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BACKGROUND COVID-19 isolation recommendations have evolved over the course of the pandemic. Initially, the US Centers for Disease Control and Prevention required 10 days of isolation after a positive test result. In December 2021, this was reduced to a minimum of 5 days with symptom improvement, followed by 5 days of mask wearing. As a result, several institutions of higher education, including the George Washington University, required persons testing positive for COVID-19 to either submit a negative rapid antigen test (RAT) with symptom resolution to leave isolation after 5 days or to maintain a 10-day isolation period in the absence of a negative RAT and the presence of continued symptoms. RATs are tools that can be used both to shorten isolation periods and to ensure that persons testing positive for COVID-19 remain in isolation if infectious. OBJECTIVE The purpose of this analysis is to report on the experience of implementing RAT policies, examine the number of days that isolation was reduced via RAT testing, determine the factors that predicted uploading a RAT, and determine RAT positivity percentages to illustrate the utility of using RATs to end isolation. METHODS In this study, 880 individuals in COVID-19 isolation at a university in Washington, DC, uploaded 887 RATs between February 21 and April 14, 2022. Daily positivity percentages were calculated, and multiple logistic regression analyses examined the odds of uploading a RAT by campus residential living status (ie, on or off campus), student or employee designation, age, and days in isolation. RESULTS A total of 76% (669/880) of individuals in isolation uploaded a RAT during the study period. Overall, 38.6% (342/887) of uploaded RATs were positive. Uploaded RATs were positive 45.6% (118/259) of the time on day 5; 45.4% (55/121) on day 6; 47.1% (99/210) on day 7; and 11.1% (7/63) on day 10 or beyond. Adjusted logistic regression modeling indicated cases living on campus had increased odds of uploading a RAT (odds ratio [OR] 2.54, 95% CI 1.64-3.92), whereas primary student affiliation (OR 0.29, 95% CI 0.12-0.69) and days in isolation (OR 0.45, 95% CI 0.39-0.52) had decreased odds of uploading a RAT. Of the 545 cases with a negative RAT, 477 were cleared prior to day 10 of their isolation due to lack of symptoms and timely submission, resulting in a total of 1547 days of lost productivity saved compared to all being in isolation for 10 days. CONCLUSIONS RATs are beneficial, as they can support a decision to release individuals from isolation when they have recovered and maintain isolation for people who may still be infectious. Future isolation policies should be guided by similar protocols and research to reduce the spread of COVID-19 and minimize lost productivity and disruption to individuals’ lives.

The George Washington University (GW) in Washington, D.C., USA established the Public Health Laboratory and Campus COVID-19 Support Team (CCST) to develop and implement its SARS-CoV-2 surveillance testing and outbreak response for the 2020-2021 academic year.Approximately 4,000 GW members had access to campus for living accommodations, limited in-person instruction, athletics, research, and university operations. The outbreak response included daily risk assessment surveys, weekly surveillance testing, symptomatic and voluntary testing, case investigation, and contact tracing.Between August 17 - November 24, 2020, 42,350 SARS-CoV-2 PCR tests were performed, and 194 (0.46%) of tests were positive. Surveillance testing identified 59 (30.4%); voluntary testing 97 (50%); and symptomatic testing 30 (15.5%) of the cases, respectively.Robust testing of asymptomatic people and rapid isolation and quarantine of members who are exposed or infected effectively limited the spread of SARS-CoV-2 during the Fall 2020 semester.

Environmental health practice is concerned with assessing, controlling, and preventing factors in the environment that can potentially affect human health. This chapter briefly discusses the roots and origins of environmental health practice from earliest times to the present day, against a backdrop of current international initiatives highlighting health, environment, and sustainable development issues of global concern. The concept and scope of environmental health is discussed, before highlighting environmental health issues and the burden of environmentally related disease, which are of importance in directing the work of the environmental health practitioner. It then addresses the multifactorial nature of environmental health effects, the role of epidemiology and toxicology, and the basic elements of the risk assessment process. Next, tools to aid decision-making are introduced followed by a discussion on the role of intersectoral action and partnerships. The final section of the chapter addresses policy elements and actions which can be taken to address environmental health issues, and the implications for environmental health management and service delivery. A greater capacity to influence policy agendas outside of the health sector will be needed in future.

The COVID-19 pandemic has greatly impacted US colleges and universities. As The George Washington University (GWU), a large urban university, prepared to reopen for the Fall 2020 semester, GWU established protocols to protect the health and wellness of all members of campus community. Reopening efforts included a cadre of COVID-19 surveillance systems including development of a public health COVID-19 laboratory, weekly and symptomatic SARS-CoV-2 testing and daily risk screening and symptom monitoring. Other activities included completion of a mandatory COVID-19 training and influenza vaccination for the on-campus population, quarantining of students returning to campus, campus-focused case investigations and quarantining of suspected close contacts, clinical follow-up of infected persons, and regular communication and monitoring. A smaller on-campus population of 4,435 students, faculty and staff returned to campus with later expansion of testing to accommodate GWU students living in the surrounding area. Between August 17 and December 4, 2020, 38,288 tests were performed; 220 were positive. The surveillance program demonstrated a relatively low positivity rate, with temporal clustering of infected persons mirroring community spread, and little evidence for transmission among the GWU on-campus population. These efforts demonstrate the feasibility of safely partially reopening a large urban college campus by applying core principles of public health surveillance, infectious disease epidemiology, behavioral measures, and increased testing capacity, while continuing to promote educational and research opportunities. GWU will continue to monitor the program as the pandemic evolves and periodically reassess to determine if these strategies will be successful upon a full return to in-person learning.Summary BoxWhat is the current understanding of this subject? When the COVID-19 pandemic began, generally universities were not prepared and it was unclear how to safely reopen colleges and universities given the uncertain risks of transmission among students, faculty and staff.What does this report add to the literature? This case report highlights the successful approaches employed, including applying the core principles of public health surveillance and increasing testing capacity, to mitigate the spread of SARS-CoV-2 on a densely populated urban college campus resulting in a safe reopening.What are the implications for public health practice? This experience can provide a roadmap for other universities to consider as they plan for the safe reopening of their campuses.

The UK is well into the second wave of COVID-19, with 60 051 lives lost to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to date, according to provisional data from the Office for National Statistics. Official UK Government data show that cases have been rising exponentially since late August, 2020, with increases across all regions in England in recent weeks.As of Nov 4, 2020, the UK had 25 177 confirmed daily cases. These are almost certainly underestimates as between Oct 17 and Oct 23, 2020, England alone had 52 000 estimated daily cases.Estimates of the effective reproduction number in England vary between 1.1 and 1.6.Daily deaths have doubled every fortnight since early September, 2020, with 2067 deaths from COVID-19 in the past week and around 12 000 deaths more are likely in the next month—the majority among people who have already been infected. With 12 000 patients currently in hospital with COVID-19, health services are close to capacity in many regions. We are seeing more than 1400 daily hospital admissions in England, a single doubling period away from the peak of 3000 daily admissions that occurred in April, 2020, which could be reached within 2–3 weeks.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 35 million people globally, with more than 1 million deaths recorded by WHO as of Oct 12, 2020. As a second wave of COVID-19 affects Europe, and with winter approaching, we need clear communication about the risks posed by COVID-19 and effective strategies to combat them. Here, we share our view of the current evidence-based consensus on COVID-19.

Summary Background Hurricane Maria struck Puerto Rico on Sept 20, 2017, devastating the island. Controversy surrounded the official death toll, fuelled by estimates of excess mortality from academics and investigative journalists. We analysed all-cause excess mortality following the storm. Methods We did a time-series analysis in Puerto Rico from September, 2017, to February, 2018. Mortality data were from the Puerto Rico Vital Statistics System. We developed two counterfactual scenarios to establish the population at risk. In the first scenario, the island's population was assumed to track the most recent census estimates. In the second scenario, we accounted for the large-scale population displacement. Expected mortality was projected for each scenario through over-dispersed log-linear regression from July, 2010, to August, 2017, taking into account changing distributions of age, sex, and municipal socioeconomic development, as well as both long-term and seasonal trends in mortality. Excess mortality was calculated as the difference between observed and expected deaths. Findings Between September, 2017, and February, 2018, we estimated that 1191 excess deaths (95% CI 836–1544) occurred under the census scenario. Under the preferred displacement scenario, we estimated that 2975 excess deaths (95% CI 2658–3290) occurred during the same observation period. The ratio of observed to expected mortality was highest for individuals living in municipalities with the lowest socioeconomic development (1·43, 95% CI 1·39–1·46), and for men aged 65 years or older (1·33, 95% CI 1·30–1·37). Excess risk persisted in these groups throughout the observation period. Interpretation Analysis of all-cause mortality with vital registration data allows for unbiased estimation of the impact of disasters associated with natural hazards and is useful for public health surveillance. It does not depend on certified cause of death, the basis for the official death toll in Puerto Rico. Although all sectors of Puerto Rican society were affected, recovery varied by municipal socioeconomic development and age groups. This finding calls for equitable disaster preparedness and response to protect vulnerable populations in disasters. Funding Forensic Science Bureau, Department of Public Safety, and Milken Institute School of Public Health of The George Washington University (Washington, DC, USA).

Prior studies addressing associations between mercury and blood pressure have produced inconsistent findings; some of this may result from measuring total instead of speciated mercury. This cross-sectional study of 263 pregnant women assessed total mercury, speciated mercury, selenium, and n-3 polyunsaturated fatty acids in umbilical cord blood and blood pressure during labor and delivery. Models with a) total mercury or b) methyl and inorganic mercury were evaluated. Regression models adjusted for maternal age, race/ethnicity, prepregnancy body mass index, neighborhood income, parity, smoking, n-3 fatty acids and selenium. Geometric mean total, methyl, and inorganic mercury concentrations were 1.40 μg/L (95% confidence interval: 1.29, 1.52); 0.95 μg/L (0.84, 1.07); and 0.13 μg/L (0.10, 0.17), respectively. Elevated systolic BP, diastolic BP, and pulse pressure were found, respectively, in 11.4, 6.8, and 19.8% of mothers. In adjusted multivariable models, a one-tertile increase of methyl mercury was associated with 2.83 mmHg (0.17, 5.50) higher systolic blood pressure and 2.99 mmHg (0.91, 5.08) higher pulse pressure. In the same models, an increase of one tertile of inorganic mercury was associated with a -1.18 mmHg (-3.72, 1.35) lower systolic blood pressure and -2.51 mmHg (-4.49, -0.53) lower pulse pressure. No associations were observed with diastolic pressure. There was a non-significant trend of higher total mercury with higher systolic blood pressure. We observed a significant association of higher methyl mercury with higher systolic and pulse pressure, yet higher inorganic mercury was significantly associated with lower pulse pressure. These results should be confirmed with larger, longitudinal studies.

Background Methylmercury (MeHg) may affect fetal growth; however, prior research often lacked assessment of mercury speciation, confounders, and interactions. Objective Our objective was to assess the relationship between MeHg and fetal growth as well as the potential for confounding or interaction of this relationship from speciated mercury, fatty acids, selenium, and sex. Methods This cross-sectional study includes 271 singletons born in Baltimore, Maryland, 2004–2005. Umbilical cord blood was analyzed for speciated mercury, serum omega-3 highly unsaturated fatty acids (n-3 HUFAs), and selenium. Multivariable linear regression models controlled for gestational age, birth weight, maternal age, parity, prepregnancy body mass index, smoking, hypertension, diabetes, selenium, n-3 HUFAs, and inorganic mercury (IHg). Results Geometric mean cord blood MeHg was 0.94 μg/L (95% CI: 0.84, 1.07). In adjusted models for ponderal index, βln(MeHg) = –0.045 (g/cm3) × 100 (95% CI: –0.084, –0.005). There was no evidence of a MeHg × sex interaction with ponderal index. Contrastingly, there was evidence of a MeHg × n-3 HUFAs interaction with birth length [among low n-3 HUFAs, βln(MeHg) = 0.40 cm, 95% CI: –0.02, 0.81; among high n-3 HUFAs, βln(MeHg) = –0.15, 95% CI: –0.54, 0.25; p-interaction = 0.048] and head circumference [among low n-3 HUFAs, βln(MeHg) = 0.01 cm, 95% CI: –0.27, 0.29; among high n-3 HUFAs, βln(MeHg) = –0.37, 95% CI: –0.63, –0.10; p-interaction = 0.042]. The association of MeHg with birth weight and ponderal index was affected by n-3 HUFAs, selenium, and IHg. For birth weight, βln(MeHg) without these variables was –16.8 g (95% CI: –75.0, 41.3) versus –29.7 (95% CI: –93.9, 34.6) with all covariates. Corresponding values for ponderal index were –0.030 (g/cm3) × 100 (95% CI: –0.065, 0.005) and –0.045 (95% CI: –0.084, –0005). Conclusion We observed an association of increased MeHg with decreased ponderal index. There is evidence for interaction between MeHg and n-3 HUFAs; infants with higher MeHg and n-3 HUFAs had lower birth length and head circumference. These results should be verified with additional studies. Citation Wells EM, Herbstman JB, Lin YH, Jarrett J, Verdon CP, Ward C, Caldwell KL, Hibbeln JR, Witter FR, Halden RU, Goldman LR. 2016. Cord blood methylmercury and fetal growth outcomes in Baltimore newborns: potential confounding and effect modification by omega-3 fatty acids, selenium, and sex. Environ Health Perspect 124:373–379; http://dx.doi.org/10.1289/ehp.1408596

Linear, short-chain polyfluorinated and perfluorinated alkyl compounds, often referred to as PFCs, have been in worldwide use as surfactants and polymer precursors for decades, and environmental dispersal of these highly persistent compounds represents a public health threat. Whereas ubiquitous low-level exposure to these compounds has been demonstrated in human populations from around the world, the exact mechanisms of toxicity and their toxic potency remain subject to investigation and scientific dispute. As with other environmental exposures, a major hurdle for gaining a better understanding of their human health impacts is the limited utility of cell culture and animal models serving as convenient, yet imperfect proxies to human physiology and disease. The present communication provides a brief overview of the current understanding of potential health effects of PFC exposure and examines how new toxicoproteomic methodologies can provide insight into the molecular mechanism of PFC exposure. Furthermore, we showcase an exemplary data set to illustrate how toxicoproteomic, population-wide studies might overcome limitations of animal models to more fully understand the metabolism and effects of PFCs and other environmental stressors where it matters most, in human populations experiencing real-world, chronic, low-level exposures.

Altered levels of selenium and copper have been linked with altered cardiovascular disease risk factors including changes in blood triglyceride and cholesterol levels. However, it is unclear whether this can be observed prenatally. This cross-sectional study includes 274 singleton births from 2004 to 2005 in Baltimore, Maryland. We measured umbilical cord serum selenium and copper using inductively coupled plasma mass spectrometry. We evaluated exposure levels vis-à-vis umbilical cord serum triglyceride and total cholesterol concentrations in multivariable regression models adjusted for gestational age, birth weight, maternal age, race, parity, smoking, prepregnancy body mass index, n-3 fatty acids and methyl mercury. The percent difference in triglycerides comparing those in the highest v. lowest quartile of selenium was 22.3% (95% confidence interval (CI): 7.1, 39.7). For copper this was 43.8% (95% CI: 25.9, 64.3). In multivariable models including both copper and selenium as covariates, copper, but not selenium, maintained a statistically significant association with increased triglycerides (percent difference: 40.7%, 95% CI: 22.1, 62.1). There was limited evidence of a relationship of increasing selenium with increasing total cholesterol. Our findings provide evidence that higher serum copper levels are associated with higher serum triglycerides in newborns, but should be confirmed in larger studies.

Background: A database for studies used for U.S. Environmental Protection Agency (EPA) pesticide and chemical reviews would be an excellent resource for increasing transparency and improving systematic assessments of pesticides and chemicals. There is increased demand for disclosure of raw data from studies used by the U.S. EPA in these reviews. Objectives: Because the Information Quality Act (IQA) of 2001 provides an avenue for request of raw data, we reviewed all IQA requests to the U.S. EPA in 2002–2012 and the U.S. EPA’s responses. We identified other mechanisms to access such data: public access databases, the Freedom of Information Act (FOIA), and reanalysis by a third party. Discussion: Only two IQA requests to the U.S. EPA were for raw data. Both of these were fulfilled under FOIA, not the IQA. Barriers to the U.S. EPA’s proactive collection of all such data include costs to the U.S. EPA and researchers, significant time burdens for researchers, and major regulatory delays. The U.S. EPA regulatory authority in this area is weak, especially for research conducted in the past, not funded by the U.S. government, and/or conducted abroad. The U.S. EPA is also constrained by industry confidential business information (CBI) claims for regulatory testing data under U.S. chemical and pesticide laws. The National Institutes of Health Clinical Trials database systematically collects statistical data about clinical trials but not raw data; this database may be a model for data from studies of chemicals and pesticides. Conclusions: A database that registers studies and obtains systematic sets of parameters and results would be more feasible than a system that attempts to make all raw data available proactively. Such a proposal would not obviate rights under the IQA to obtain raw data at a later point.

Correspondence avoid surgery in rapidly progressive or chemo-insensitive disease. 4 Genotyping of pancreatic tumours via fine needle aspiration could influence the clinical management of pancreatic cancer. Fine-needle aspiration sequencing was used to identify subgroups of patients with specific actionable mutations related to resectable or locally advanced tumours. 5 In patients with radiologically resectable or borderline resectable tumours, preoperative fine-needle aspiration sequencing could distinguish between patients with a genetic pattern associated with micrometastatic tumours, who should undergo neoadjuvant therapy, and those with a truly localised disease that would be amenable to a surgery-first strategy. Michele Reni has served as a consultant for or on the advisory boards of Celgene, Boehringer-Ingelheim, Lilly, Genentech, Baxalta, Novocure, Astra-Zeneca, Pfizer, and Merck-Serono, and has received honoraria from Celgene. Massimo Falconi has received honoraria from Celgene, Ipsen and Novartis. The other authors declare no competing interests. *Stefano Crippa, Michele Reni, Gianpaolo Balzano, Claudio Doglioni, Massimo Falconi crippa1.stefano@hsr.it Division of Pancreatic Surgery, IRCCS San Raffaele Hospital, Milan, Italy (SC, GB, MF); Medical Oncology Department, IRCCS San Raffaele Hospital , Milan, Italy (MR); Department of Pathology, IRCCS San Raffaele Hospital , Milan, Italy (CD); Clinical and Translational Research Program on Pancreatic Cancer, IRCCS San Raffaele Hospital, Milan, Italy (SC, MR, GB, CD, MF) e178 Barreto SG, Windsor JA. Justifying vein resection with pancreatoduodenectomy. Lancet Oncol 2016; 17: e118–24 Giovinazzo F, Turri G, Katz MH, Heaton N, Ahmed I. Meta-analysis of benefit of portal-superior mesenteric vein resection in pancreatic resection for ductal adenocarcinoma. Br J Surg 2016; 103: 179–91. Bapat AA, Hostetter G, Von Hoff DD, Han H. Perineural invasion and associated pain in pancreatic cancer. Nat Rev Cancer 2011; Sohal DP, Walsh RM, Ramanathan RK, Khorana AA. Pancreatic adenocarcinoma: treating a systemic disease with systemic therapy. J Natl Cancer Inst 2014; 106: dju011 Valero V, Saunders TJ, He J, et al. Reliable detection of somatic mutations in fine needle aspirates of pancreatic cancer with next-generation sequencing: implications for surgical management. Ann Surg 2016; Author’s reply Stefano Crippa and colleagues, in responding to our manuscript, 1 agree that increasing the radicality of surgery for pancreatic ductal adenocarcinoma, including synchronous vein resection, is suspect. Indeed, a recent meta-analysis 2 indicates that synchronous vein resection, as reported, increases mortality and decreases survival. Crippa and colleagues put forward two interesting ideas that warrant further discussion. The first is that the surgery-first approach for pancreatic ductal adenocarcinoma might ultimately be retired, given that pancreatic ductal adenocarcinoma is usually systemic at presentation, local treatments have little effect, and neoadjuvant therapy has possible benefits. For now, the absence of high-level evidence for neoadjuvant therapy leaves largely theoretical benefits; namely that neoadjuvant therapy will reveal the biology (ie, those patients that can progress on neoadjuvant therapy will avoid futile surgery), or alter the biology (ie, those patients that are downstaged will become resectable). The preliminary results of the ALLIANCE trial 3 damages the lustre of these purported benefits with no improvement in the number of resections (10 [50%] of 20 patients who completed all preoperative therapy), and no rescue of aggressive tumour biology. This leads to the second idea, in which Crippa and colleagues suggest a biological (rather than radiological) basis for selecting patients for neoadjuvant therapy with a view to reduce the number of synchronous vein resections. Endoscopic ultrasonography- guided genotyping is a possible way to select subgroups of patients with heterogenous pancreatic ductal adenocarcinoma 4 who will benefit from neoadjuvant therapy. In support of this method, Hruban and colleagues 5 suggested that an intact SMAD4/DPC4 gene might be used to select surgery because there is lesser risk of distant metastases for this genotype. 6 In the future, we hope to more accurately select a subgroup of patients in whom a surgery-first approach, and even synchronous vein resection, is justified, but it is much more likely that precision neoadjuvant therapy will ultimately result in less radical surgery and the introduction of non-surgical techniques to support the response to neoadjuvant therapy. We declare no competing interests. Savio G Barreto, *John A Windsor j.windsor@auckland.ac.nz Department of Gastrointestinal Surgery, Gastrointestinal Oncology, and Bariatric Surgery, Medanta Institute of Digestive and Hepatobiliary Sciences, Medanta, The Medicity, Gurgaon, India (SGB); Hepatobiliary Pancreatic and Upper GI Unit, Department of General Surgery, Auckland City Hospital, Auckland, New Zealand (JAW) Barreto S, Windsor J. Justifying vein resection with pancreatoduodenectomy. Lancet Oncol 2016; 17: e118–24. Giovinazzo F, Turri G, Katz MH, Heaton N, Ahmed I. Meta-analysis of benefits of portal-superior mesenteric vein resection in pancreatic resection for ductal adenocarcinoma. Br J Surg 2016; Varadhachary G, Fleming J, Crane C, et al. Phase II study of preoperation mFOLFIRINOX and chemoradiation for high-risk resectable and borderline resectable pancreatic adenocarcinoma. Proc Am Soc Clin Oncol 2015; 33 (suppl 3): abstr 362. Killock D. Pancreatic cancer: a problem quartered—new subtypes, new solutions? Nat Rev Clin Oncol 2016; 13: 201. Hruban RH, Adsay NV. Molecular classification of neoplasms of the pancreas. Hum Pathol Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 2009; The US Cancer Moonshot initiative We recently sent the following letter to Vice President of the USA, Joe Biden, to state that we, as Deans and Directors of Public Health schools and programmes around the USA, strongly support the goals of the Cancer Moonshot initiative to www.thelancet.com/oncology Vol 17 May 2016

We appreciate the opportunity to respond to the letter from Stahlhut et al. regarding our Brief Communication. We stressed the importance of biospecimen integrity and the potential danger of unrecognized contamination of convenience samples, particularly with ubiquitous environmental chemicals such as bisphenol A (BPA) and phthalates. We did not discuss the important area of experimental research and specifically pharmacokinetic studies, although we based our argument partly on knowledge of concentration changes in various compartments postexposure. We agree that information from pharmacokinetic models is quite valuable and note that experimental studies that use isotope-labeled materials are not susceptible to extraneous contamination. Such experimental studies do not support using polar metabolites, such as unmetabolized BPA, as biomarkers in epidemiologic studies (Thayer et al. 2015). For example, even in situations that may result in exposures higher than background levels, such as handling cash register receipts, BPA serum concentrations are below or near the detection limit and much lower than urinary concentrations (Thayer et al. 2016). The figure in our Brief Communication revealed the sharp increase in the number of publications using blood-based polar biomarkers over the past 15 years, especially etiologic studies. Our main point was that urine is the most dependable biomonitoring matrix for population research, a position that Stahlhut et al. also support in their letter. Target-organ dose may inform biological models, but measuring this dose is not always possible, although it can be inferred from pharmacokinetic studies. For environmental epidemiology, reliable measurements in urine can be used to quantify exposures. A suitable exposure biomarker involves more than detecting the analyte with precise and accurate methods. For pervasive chemicals and particularly for archived samples, specimen integrity must be confirmed. This is true for any matrix, including urine (Guidry et al. 2015; Koch et al. 2012), to ensure valid results.

In a recent Brief Communication, Calafat et al. expressed concern that epidemiological studies inappropriately assess exposure to nonpersistent chemicals such as bisphenol A (BPA) and phthalates by measuring chemical concentrations in serum and tissues. They assert that urine is the most scientifically valid matrix and that accurate measurement of other matrices is difficult due to contamination of samples and assays. We believe their assertions require clarification. The scientifically appropriate matrix is determined by the study objectives. For population studies, we agree urine is an appropriate matrix to initially probe whether exposure to a nonpersistent chemical is associated with a disease or risk factor. However, Calafat et al. appear to target more than population studies. They illustrate the purportedly growing problem of non-urine measurement in epidemiology with a list of 80 studies, cited by PubMed identification numbers (PMIDs), which surprisingly includes pharmacokinetic and experimental studies. Of these 80 studies, 35 arguably required non-urine matrices to achieve study objectives. For example, in five studies (PMIDs 10716589, 10964036, 11604266, 17661831, 23145999) the subjects were dialysis patients—i.e., people without normal capacity to produce urine. One study used a placenta perfusion system to examine phthalate distribution between maternal and fetal circulation (PMID 17049806). A dog study (PMID 23761051) found unmetabolized BPA was rapidly absorbed into circulation following sublingual administration. A human study (PMID 25337790) exposed participants to BPA-containing thermal receipt paper and found a substantial increase of unmetabolized BPA in serum. It seems inconceivable to us that Calafat et al. would consider such studies inherently flawed. For chemicals excreted in urine, the urinary concentration provides an estimate of exposure. However, the bioactive form in serum and tissue is what alters physiology. When a nonpersistent chemical is absorbed via the gut, first-pass metabolism by the liver can dramatically reduce the amount of unmetabolized compound reaching the bloodstream as compared with other routes (Soeborg et al. 2014). Therefore, for chemicals in widespread undocumented use—where route-of-exposure information is unavoidably incomplete—one cannot accurately predict the internal concentrations of the unmetabolized compounds with urine measurements and a model that includes only gut absorption. Such models may grossly underestimate internal bioactive dose from non-gut exposures and incorrectly suggest that measurement of higher-than-predicted serum concentrations is due to contamination. In our view, Calafat et al. suggest that non-urine measurements are invariably contaminated. However, contamination cannot explain the results of the studies by Gayrard et al. (2013) and Hormann et al. (2014), which demonstrated classic pharmacokinetic curves with logical interrelationships between the parent compound and metabolites. Furthermore, the proposition that contamination is unavoidable is contradicted by numerous studies spanning 15 years (vom Saal and Welshons 2014). For example, in a paper coauthored by Calafat (Ye et al. 2013), the authors reported accurately measuring BPA in human serum after identifying and eliminating contamination. Subsequently, Vandenberg et al. (2014) reported a blinded study directed by the National Institutes of Health (NIH) in which several U.S. laboratories accurately measured BPA in human serum spiked by NIH personnel. Arguing that chemical X cannot be measured in tissue Y because of contamination is an odd position to take, given that eliminating sources of contamination is a normal part of the development and validation of any assay—as was clearly described by Ye et al. (2013). In summary, without further clarification, the Brief Communication by Calafat et al. could easily be interpreted as proposing that human environmental studies of any kind must measure nonpersistent chemicals and metabolites only in urine if they are to be funded and published. Such an interpretation would greatly restrict our ability to move from surface-level exposure measures to internal dose, pharmacokinetics, and in vivo pathophysiology. Given the prominence of the authors in environmental health research, this issue needs to be clarified.

* Abbreviations: CCAV — : clear cell adenocarcinoma of the vagina DES — : diethylstilbesterol This interesting series of articles on Opportunities for Cancer Prevention During Early Life brings many ideas for the primary prevention of cancer in childhood, or in adults due to early life events. The economic burden not only of cancer mortality but also of lifelong morbidity among cancer survivors, as shown by Guy et al,1 raises the importance of this critical public health issue. The topics of these articles were developed during online seminars with the pioneers in this area, some of whom authored the articles. They reflect the determinants of health diagrammed so eloquently in Healthy People 2020.2 Broadly, the determinants of health outcomes are biology/genetics, the physical environment, individual behavior, the social environment, and health services. The articles have been grouped according to these categories. For example, the article by Terry and Forman3 focuses on interventions at the individual level, and the article by Massetti et al,4 focuses on interventions aimed at social determinants. Classically, mutagenesis was the first basic mechanism clearly identified for carcinogenesis, and either inherited mutations or the mutagenesis of agents, such as tobacco and radiation, were the focus. Viral infections also have long been recognized to be involved with certain cancers. Our current models for carcinogenicity recognize that, for most cancers, multiple stages are required to not only initiate the cancer but also to elude biological mechanisms for repairing DNA, immune surveillance, and other natural defenses against cancer. One carcinogen, diethylstilbestrol (DES), did not neatly fit either the mutagen or viral hypotheses,5,6 and we now understand that in addition to inherited or acquired genetic susceptibilities, a basic mechanism for carcinogenesis due to … Address correspondence to Cynthia F. Bearer, MD, PhD, Division of Neonatology, Department of Pediatrics, University of Maryland, School of Medicine, 110 South Paca St, 8th Floor, Baltimore, MD 21211. E-mail: cbearer{at}peds.umaryland.edu

Background Gestational age at birth strongly predicts neonatal, adolescent and adult morbidity and mortality through mostly unknown mechanisms. Identification of specific genes that are undergoing regulatory change prior to birth, such as through changes in DNA methylation, would increase our understanding of developmental changes occurring during the third trimester and consequences of pre-term birth (PTB). Methods We performed a genome-wide analysis of DNA methylation (using microarrays, specifically CHARM 2.0) in 141 newborns collected in Baltimore, MD, using novel statistical methodology to identify genomic regions associated with gestational age at birth. Bisulphite pyrosequencing was used to validate significant differentially methylated regions (DMRs), and real-time PCR was performed to assess functional significance of differential methylation in a subset of newborns. Results We identified three DMRs at genome-wide significance levels adjacent to the NFIX, RAPGEF2 and MSRB3 genes. All three regions were validated by pyrosequencing, and RAGPEF2 also showed an inverse correlation between DNA methylation levels and gene expression levels. Although the three DMRs appear very dynamic with gestational age in our newborn sample, adult DNA methylation levels at these regions are stable and of equal or greater magnitude than the oldest neonate, directionally consistent with the gestational age results. Conclusions We have identified three differentially methylated regions associated with gestational age at birth. All three nearby genes play important roles in the development of several organs, including skeletal muscle, brain and haematopoietic system. Therefore, they may provide initial insight into the basis of PTB's negative health outcomes. The genome-wide custom DNA methylation array technology and novel statistical methods employed in this study could constitute a model for epidemiologic studies of epigenetic variation.

Background: Early diagnosis represents one of the best lines of defense in the fight against a wide array of human diseases. Umbilical cord blood (UCB) is one of the first easily available diagnostic biofluids and can inform about the health status of newborns. However, compared with adult blood, its diagnostic potential remains largely untapped. Objectives: Our goal was to accelerate biomarker research on UCB by exploring its detectable protein content and providing a priority list of potential biomarkers based on known proteins involved in disease pathways. Methods: We explored cord blood serum proteins by profiling a UCB pool of 12 neonates with different backgrounds using a combination of isoelectric focusing and liquid chromatography coupled with matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS) and by comparing results with information contained in metabolic and disease databases available for adult blood. Results: A total of 1,210 UCB proteins were identified with a protein-level false discovery rate of ~ 5% as estimated by naive target-decoy and MAYU approaches, signifying a 6-fold increase in the number of UCB proteins described to date. Identified proteins correspond to 138 different metabolic and disease pathways and provide a platform of mechanistically linked biomarker candidates for tracking disruptions in cellular processes. Moreover, among the identified proteins, 38 were found to be approved biomarkers for adult blood. Conclusions: The results of this study advance current knowledge of the human cord blood serum proteome. They showcase the potential of UCB as a diagnostic medium for assessing infant health by detection and identification of candidate biomarkers for known disease pathways using a global, nontargeted approach. These biomarkers may inform about mechanisms of exposure–disease relationships. Furthermore, biomarkers approved by the U.S. Food and Drug Administration for screening in adult blood were detected in UCB and represent high-priority targets for immediate validation.

Background Lead exposure is associated with elevated blood pressure during pregnancy; however, the magnitude of this relationship at low exposure levels is unclear. Objectives Our goal was to determine the association between low-level lead exposure and blood pressure during late pregnancy. Methods We collected admission and maximum (based on systolic) blood pressures during labor and delivery among 285 women in Baltimore, Maryland. We measured umbilical cord blood lead using inductively coupled plasma mass spectrometry. Multivariable models were adjusted for age, race, median household income, parity, smoking during pregnancy, prepregnancy body mass index, and anemia. These models were used to calculate benchmark dose values. Results Geometric mean cord blood lead was 0.66 μg/dL (95% confidence interval, 0.61–0.70). Comparing blood pressure measurements between those in the highest and those in the lowest quartile of lead exposure, we observed a 6.87-mmHg (1.51–12.21 mmHg) increase in admission systolic blood pressure and a 4.40-mmHg (0.21–8.59 mmHg) increase in admission diastolic blood pressure after adjustment for confounders. Corresponding values for maximum blood pressure increase were 7.72 (1.83–13.60) and 8.33 (1.14–15.53) mmHg. Benchmark dose lower limit values for a 1-SD increase in blood pressure were < 2 μg/dL blood lead for all blood pressure end points. Conclusions A significant association between low-level lead exposures and elevations in maternal blood pressure during labor and delivery can be observed at umbilical blood lead levels < 2 μg/dL.

Background: Metals can interfere with hormonal functioning by binding at the receptor site and through indirect mechanisms; thus, they may be associated with hormonal changes in premenopausal women. Objectives: We examined the associations between cadmium, lead, and mercury, and anovulation and patterns of reproductive hormones [estradiol, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone] among 252 premenopausal women 18–44 years of age who were enrolled in the BioCycle Study in Buffalo, New York. Methods: Women were followed for up to two menstrual cycles, with serum samples collected up to eight times per cycle. Metal concentrations were determined at baseline in whole blood by inductively coupled mass spectroscopy. Marginal structural models with stabilized inverse probability weights and nonlinear mixed models with harmonic terms were used to estimate the effects of cadmium, lead, and mercury on reproductive hormone levels during the menstrual cycle and anovulation. Results: Geometric mean (interquartile range) cadmium, lead, and mercury levels were 0.29 (0.19–0.43) μg/L, 0.93 (0.68–1.20) μg/dL, and 1.03 (0.58–2.10) μg/L, respectively. We observed decreases in mean FSH with increasing cadmium [second vs. first tertile: –10.0%; 95% confidence interval (CI), –17.3% to –2.5%; third vs. first tertile: –8.3%; 95% CI, –16.0% to 0.1%] and increases in mean progesterone with increasing lead level (second vs. first tertile: 7.5%; 95% CI, 0.1–15.4%; third vs. first tertile: 6.8%; 95% CI, –0.8% to 14.9%). Metals were not significantly associated with anovulation. Conclusions: Our findings support the hypothesis that environmentally relevant levels of metals are associated with modest changes in reproductive hormone levels in healthy, premenopausal women.

Epigenomics refers to the study of genome-wide heritable changes in gene activity and expression in the progeny of cells or individuals, without a change in nucleotide sequence, and its contribution to cellular growth and differentiation, disease and aging. Epigenomics provides a window through which we can understand the exposome [1], that is the life-course impact of environment, nutrition and lifestyle choices on health and disease susceptibility, as well as risk [2]. Epigenomic processes, a whole-genome concert of heritable epigenetic changes acting with choreographed precision, behave in a cell-specific, temporally regulated fashion to direct normal development, differentiation, organogenesis, tissue formation, tissue maintenance and aging [3]. While genetic processes rely on the nucleotide sequence of the DNA, epigenomic processes depend on reversible biochemical alterations of the DNA strands or higher order chromatin packaging to regulate gene activity and expression. As such, epigenomic processes can be both appealing and elusive targets for biomonitoring environmental exposures. Epigenomic mechanisms are linked to gene activation, gene silencing and chromosomal instability, but questions still remain regarding the timing, maintenance and stability of epigenomic marks. Additional knowledge of how critical epigenomic patterns are inherited and maintained is needed to understand the role of the human epigenome in health and disease. For example, little is known regarding how normal growth and development are impacted by the epigenome, which is not a stable entity but rather highly dynamic, as it responds to micro- and macro-environments throughout the life course [4]. Epigenomic changes are tissue, exposure or disease specific and seem to be in a dynamic flux during the cell cycle and in mitotic divisions [5]. The epigenome is linked to circadian rhythms, is highly dependent on lifestyle and context and may be associated with maternal and grand-maternal exposures. As such, it is a magnificent molecular tapestry of ourselves, providing a record of where we come from and a roadmap of who we will become – invaluable information pending our ability to decipher it. Furthermore, because of its potentially modifiable, yet fundamentally stable nature, there in lies the possibility that we might learn how to manipulate the epigenome to nurture and promote health, as well as to prevent or treat disease [6].

We sought to characterize the relationships between cord serum concentrations of chlordane and permethrin pesticides, inflammatory cytokines, gestational age, and size at birth. Umbilical cord serum levels of trans-nonachlor, oxychlordane, cis- and trans-permethrin, piperonyl butoxide, and cytokines (TNF-α, IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, GMCSF) were quantified in 300 newborns at the Johns Hopkins Hospital in Baltimore, MD (2004-2005). Principal component analyses were used to quantitate chlordane and permethrin mixtures and to identify independent cytokine components. Five cytokine components described 87% of the variance in cord serum cytokine levels; these (and predominant loadings) were as follows: (1) all 9 cytokines; (2) acute phase (IL-1β, IL-6); (3) anti-inflammatory (IL-10); (4) TNF-α; and (5) IL-1β. Of these, the TNF-α component was significantly associated with a 2-day decrease in gestational age. Chlordane was associated with lower levels of the pro-inflammatory IL-1β [β: -0.11 (-0.20, -0.02)]. Permethrin was negatively associated with the anti-inflammatory cytokine IL-10 [β: -0.14 (-0.22, -0.05)]. Neither pesticides nor cytokines were significantly associated with birthweight, length, or head circumference, and pesticides were not associated with gestational age. Our findings suggest that chlordane and permethrin concentrations in cord blood may be associated with levels of inflammatory cytokines in the fetus.

Environmental exposures in utero may alter the epigenome, thus impacting chromosomal stability and gene expression. We hypothesized that in utero exposures to maternal smoking and perfluoroalkyl compounds (PFCs) are associated with global DNA hypomethylation in umbilical cord serum. Our objective was to determine if global DNA methylation could be used as a biomarker of in utero exposures to maternal smoking and PFCs. Using an ELISA-based method, global DNA methylation was quantified in umbilical cord serum from 30 newborns with high (>10 ng/ml, mean 123.8 ng/ml), low (range 1–10 ng/ml, mean 1.6 ng/ml) and very low (

We characterized the distribution and determinants of fetal exposures to pesticide mixtures using a cross-sectional study of 297 singletons delivered at Johns Hopkins Hospital in Baltimore, MD (2004-2005). Concentrations of nine persistent and twelve nonpersistent pesticides were measured in cord serum. Mixtures were identified using principal components analysis. Associations between mixtures and maternal and infant characteristics were evaluated using multivariate analysis. p,p'-DDE, p,p'-DDT, trans-nonachlor, oxychlordane, bendiocarb, propoxur, and trans- and cis-permethrin were detected in 100, 90, 93, 84, 73, 55, 52, and 41% of serum samples, respectively. There were four independent pesticide components: DDT (p,p'-DDT + p,p'-DDE), chlordane (trans-nonachlor + oxychlordane), permethrin (trans- and cis-permethrins + PBUT), and carbamate (bendiocarb + propoxur). DDT and chlordane were 6.1 (95%CI: 2.4, 15.5) and 2.1 (95%CI: 1.0, 4.2) times higher for infants of women35, and 1.8 (95%CI: 1.2, 2.9) and 1.5 (95%CI: 1.1, 2.1) times higher in smoking mothers. DDT and carbamate were 15 (95%CI: 7, 30) and 2 (95%CI: 1, 4) times higher for infants of Asian compared with Caucasian mothers. No significant differences were observed for permethrin. Fetal exposures to pesticides are widespread, occur as mixtures, and differ by maternal race, age, and smoking status.

While elevated levels of proinflammatory cytokines are clearly associated with preterm birth, the relation between cytokines and fetal growth is unclear. The authors examined associations between umbilical cord serum cytokine concentrations and risk of small-for-gestational-age (SGA) and preterm birth. This cross-sectional analysis was nested within a National Institute of Child Health and Human Development-University of Alabama population-based cohort study of high-risk prenatal care patients in Jefferson County, Alabama. Patients were enrolled between 1985 and 1988. For 370 singletons, umbilical cord serum concentrations of interferon gamma (IFN-gamma), tumor necrosis factor alpha, and interleukins 12p70, 4, and 10 were determined. Associations between each cytokine and SGA and preterm delivery were evaluated using log binomial regression. Increasing log concentration of tumor necrosis factor alpha was associated with an increased risk of preterm birth (risk ratio (RR) = 2.00, 95% confidence interval (CI): 1.31, 3.06). IFN-gamma was associated with a decreased risk of SGA birth (RR = 0.78, 95% CI: 0.61, 1.01). After stratification for preterm birth status, the association between IFN-gamma concentration and SGA birth was pronounced among preterm babies (RR = 0.56, 95% CI: 0.31, 1.01). The observations regarding IFN-gamma, which is involved in the activation of adaptive immune responses and regulation of trophoblast function, suggest that IFN-gamma levels at birth may be related to fetal growth restriction.

Genetic variation influences differential vulnerability to addiction within populations. However, it remains unclear whether differences in frequencies of vulnerability alleles contribute to disparities between populations and to what extent ancestry correlates with differential exposure to environmental risk factors, including poverty and trauma.The authors used 186 ancestry-informative markers to measure African ancestry in 407 addicts and 457 comparison subjects self-identified as African Americans. The reference group was 1,051 individuals from the Human Genome Diversity Cell Line Panel, which includes 51 diverse populations representing most worldwide genetic diversity.African Americans varied in degrees of African, European, Middle Eastern, and Central Asian genetic heritage. The overall level of African ancestry was actually smaller among cocaine, opiate, and alcohol addicts (proportion=0.76-0.78) than nonaddicted African American comparison subjects (proportion=0.81). African ancestry was associated with living in impoverished neighborhoods, a factor previously associated with risk. There was no association between African ancestry and exposure to childhood abuse or neglect, a factor that strongly predicted all types of addictions.These results suggest that African genetic heritage does not increase the likelihood of genetic risk for addictions. They highlight the complex interrelation between genetic ancestry and social, economic, and environmental conditions and the strong relation of those factors to addiction. Studies of epidemiological samples characterized for genetic ancestry and social, psychological, demographic, economic, cultural, and historical factors are needed to better disentangle the effects of genetic and environmental factors underlying interpopulation differences in vulnerability to addiction and other health disparities.

Practice-based scholarship in public health addresses community health issues. The accredited schools of public health (SPHs) have played a significant role in defining and implementing the multidisciplinary, interprofessional, ecological approach to improving the health and safety of communities through academic public health practice. These schools have addressed the challenges raised by the Institute of Medicine for enhancing academic-practice linkages. 1,2 The Association of Schools of Public Health (ASPH) established the Council of Public Health Practice Coordinators (Practice Council), whose members are delegates from each of the SPHs accredited by the Council on Education for Public Health (CEPH); there were 40 as of 2008. The Practice Council's priorities are to (1) promote greater commitment to scholarship in public health practice-based research, teaching, and service within SPHs, and (2) facilitate recognition and reward for practice- based scholarship in academic institutions. Extensive alignment of efforts by the Practice Council, SPHs, federal agencies, private institutions, and the practice sec- tor have invigorated scholarship in academic public health practice.

Background Exposures of pregnant women to natural and manmade chemicals can lead to negative health effects in the baby, ranging from low birth weight to developmental defects. In some cases, diseases were postulated to have their basis in toxic exposure in utero or in early childhood. Therefore, an understanding of fetal responses to environmental exposures is essential. To that end, cord blood is a readily accessible biofluid whose proteomic makeup remains mostly unexplored when compared with that of adults. Objectives Our goal was an initial global assessment of the fetal serum proteome and for the identification of protein biomarkers indicative of toxic in utero exposures related to maternal cigarette smoking. Methods Drawing from a repository of 300 samples, we selected umbilical cord blood sera from 12 babies born to six smokers and six nonsmokers and analyzed both sample pools by tandem mass spectrometry in conjunction with isobaric tags (iTRAQ) for protein quantification. Results We identified 203 proteins, 17 of which were differentially expressed between the cigarette smoke–exposed and control populations. Most of the identified candidate biomarkers were biologically plausible, thereby underscoring the feasibility of screening neonates with global proteomic techniques for biomarkers of exposure and early biological effects triggered by in utero chemical exposures. Conclusions This validation study provides an initial view of the proteome of human cord blood sera; it demonstrates the feasibility of identifying therein by use of proteomics, biomarkers of environmental, toxic exposures.

We investigated if prenatal exposures to tobacco smoke lead to changes in mitochondrial DNA content (mtDNA) in cord serum and adversely affect newborns’ health. Umbilical cord serum cotinine levels were used to determine in utero exposure to smoking. Cord serum mtDNA was measured by quantitative polymerase chain reaction analysis of the genes coding for cytochrome c oxidase1 (MT-CO1) and cytochrome c oxidase2 (MT-CO2). Log transformed levels of mtDNA coding for MT-CO1 and MT-CO2 were significantly higher among infants of active smokers with higher serum level of cotinine (p

Use of polybrominated diphenyl ethers (PBDEs) as flame retardants (FRs) in plastics, including electronic enclosures and poly-urethane used in upholstery cushioning and carpet pads, has increased steadily in the past 30 years (Alaee et al. 2003; de Wit 2002; Hardy 2002b). PBDEs used as additive FRs are more likely to leach over time than reactive FRs, which are chemically bonded to the plastic polymer (Alaee and Wenning 2002; Eriksson et al. 2001; Sjodin et al. 2001a). PBDEs are similar to polychlorinated biphenyls (PCBs) in structure, lipophilicity, persistence, and ability to bioaccumulate (Hardy 2002a; McDonald 2002). Since the 1970s, environmental concentrations of PCBs and other persistent organic pollutants (POPs) have fallen whereas levels of PBDEs have increased exponentially (Alaee and Wenning 2002; Eriksson et al. 2001; Meironyte et al. 1999; Sjodin et al. 2001b). Currently, human PBDE levels are of a magnitude similar to PCB concentrations in some regions (Hites 2004; Petreas et al. 2004). Human levels of PBDEs are higher in North America than in Europe and within a given population, a small fraction (5–10%) of individuals have concentrations far exceeding average levels (Betts 2003; Hites 2004; Schecter et al. 2005; Sjodin et al. 2003; Wilford et al. 2005). Although there have been no studies investigating the health effects associated with PBDEs in humans, there are reports of human exposure levels that may be on par with levels eliciting harmful effects in laboratory animals (McDonald 2005). Animal studies have shown evidence of the disruption of normal endocrine function and neurodevelopmental, hepatic, and reproductive toxicity (Betts 2004, 2005; Johnson-Restrepo et al. 2005). Currently, there is an incomplete understanding of how humans are exposed to PBDEs. It is reasonable to posit that among those with high concentrations, occupational exposures may be involved in some cases (Sjodin et al. 1999; Thuresson et al. 2005). In the general population, several potential routes of PBDE exposure have been identified: a) direct contact with treated products; b) dietary, as these lipophilic compounds are stored in the fat of meats, fish, and dairy products (Harrad et al. 2004; Schecter et al. 2004, 2006; Wilford et al. 2005); and c) ingestion and to a lesser degree inhalation of PBDE-containing house dust (Jones-Otazo et al. 2005; Stapleton et al. 2005; Wilford et al. 2005; Wu et al. 2007) Only a few studies have been able to explore individual determinants of PBDE body burdens in much detail (Morland et al. 2005; Wu et al. 2007). Levels of PBDEs (as well as PCBs and organochlorine pesticides) measured in adipose tissue, blood, or milk can be used to assess exposures (Sjodin et al. 2003). Infants and fetuses are sensitive subpopulations to consider, because these stages of development may be especially susceptible to effects of chemical exposures (Howdeshell 2002). Toxicologic models have indicated that immature animals have slower metabolism and excretion of PBDEs; approximately 50% of the administered 2,2′,4,4′-tetraBDE (BDE-47) dose is excreted in the first 24 hr in adult animals compared with 31% and 41% in animals dosed at 10 and 22 days after birth (Staskal et al. 2006). Measuring PBDEs in cord blood serum is noninvasive, using a blood sample that is otherwise usually discarded, and is a direct measure of prenatal exposure. The estimated half-lives of these compounds in humans are long enough—BDE-47 1.8–3.0 years, 2,2′,4,4′,5-pentaBDE (BDE-99) 2.9–5.4 years, and 2,2′,4,4′,5,5′-hexaBDE (BDE-153) 6.5–11.7 years (Geyer et al. 2004)—that cord blood concentrations reflect exposure through the course of pregnancy. Such levels also provide a reasonable estimate of maternal serum concentrations (Mazdai et al. 2003). The principal objective of this investigation was to characterize fetal exposure to PBDEs and selected PCBs among newborns from Baltimore, Maryland, via the assessment of concentrations in umbilical cord serum. We explored demographic characteristics and attributes to identify determinants and to explain variations in exposure levels and patterns within this largely urban and African-American population.

This paper provides an overview of U.S. government pesticide risk management efforts over time and in recent years, relevant to chronic health risks of pesticides. Pesticides are in widespread usage in the U.S. With hundreds of active ingredients and thousands of products on the market, management of pesticide risks has been a daunting challenge. The first legislation providing federal authority for regulating pesticides was enacted in 1910. With the establishment of the U.S. Environmental Protection Agency in 1970 and amendments to the pesticide law in 1972, the federal government was for the first time given the authority to regulate health and environmental risks of pesticides. However, older pesticide risks were not addressed until legislation was enacted in 1988, requiring "reregistration" and 1996, requiring that pesticide food standards are safe for children. In result, the U.S. has seen an expansion of development of pesticide products that are registered as "reduced risk" or are biologicals. Additionally a large number of older pesticides have been cancelled or reduced from the market and/or from individual food uses. Through biomonitoring data, the U.S. may now be seeing trends in reduction of exposure to certain pesticides, the organophosphate insecticides. However, pesticide sales data through 2001 do not provide evidence for such trends.

Polyfluoroalkyl compounds (PFCs) comprise a class of man-made, fluorinated organic compounds that have been used in a variety of consumer and industrial applications. Although these have been produced for many years, only recently have reports surfaced suggesting widespread exposure in wildlife and humans (Butenhoff et al. 2006; Calafat et al. 2007; Giesy and Kannan 2001; Houde et al. 2006; Kannan et al. 2004). Two of the most widely detected and studied compounds in this class are perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA). PFOS and related compounds (polyfluorinated sulfonamides) are surfactants used in applications ranging from oil and water repellents for fabrics, apparel, carpets, and paper coatings to specialty chemical applications such as insecticides and fire fighting foams (3M Company 1999). PFOA and its salts are used as chemical intermediates and processing aids in the production of fluoropolymers and fluoroelastomers. Both PFOS and PFOA have shown the potential for developmental toxicity in animal studies. PFOS has been shown, in rats and mice, to induce developmental and reproductive effects, such as reduced birth weight, decreased gestational length, structural defects, developmental delays, and increased neonatal mortality (Fuentes et al. 2006; Grasty et al. 2003; Lau et al. 2003; Luebker et al. 2005a, 2005b; Thibodeaux et al. 2003). Recent studies have also reported developmental toxicity from PFOA in rodents, including pregnancy loss, reduced fetal weight, reduced postnatal survival, and delays in postnatal growth and development in offspring (Butenhoff et al. 2004; Lau et al. 2004, 2006). However, such studies of PFOS and PFOA have been conducted using doses that produce serum concentrations much higher than general population human exposures. There are limited epidemiologic data on the potential impacts of PFC exposure on fetal growth and development. However, one recent occupational study found no association between employment in jobs with high exposure to PFOS before the end of pregnancy and maternally reported birth weight (Grice et al. 2007). PFOS and PFOA have also been shown to cause reductions in serum cholesterol and/or triglycerides in several animal species (Haughom and Spydevold 1992; Seacat et al. 2002, 2003; Thibodeaux et al. 2003). Conversely, a few cross-sectional occupational studies conducted among fluorochemical production employees have reported positive relationships between PFOS and/or PFOA concentrations and serum lipid levels (Gilliland and Mandel 1996; Olsen et al. 1999, 2003). The fetus is likely to be sensitive to the availability of cholesterol and triglycerides, which support cellular growth, differentiation, and adipose accumulation (Woollett 2001). Disruptions to normal fetal growth and development have been associated with effects across the lifespan, including adverse neonatal and childhood outcomes (Hofman et al. 1997; Kramer et al. 1990) and metabolic diseases in adulthood (Barker 2006). In a previous report, we documented factors associated with cord serum concentrations of PFOS and PFOA in a population of newborn deliveries known as the Baltimore THREE study (Apelberg et al. 2007). In this study, we examined the relationship between these concentrations and gestational age, birth weight, and measures of birth size, including head circumference, length, and ponderal index (a measure of body mass at birth).

BackgroundEpigenetic mechanisms such as altered DNA methylation have been suggested to play a role in autism, beginning with the classical association of Prader-Willi syndrome, an imprinting disorder, with autistic features.ObjectivesHere we tested for the relationship of paternal sperm DNA methylation with autism risk in offspring, examining an enriched-risk cohort of fathers of autistic children.MethodsWe examined genome-wide DNA methylation (DNAm) in paternal semen biosamples obtained from an autism spectrum disorder (ASD) enriched-risk pregnancy cohort, the Early Autism Risk Longitudinal Investigation (EARLI) cohort, to estimate associations between sperm DNAm and prospective ASD development, using a 12-month ASD symptoms assessment, the Autism Observation Scale for Infants (AOSI). We analysed methylation data from 44 sperm samples run on the CHARM 3.0 array, which contains over 4 million probes (over 7 million CpG sites), including 30 samples also run on the Illumina Infinium HumanMethylation450 (450K) BeadChip platform (∼485000 CpG sites). We also examined associated regions in an independent sample of post-mortem human brain ASD and control samples for which Illumina 450K DNA methylation data were available.ResultsUsing region-based statistical approaches, we identified 193 differentially methylated regions (DMRs) in paternal sperm with a family-wise empirical P-value [family-wise error rate (FWER)]

Drinking water at Shatila Palestinian Refugee Camp in Beirut, Lebanon is of poor quality and unpredictably intermittent quantity. We aimed to characterize drinking water sources and contamination at Shatila and determine how drinking water can be managed to reduce community health burdens. We interviewed the Popular Committee, well owners, water vendors, water shopkeepers and preschool administrators about drinking water sources, treatment methods and the population served. Water samples from the sources and intermediaries were analysed for thermotolerant faecal coliforms (FCs), Giardia lamblia, Cryptosporidium parvum and microsporidia, using immunofluorescent antibody detection for G. lamblia and C. parvum, and chromotrope-2 stain for microsporidia. All drinking water sources were contaminated with FCs and parasites. FC counts (cfu/mL) were as follows: wells (35-300), water vendors (2-178), shops (30-300) and preschools (230-300). Responsible factors identified included: unskilled operators; improper maintenance of wells and equipment; lack of proper water storage and handling; and misperception of water quality. These factors must be addressed to improve water quality at Shatila and other refugee camps.معالجة منظومة مياه الشرب والتلوثُ في مخيم شاتيلا للاجئين في بيروت بلبنان.سمر خوري، ثاديوس غريسيك، غيلبرت برنم، ماي جردي، لين غولدمان.إن مياه الشرب في مخيم شاتيلا للاجئين الفلسطينيين في بيروت بلبنان رديئة الجودة، ومن حيث الكمية فإنها تتعرض للانقطاع على نحو لا يمكن التكهن به. وقد هدفنا إلى الوقوف على خصائص مصادر مياه الشرب وعلى تلوث المياه في شاتيلا، وإلى تحديد الكيفية التي يمكن أن تعالج بها مياه الشرب للحد من أعباء صحة المجتمع. فأجرينا مقابلات مع اللجنة الشعبية ومُلاك الآبار وبائعي المياه وأصحاب متاجر المياه ومشرفي رياض الأطفال، حول مصادر مياه الشرب وطرق معالجتها والسكان الذين تقدم لهم. وتم تحليل عينات مياه من المصادر ومن أماكن وسيطة بحثاً عن القولونيات البرازية المتحملة للحرارة والجياردية اللمبلية وخفية الأبواغ الصغيرة (كريبتوسبوريديم بارفوم) ومكرويّات الأبواغ، وذلك باستخدام الكشف المتألق للأجسام المضادة للجياردية اللمبلية وخفية الأبواغ الصغيرة، وملوِّن 2-chromotrope لمكرويات الأبواغ. فوجِد أن جميع مصادر مياه الشرب ملوثة بالقولونيات البرازية والطفيليات. وكان تعداد القولونيات البرازية (cfu/mL) على النحو التالي: في الآبار (35-300)، وعند بائعي المياه (2-178)، وفي المتاجر (30-300)، وفي رياض الأطفال (230-300). ومن العوامل المسؤولة التي تم تحديدها: عدم مهارة العمال، وسوء صيانة الآبار والمعدات، وعدم تخزين المياه وتداولها بصورة صحيحة، والتصور الخاطئ لجودة المياه. يجب معالجة هذه العوامل لتحسين جودة المياه في شاتيلا وغيرها من مخيمات اللاجئين.Traitement et contamination des systèmes d’eau potable dans le camp de réfugiés de Chatila à Beyrouth, au Liban.L’eau potable dans le camp de réfugiés palestiniens de Chatila, au Liban, est de mauvaise qualité et n’est disponible qu’en quantités imprévisibles et irrégulières. La présente étude avait pour objectif d’identifier les sources d’eau potable et de contamination à Chatila, et de déterminer la façon dont l’eau potable peut être gérée pour réduire la charge des problèmes de santé communautaires. Nous avons interrogé le Comité populaire, les propriétaires de puits, les vendeurs d’eau ambulants, les marchands d’eau, les responsables de structures préscolaires sur les sources d’eau potable, les méthodes de traitement et la population desservie. Des échantillons d’eau à la source et au niveau des intermédiaires ont été analysés afin de détecter la présence de coliformes thermotolérants, de Giardia lamblia, de Cryptosporidium parvum et de microsporidies, à l’aide de la recherche des anticorps par immunofluorescence pour G. lamblia and C. parvum, et de la coloration au chromotrope 2R pour les microsporidies. Toutes les sources d’eau potable étaient contaminées par des coliformes thermotolérants et des parasites. Les taux (ufc/ml) de coliformes thermotolérants étaient les suivants : puits (35-300), vendeurs d’eau ambulants (2-178), commerces (30-300) et structures préscolaires (230-300). Les facteurs responsables identifiés incluaient les points suivants : des opérateurs non formés, une mauvaise maintenance des puits et des équipements, un stockage et une manutention de l’eau inappropriés, et une perception erronée de la qualité de l’eau. Il est nécessaire d’agir sur ces facteurs afin d’améliorer la qualité de l’eau à Chatila et dans les autres camps de réfugiés.

Background: Human exposure to the widespread environmental contaminant mercury is a known risk factor for common diseases such as cancer, cardiovascular disease and neurological disorders through poorly characterized mechanisms. Evidence suggests mercury exposure may alter DNA methylation levels, but to date, the effects in early life on a genome-wide scale have not been investigated. Methods: A study sample of 141 newborns was recruited in Baltimore, MD, USA and total mercury and methylmercury were measured in cord blood samples. We quantified genome-wide DNA methylation data using CHARM 2.0, an array-based method, and used region-finding analyses to identify concentration-associated differentially methylated regions (DMRs). To test for replication of these identified DMRs in the pilot, or Vanguard, phase of the National Children’s Study (NCS), we compared bisulfite-pyrosequenced DNA at candidate regions from 85 whole cord blood samples with matched first trimester maternal mercury concentration measures. Results: Total mercury concentration was associated with methylation at DMRs inside ANGPT2 and near PRPF18 genes [false discovery rate (FDR) < 0.05], as well as DMRs near FOXD2 and within TCEANC2 (FDR< 0.1) genes. Methylmercury concentration was associated with an overlapping DMR within TCEANC2 (FDR< 0.05). In NCS replication analyses, methylation levels at three of four cytosine-guanine DNA dinucleotides (CpG sites) within the TCEANC2 DMR were associated with total mercury concentration (P

There is broad agreement that regulatory decisions should be based on evidence. But interested parties have used the “sound science” mantle to demand extended research, analysis, and review of evidence for the sole purpose of delaying health-protective regulation. This historical review shows how the forces behind the “sound science” reasoning leading to the Daubert v Merrell Dow Pharmaceuticals, Inc decision on science in the courtroom have operated in parallel in environmental regulation. Like Daubert, certain “sound science” regulatory tools can be used to improve decision quality. However, these tools can also challenge the federal government’s ability to safeguard the public’s health and well-being. Most recently, political tampering with science provides the foundation for some policymakers to disregard science completely in the environmental regulatory process.

On May 22, 2013, the late Senator Frank Lautenberg (D-NJ), Senator David Vitter (R-LA) and 19 of their colleagues introduced bipartisan chemical safety legislation in the US Senate, “The Chemical Safety Improvement Act of 2013.” The bill's purpose is to protect human health and the environment against the hazards of toxic chemicals, by requiring the US Environmental Protection Agency (EPA) to examine the safety of all chemicals in consumer products. The bill is currently before the Senate Committee on Environment and Public Works, chaired by Senator Barbara Boxer (D-CA). This legislation is critically important for physicians and healthcare organizations because it creates significant new opportunities to prevent disease and cut healthcare costs. Am. J. Ind. Med. 57:1–3, 2014. © 2013 Wiley Periodicals, Inc.

Recent public recognition that children are different from adults in their exposures and susceptibilities to environmental contaminants has its roots in work that began >46 years ago, when the American Academy of Pediatrics (APA) established a standing committee to focus on children’s radiation exposures. We summarize the history of that important committee, now the AAP Committee on Environmental Health, including its statements and the 1999 publication of the AAP Handbook of Pediatric Environmental Health, and describe the recent emergence of federal and state legislative and executive actions to evaluate explicitly environmental health risks to children. As a result in large part of these efforts, numerous knowledge gaps about children’s health and the environment are currently being addressed. Government efforts began in the 1970s to reduce childhood lead poisoning and to monitor birth defects and cancer. In the 1990s, federal efforts accelerated with the Food Quality Protection Act, an executive order on children’s environmental health, the Agency for Toxic Substances and Disease Registry/Environmental Protection Agency Pediatric Environmental Health Specialty Units, and National Institute of Environmental Health Sciences/Environmental Protection Agency Centers of Excellence in Research in Children’s Environmental Health. In this decade, the Children’s Environmental Health Act authorized the National Children’s Study, which has the potential to address a number of critical questions about children’s exposure and health. The federal government has expanded efforts in control and prevention of childhood asthma and in tracking of asthma, birth defects, and other diseases that are linked to the environment. Efforts continue on familiar problems such as the eradication of lead poisoning, but new issues, such as prevention of childhood exposure to carcinogens and neurotoxins other than lead, and emerging issues, such as endocrine disruptors and pediatric drug evaluations, are in the forefront. More recently, these issues have been taken up by states and in the international arena.

Pesticide manufacturers have tested pesticides increasingly in human volunteers over the past decade. The apparent goal of these human studies is to establish threshold levels for symptoms, termed "no observed effect levels." Data from these studies have been submitted to the U.S. Environmental Protection Agency (EPA) for consideration in standard setting. There are no required ethical guidelines for studies of pesticides toxicity conducted in humans, no governmental oversight is exercised, and no procedures have been put in place for the protection of human subjects. To examine ethical and policy issues involved in the testing of pesticides in humans and the use of human data in standard setting, in February 2002 the Center for Children's Health and the Environment of the Mount Sinai School of Medicine convened an expert workshop for ethicists, physicians, toxicologists, and policy analysts. After a peer consensus process, participants developed a number of ethical and public policy recommendations regarding the testing of pesticides in humans. Participants also strongly encouraged active biomonitoring of every pesticide currently in use to track human exposure, particularly in vulnerable populations, and to assess adverse effects on health.

A total of 20 commercial cigarette and 16 commercial smokeless tobacco products were assayed for 96 25 compounds listed as harmful and potentially harmful constituents (HPHCs) by the US Food and Drug 26 Administration. For each product, a single lot was used for all testing. Both International Organization 27 for Standardization and Health Canada smoking regimens were used for cigarette testing. For those 28 HPHCs detected, measured levels were consistent with levels reported in the literature, however substan29 tial assay variability (measured as average relative standard deviation) was found for most results. Using 30 an abbreviated list of HPHCs, statistically significant differences for most of these HPHCs occurred when

The risk assessment process as spelled out in the National Research Council's (NRC's) report Risk Assessment in the Federal Government: Managing the Process, called the “Red Book,” has created a framework for incorporation of toxicology into environmental decision-making that has withstood the test of time. However, the time has come for a reassessment of this framework. Risk assessment is often unsuccessful as a public health tool when data are limited and it does not, in itself, provide an incentive for the generation of new data. The risk assessment framework did not envision the need to develop formal methods for the incorporation of precautionary approaches into the formal regulatory/analytical process. This needs to be addressed, as we see a widening gulf in approaches between the U.S. and Europe. Likewise, the process has not provided a clear road map for the utilization of epidemiology and health tracking information to guide environmental regulation. Finally, the concept of separating the intelle...

Technology has improved the food supply since the first cultivation of crops. Genetic engineering facilitates the transfer of genes among organisms. Generally, only minute amounts of a specific protein need to be expressed to obtain the desired trait. Food allergy affects only individuals with an abnormal immunologic response to food--6% of children and 1.5-2% of adults in the United States. Not all diseases caused by food allergy are mediated by IgE. A number of expert committees have advised the U.S. government and international organizations on risk assessment for allergenicity of food proteins. These committees have created decision trees largely based on assessment of IgE-mediated food allergenicity. Difficulties include the limited availability of allergen-specific IgE antisera from allergic persons as validated source material, the utility of specific IgE assays, limited characterization of food proteins, cross-reactivity between food and other allergens, and modifications of food proteins by processing. StarLink was a corn variety modified to produce a (Italic)Bacillus thuringiensis(/Italic) (Bt) endotoxin, Cry9C. The Centers for Disease Control and Prevention investigated 51 reports of possible adverse reactions to corn that occurred after the announcement that StarLink, allowed for animal feed, was found in the human food supply. Allergic reactions were not confirmed, but tools for postmarket assessment were limited. Workers in agricultural and food preparation facilities have potential inhalation exposure to plant dusts and flours. In 1999, researchers found that migrant health workers can become sensitized to certain Bt spore extracts after exposure to Bt spraying.

On the final afternoon of the workshop "Assessment of the Allergenic Potential of Genetically Modified Foods," held 10-12 December 2001 in Chapel Hill, North Carolina, USA, speakers and participants met in breakout groups to discuss specific questions in the areas of use of human clinical data, animal models to assess food allergy, biomarkers of exposure and effect, sensitive populations, dose-response assessment, and postmarket surveillance. Each group addressed general questions regarding allergenicity of genetically modified foods and specific questions for each subject area. This article is a brief summary of the discussions of each of the six breakout groups regarding our current state of knowledge and what information is needed to advance the field.

Modern biotechnology has dramatically increased our ability to alter the agronomic traits of plants. Among the novel traits that biotechnology has made available, an important group includes Bacillus thuringiensis-derived insect resistance. This technology has been applied to potatoes, cotton, and corn. Benefits of Bt crops, and biotechnology generally, can be realized only if risks are assessed and managed properly. The case of Starlink corn, a plant modified with a gene that encodes the Bt protein Cry9c, was a severe test of U.S. regulatory agencies. The U.S. Environmental Protection Agency had restricted its use to animal feed due to concern about the potential for allergenicity. However, Starlink corn was later found throughout the human food supply, resulting in food recalls by the Food and Drug Administration and significant disruption of the food supply. Here we examine the regulatory history of Starlink, the assessment framework employed by the U.S. government, assumptions and information gaps, and the key elements of government efforts to manage the product. We explore the impacts on regulations, science, and society and conclude that only significant advances in our understanding of food allergies and improvements in monitoring and enforcement will avoid similar events in the future. Specifically, we need to develop a stronger fundamental basis for predicting allergic sensitization and reactions if novel proteins are to be introduced in this fashion. Mechanisms are needed to assure that worker and community aeroallergen risks are considered. Requirements are needed for the development of valid assays so that enforcement and post market surveillance activities can be conducted.