [synopsis(https://factor.niehs.nih.gov/2010/august/science-intramural.cfm#two)]
Genome instability due to ribonucleotide incorporation into DNA
DNA is more stable for storing genetic information than is RNA, because the ribose sugar in RNA is intrinsically more prone to strand cleavage that could led to mutations. Although most DNA polymerases efficiently prevent ribonucleotides from being incorporated into DNA, this exclusion is not absolute. This finding implies that some ribonucleotides will be incorporated into DNA in vivo, and that they need to be removed to maintain the chemical identity of organisms such as humans, whose genomes are comprised of DNA.
When researchers at the NIEHS and Umea University in Sweden recently tested these ideas, the results established three important facts about DNA replication: Ribonucleotides are indeed incorporated during replication in vivo; the ribonucleotides are normally removed by RNase H2-dependent repair; and defective repair causes cellular stress and genome instability.
Citation: Nick McElhinny SA, Kumar D, Clark AB, Watt DL, Watts BE, Lundstrom EB, Johansson E, Chabes A, Kunkel TA. 2010. Genome instability due to ribonucleotide incorporation into DNA. Nat Chem Biol 6(10):774-781. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/20729855) ] [synopsis(https://factor.niehs.nih.gov/2010/november/science-intramural.cfm#three)]
Gender differences in glucocorticoid-mediated inflammation
Research performed by scientists from NIEHS and Wake Forest University School of Medicine suggests that glucocorticoids, stress-induced steroids that regulate intermediary metabolism, may contribute to the development, progression, or susceptibility to inflammatory diseases in a gender-specific manner. This finding offers a possible explanation for why more females tend to have certain inflammatory diseases.
This work determined glucocorticoids regulate more liver genes in inflammatory pathways in males than females, suggesting that the failure by females to mount an adequate glucocorticoid inflammatory response may lead to more autoimmune diseases in women.
Citation: Duma D, Collins JB, Chou JW, Cidlowski JA. 2010. Sexually dimorphic actions of glucocorticoids provide a link to inflammatory diseases with gender differences in prevalence. Sci Signal 3(143):ra74. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/20940427) ] [synopsis(https://factor.niehs.nih.gov/2010/december/science-intramural.cfm#four)]
Paused Pol II regulates gene activity
Recent research, completed by investigators from NIEHS and the Lieber Institute for Brain Development at Johns Hopkins University, indicates that a main function of paused RNA polymerase II (Pol II) is to compete with nucleosomes for occupancy of a gene promoter. This action prevents the formation of chromatin, which represses gene activation. The new mechanism offers an explanation as to why some genes remain constitutively active, while others are highly regulated and activated only in response to external stimuli.
Housekeeping genes that should be continuously active contain a chromatin-unfriendly sequence and, as a result, exhibit low nucleosomal occupancy on their gene start sites. In contrast, highly regulated genes exhibit a chromatin-friendly sequence that invites nucleosomes or chromatin to bind to the promoter and prevent transcription.
Using genome-wide analysis of Pol II recruitment and nucleosomal occupancy in Drosophila cells, the study proposes that at tightly regulated genes, paused Pol II outcompetes nucleosomes for promoter occupancy and thus allows efficient gene activation in response to environmental cues.
Citation: Gilchrist DA, Dos Santos G, Fargo DC, Xie B, Gao Y, Li L, Adelman K. 2010. Pausing of RNA polymerase II disrupts DNA-specified nucleosome organization to enable precise gene regulation. Cell 143(4):540-551. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/21074046) ] [newsletter article(https://factor.niehs.nih.gov/2010/december/science-researcher.cfm)]
Effects of low dose atrazine on pubertal timing and prostate development of male rats
In a study partly funded by NIEHS, researchers concluded that prenatal exposure to metabolites of the herbicide atrazine can cause chronic prostatitis in Long-Evans rats.
Pregnant rats were treated with an atrazine metabolite mixture consisting of atrazine and its environmental metabolites diaminochlorotriazine, hydroxyatrazine, deethylatrazine, and deisopropylatrazine. Exposed males demonstrated a significant delay in preputial separation and a significant increase in incidence and severity of inflammation in the prostate.
Citation: Stanko JP, Enoch RR, Rayner JL, Davis CC, Wolf DC, Malarkey DE, Fenton SE. 2010. Effects of prenatal exposure to a low dose atrazine metabolite mixture on pubertal timing and prostate development of male Long-Evans rats. Reprod Toxicol 30(4):540-549. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/20727709) ]
Genetic and epigenetic mechanisms in liver tumors of oxazepam-exposed mice
NTP studies examining liver tumors from a previous study revealed insight into the mechanisms of carcinogenesis in mice exposed to oxazepam. Data suggest that formation of hepatocellular adenomas and carcinomas in the mice involved alteration of the Wnt signaling pathway, oxidative stress, and potential epigenetic alterations.
Citation: Lahousse SA, Hoenerhoff M, Collins J, Ton TV, Masinde T, Olson D, Rebolloso Y, Koujitani T, Tomer KB, Hong HH, Bucher J, Sills RC. 2010. Gene expression and mutation assessment provide clues of genetic and epigenetic mechanisms in liver tumors of oxazepam-exposed mice. Vet Pathol; doi: 10.1177/0300985810390019 [Online 7 December 2010] [abstract(https://www.ncbi.nlm.nih.gov/pubmed/21147764) ]
Useful immunohistochemical markers of tumor differentiation
Several experimental and diagnostic examples were presented to illustrate the utility of immunohistochemistry (IHC) as a supplement to standard staining techniques.
IHC has been somewhat underutilized in the practice of toxic pathology, but can be a valuable tool for the evaluation of rodent neoplasms, both in a diagnostic and investigational role.
Experimentally, IHC can be employed to investigate the earliest changes in transformed tissues, identifying cellular changes not normally visible with standard hematoxylin and eosin staining.
Citation: Painter JT, Clayton NP, Herbert RA. 2010. Useful immunohistochemical markers of tumor differentiation. Toxicol Pathol 38(1):131-141. [abstract(https://www.ncbi.nlm.nih.gov/pubmed/20028992) ]
Arsenic, stem cells and the developmental basis of adult cancer
NTP researchers, in an invited review, looked at available studies on the effects of arsenic on the development of cancer.
A mouse transplacental model has been developed, where maternal exposure to inorganic arsenic either acts as a complete carcinogen or enhances carcinogenic response to other agents given subsequently in the offspring, producing tumors during adulthood.
Arsenic impacts human stem cell population dynamics in vitro, by blocking differentiation pathways, and arsenic impacts key, long-lived stem cell populations as critical targets to cause or facilitate later oncogenic events in adulthood as a possible mechanism of developmental basis of adult disease.
Citation: Tokar EJ, Qu W, Waalkes MP. 2010. Arsenic, stem cells and the developmental basis of adult cancer. Toxicol Sci; doi: 10.1093/toxsci/kfq342 [Online 11 November 2010] [abstract(https://www.ncbi.nlm.nih.gov/pubmed/21071725) ]
Cancer in experimental animals exposed to arsenic and arsenic compounds
NIEHS/NTP researchers reviewed the available rodent studies considered relevant to carcinogenic assessment of arsenic, discussing them in the context of the persistent argument that arsenic is not carcinogenic in animals.
It has proven difficult to provide experimental evidence of the carcinogenicity of inorganic arsenic in laboratory animals, but more recent work with arsenical methylation metabolites and early life exposures to inorganic arsenic has now provided evidence of carcinogenicity in rodents.
Given that tens of millions of people worldwide are exposed to potentially unhealthy levels of environmental arsenic, in vivo rodent models of arsenic carcinogenesis are a clear necessity for resolving critical issues.
Citation: Tokar EJ, Benbrahim-Tallaa L, Ward JM, Lunn R, Sams RL 2nd, Waalkes MP. 2010. Cancer in experimental animals exposed to arsenic and arsenic compounds. Crit Rev Toxicol 40(10):912-927 [abstract(https://www.ncbi.nlm.nih.gov/pubmed/20812815) ]
(Matt Goad is a contract writer with the NIEHS Office of Communications and Public Liaison.)