Faculty Bibliography

BACKGROUND/UNASSIGNED:Men stationed on nuclear-powered submarines are occupationally exposed to external ionizing radiation at very low levels and radiation dose for each individual is closely monitored. Little is known about ionizing radiation (IR) risks of cancer mortality for populations with levels of cumulative ionizing radiation exposure this low. MATERIALS AND METHODS/UNASSIGNED:This historical cohort study followed 85,033 enlisted men who had served on a nuclear-powered submarine in the U.S. Navy between 1969 and 1982 to determine patterns of cancer mortality. Occupational radiation doses were measured by badge dosimeters for each individual for all periods of Navy service potentially involving radiation exposure. Deaths were ascertained through 1995 by searches of multiple national mortality databases. Within-cohort dose-response relationships for cancer mortality were estimated using linear Poisson regression models. Individual-level smoking status was not available so cancer risks were estimated separately for cancers with and without previously published evidence of consistently moderate or strong associations with smoking. RESULTS/UNASSIGNED:A total of 584 cancer deaths occurred during a follow-up period of up to 27 years. The mean and median cumulative occupational radiation doses received while in the Navy were 5.7 and 1.1 milliSieverts (mSv), respectively, range 0-242 mSv. Mortality Excess Relative Risks (ERRs) per 10 mSv and 95% confidence intervals (CI) were 0.053 (CI -0.03, 0.17) for all cancers, 0.052 (CI -0.03, 0.18) for all solid cancers, and 0.003 (CI -0.29, 0.30) for leukemias excluding chronic lymphocytic leukemia. The ERRs per 10 mSv were 0.052 (CI -0.07, 0.17) for cancers previously associated with smoking and 0.012 (CI -0.10, 0.12) for cancers that were not. CONCLUSIONS/UNASSIGNED:The ERR point estimates for solid cancers and leukemia were statistically compatible with those reported in previously published studies of other ionizing radiation-exposed and monitored cohorts, albeit with wide confidence intervals. This study, with high-quality measurements of in-Navy occupational external IR doses, high follow-up proportion, and detailed IR dose-response analyses, is consistent with the premise of small excess cancer risks from low-dose IR.

OBJECTIVE:To describe the long-term mortality experience of a cohort of enlisted men who served on nuclear-powered submarines in the United States Navy and breathed recirculated filtered air for extended periods of time. METHODS:In this historical cohort study we estimated standardized mortality ratios (SMRs) and used within-cohort Poisson regression analyses to address healthy worker biases. RESULTS:Three thousand two hundred sixty three deaths occurred among 85,498 men during 1,926,875 person-years of follow-up from 1969 to 1995. SMRs were reduced for most cause-of-death categories, prostate cancer had a twofold elevation. In within-cohort comparisons, prostate cancer mortality did not increase with duration of submarine service, but ischemic heart disease mortality increased 26% per 5 years of submarine service. CONCLUSIONS:Long periods of submarine service do not increase mortality in most cause-of-death categories. Increased mortality from ischemic heart disease likely reflects the effects of tobacco smoke.

The rapid growth of the coronavirus disease 2019 (COVID-19) pandemic, limited availability of personal protective equipment, and uncertainties regarding transmission modes of the novel severe acute respiratory syndrome coronavirus - 2 (SARS-CoV-2) have heightened concerns for safety of healthcare workers (HCWs). Systematic studies of occupational risks for COVID-19 in the context of community risks are difficult and are only recently starting to be reported. Ongoing quality improvement studies in various locales and within many affected healthcare institutions are needed. We propose a template design for small-scale quality improvement surveys. Such surveys have the potential for rapid implementation and completion, are cost-effective, impose little administrative or workforce burden, can reveal occupational risks while taking into account community risks, and can be easily repeated with short intervals of time between repetitions. We describe a template design and propose a survey instrument that is easily modifiable to fit the particular needs of various healthcare institutions in the hope of beginning a collaborative effort to refine the design and instrument. These methods, along with data management and analytic techniques, can be widely useful and shared globally. Our goal is to facilitate quality improvement surveys aimed at reducing the risk of occupational infection of healthcare workers during the COVID-19 pandemic.

Introduction The process of determining occupational aetiology of a disease in an individual patient (etiologic diagnosis or Specific Causation) is central to the current practice of occupational medicine. We typically need to determine Specific Causation to assist us in decision-making related to safe return-to-work, prevention of worsening of disease or re-injury of a patient, as well as wage replacement and reimbursement of medical care expenses for patients with disabling diseases potentially of occupational aetiology. Incorrectly attributing or denying occupational causes of disease can each cause serious harm to patients, their families, their employers, coworkers, and society. Potential contributors to inaccurate determination of Specific Causation include diagnostic, toxicologic, mechanistic and exposure-related uncertainties as well as scientific limitations of medicolegal concepts, including the 'probability of causation' and 'more likely than not' criteria sometimes used in workers' compensation decision-making. Improving accuracy of determination of Specific Causation is deserving of additional research attention. Methods We review the current status of causal inference at the individual level in occupational medicine and apply some of the recently developed concepts in causal inference theory from epidemiology and statistics to the decision-making process in clinical occupational medicine. Results We illustrate with examples of patients with cancer, respiratory disorders or chemical toxicity some of the limitations of the current decision-making process. We propose some modifications in approach to determination of Specific Causation that may better address issues of multiple additive or interacting causal factors, acceleration of phenotypic expression of a disease, aggravation of pre-existing disease, and challenges of applying medicolegal criteria that do not account for these factors. Discussion We discuss alternative approaches to Specific Causation that incorporate recent scientific developments in causal inference, explicitly address some of the existing inadequacies, and aim to enable more fair and accurate decision-making with respect to occupational disease causation in individuals

Endothelin-1 (ET-1) is a vasoactive peptide that also plays a role in the tanning response of the skin. Animal and cell culture studies have also implicated ET-1 in melanoma progression, but no association studies have been performed to link ET-1 expression and melanoma in humans. Here, we present the first in-vivo study of ET-1 expression in pigmented lesions in humans: an ET-1 immunohistochemical screen of melanocytic nevi, melanoma in situ lesions, invasive melanomas, metastatic melanomas, and blue nevi was performed. Twenty-six percent of melanocytic nevi and 44% of melanoma in situ lesions demonstrate ET-1 expression in the perilesional microenvironment, whereas expression in nevus or melanoma cells was rare to absent. In striking contrast, 100% of moderately to highly pigmented invasive melanomas contained numerous ET-1-positive cells in the tumor microenvironment, with 79% containing ET-1-positive melanoma cells, confirmed by co-staining with melanoma tumor marker HMB45. Hypopigmented invasive melanomas had reduced ET-1 expression, suggesting a correlation between ET-1 expression and pigmented melanomas. ET-1-positive perilesional cells were CD68-positive, indicating macrophage origin. Sixty-two percent of highly pigmented metastatic melanomas demonstrated ET-1 expression in melanoma cells, in contrast to 28.2% of hypopigmented specimens. Eighty-nine percent of benign nevi, known as blue nevi, which have a dermal localization, were associated with numerous ET-1-positive macrophages in the perilesional microenvironment, but no ET-1 expression was detected in the melanocytes. We conclude that ET-1 expression in the microenvironment increases with advancing stages of melanocyte transformation, implicating a critical role for ET-1 in melanoma progression, and the importance of the tumor microenvironment in the melanoma phenotype.

Occupational asthma (OA) and work-exacerbated asthma (WEA), collectively known as work-related asthma (WRA), have been recognized as the most prevalent work-related lung diseases in the industrialized world. OA is asthma caused by workplace conditions, and is subdivided into sensitizer-induced (allergic) OA and irritant-induced (nonallergic) OA. WEA is asthma that is made worse, but was not initially caused, by workplace conditions. Although WRA is rarely fatal, patients with WRA frequently experience excessive time lost from work, workplace-specific severe disability, loss of income, job loss, and related psychosocial and financial problems. More than 400 workplace environmental agents have been reported to cause WRA, and are classified by molecular weight and allergenic and irritant properties. Diagnosis of WRA requires confirmation of a diagnosis of asthma plus evidence that the asthma was caused or worsened by workplace conditions. Accuracy of diagnosis is important because either overdiagnosis or missed diagnosis of WRA can be problematic for the patient. Self-reported clinical symptoms alone have only fair sensitivity and specificity for OA. If possible, diagnostic assessment should also include objective evidence with functional and immunologic testing. Treatment and prevention of onset or worsening of WRA can be highly effective and typically include both optimal medical management (generally the same as for non-WRA) and, importantly, avoidance of sensitizer or irritant exposures that caused or exacerbate the asthma. In most cases of OA, prognosis is better with cessation rather than reduction of exposure, and this may require substantial changes in the workplace environment or change of job or even profession.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with high medical morbidity, but the nature of this association remains unclear. Among responders to the World Trade Center (WTC) disaster, PTSD is highly comorbid with lower respiratory symptoms (LRS), which cannot be explained by exposure alone. We sought to examine this association longitudinally to establish the direction of the effects and evaluate potential pathways to comorbidity. METHODS: 18,896 responders (8466 police and 10,430 nontraditional responders) participating in the WTC-Health Program were first evaluated between 2002 and 2010 and assessed again 2.5 years later. LRS were ascertained by medical staff, abnormal pulmonary function by spirometry, and probable WTC-related PTSD with a symptom inventory. RESULTS: In both groups of responders, initial PTSD (standardized regression coefficient: beta = 0.20 and 0.23) and abnormal pulmonary function (beta = 0.12 and 0.12) predicted LRS 2.5 years later after controlling for initial LRS and covariates. At follow-up, LRS onset was 2.0 times more likely and remission 1.8 times less likely in responders with initial PTSD than in responders without. Moreover, PTSD mediated, in part, the association between WTC exposures and development of LRS (p < .0001). Initial LRS and abnormal pulmonary function did not consistently predict PTSD onset. CONCLUSIONS: These analyses provide further evidence that PTSD is a risk factor for respiratory symptoms and are consistent with evidence implicating physiological dysregulation associated with PTSD in the development of medical conditions. If these effects are verified experimentally, treatment of PTSD may prove helpful in managing physical and mental health of disaster responders.

BACKGROUND: Thousands of rescue and recovery workers descended on the World Trade Center (WTC) in the wake of the terrorist attack of September 11, 2001 (9/11). Recent studies show that respiratory illness and post-traumatic stress disorder (PTSD) are the hallmark health problems, but relationships between them are poorly understood. The current study examined this link and evaluated contributions of WTC exposures.MethodParticipants were 8508 police and 12 333 non-traditional responders examined at the WTC Medical Monitoring and Treatment Program (WTC-MMTP), a clinic network in the New York area established by the National Institute for Occupational Safety and Health (NIOSH). We used structural equation modeling (SEM) to explore patterns of association among exposures, other risk factors, probable WTC-related PTSD [based on the PTSD Checklist (PCL)], physician-assessed respiratory symptoms arising after 9/11 and present at examination, and abnormal pulmonary functioning defined by low forced vital capacity (FVC). RESULTS: Fewer police than non-traditional responders had probable PTSD (5.9% v. 23.0%) and respiratory symptoms (22.5% v. 28.4%), whereas pulmonary function was similar. PTSD and respiratory symptoms were moderately correlated (r=0.28 for police and 0.27 for non-traditional responders). Exposure was more strongly associated with respiratory symptoms than with PTSD or lung function. The SEM model that best fit the data in both groups suggested that PTSD statistically mediated the association of exposure with respiratory symptoms. CONCLUSIONS: Although longitudinal data are needed to confirm the mediation hypothesis, the link between PTSD and respiratory symptoms is noteworthy and calls for further investigation. The findings also support the value of integrated medical and psychiatric treatment for disaster responders.

There are compelling reasons to conduct studies of cancer in Hispanics, the fastest growing major demographic group in the United States (from 15% to 30% of the U.S. population by 2050). The genetically admixed Hispanic population coupled with secular trends in environmental exposures and lifestyle/behavioral practices that are associated with immigration and acculturation offer opportunities for elucidating the effects of genetics, environment, and lifestyle on cancer risk and identifying novel risk factors. For example, traditional breast cancer risk factors explain less of the breast cancer risk in Hispanics than in non-Hispanic whites (NHW), and there is a substantially greater proportion of never-smokers with lung cancer in Hispanics than in NHW. Hispanics have higher incidence rates for cancers of the cervix, stomach, liver, and gall bladder than NHW. With respect to these cancers, there are intriguing patterns that warrant study (e.g., depending on country of origin, the five-fold difference in gastric cancer rates for Hispanic men but not Hispanic women). Also, despite a substantially higher incidence rate and increasing secular trend for liver cancer in Hispanics, there have been no studies of Hispanics reported to date. We review the literature and discuss study design options and features that should be considered in future studies. Cancer Prev Res; 5(2); 150-63. (c)2012 AACR.