A framework for integrating evidence to assess hazards and risk.

To accurately characterize human health hazards, human, animal, and mechanistic data must be integrated and the relevance to the research question of all three lines of evidence must be considered. Mechanistic data are often critical to the full integration of animal and human data and to characterizing relevance and uncertainty. This novel evidence integration framework (EIF) provides a method for synthesizing data from comprehensive, systematic, quality-based assessments of the epidemiological and toxicological literature, including in vivo and in vitro mechanistic studies. It organizes data according to both the observed human health effects and the mechanism of action of the chemical, providing a method to support evidence synthesis. The disease-based component uses the evidence of human health outcomes studied in the best quality epidemiological literature to organize the toxicological data according to authors' stated purpose, with the pathophysiology of the disease determining the potential relevance of the toxicological data. The mechanism-based component organizes the data based on the proposed mechanisms of effect and data supporting events leading to each endpoint, with the epidemiological data potentially providing corroborating information. The EIF includes a method to cross-classify and describe the concordance of the data, and to characterize its uncertainty. At times, the two methods of organizing the data may lead to different conclusions. This facilitates identification of knowledge gaps and shows the impact of uncertainties on the strength of causal inference.

Estimating the Population Health Impact of Recently Introduced Modified Risk Tobacco Products: A Comparison of Different Approaches.

INTRODUCTION: Various approaches have been used to estimate the population health impact of introducing a Modified Risk Tobacco Product (MRTP). AIMS AND METHODS: We aimed to compare and contrast aspects of models considering effects on mortality that were known to experts attending a meeting on models in 2018. RESULTS: Thirteen models are described, some focussing on e-cigarettes, others more general. Most models are cohort-based, comparing results with or without MRTP introduction. They typically start with a population with known smoking habits and then use transition probabilities either to update smoking habits in the "null scenario" or joint smoking and MRTP habits in an "alternative scenario". The models vary in the tobacco groups and transition probabilities considered. Based on aspects of the tobacco history developed, the models compare mortality risks, and sometimes life-years lost and health costs, between scenarios. Estimating effects on population health depends on frequency of use of the MRTP and smoking, and the extent to which the products expose users to harmful constituents. Strengths and weaknesses of the approaches are summarized. CONCLUSIONS: Despite methodological differences, most modellers have assumed the increase in risk of mortality from MRTP use, relative to that from cigarette smoking, to be very low and have concluded that MRTP introduction is likely to have a beneficial impact. Further model development, supplemented by preliminary results from well-designed epidemiological studies, should enable more precise prediction of the anticipated effects of MRTP introduction. IMPLICATIONS: There is a need to estimate the population health impact of introducing modified risk nicotine-containing products for smokers unwilling or unable to quit. This paper reviews a variety of modeling methodologies proposed to do this, and discusses the implications of the different approaches. It should assist modelers in refining and improving their models, and help toward providing authorities with more reliable estimates.

Using residential proximity to wind turbines as an alternative exposure measure to investigate the association between wind turbines and human health.

This analysis uses data from the Community Noise and Health Study developed by Statistics Canada to investigate the association between residential proximity to wind turbines and health-related outcomes in a dataset that also provides objective measures of wind turbine noise. The findings indicate that residential proximity to wind turbines is correlated with annoyance and health-related quality of life measures. These associations differ in some respects from associations with noise measurements. Results can be used to support discussions between communities and wind-turbine developers regarding potential health effects of wind turbines.

Risk Factors for Training-Related Injuries During U.S. Army Basic Combat Training.

Background: Injuries during basic combat training (BCT) impact military health and readiness in the U.S. Army. Identifying risk factors is crucial for injury prevention, but few Army-wide studies to identify risk factors for injury during BCT have been completed to date. This study examines associations between individual and training-related characteristics and injuries during Army BCT. Methods: Using administrative data from the Total Army Injury and Health Outcomes Database (TAIHOD), we identified individuals who apparently entered BCT for the first time between 1 January 2002 and 30 September 2007, based on review of administrative records. Injuries were identified and categorized based on coded medical encounter data. When combined with dates of medical services, we could count injuries per person, identify unique injuries, and identify the quantity and type of medical care delivered. Regression models produced odds ratios (ORs) and 95% confidence intervals (CIs) to identify risk factors for injury during BCT (yes/no), adjusted for potential confounders. Results: Of the 278,045 (83.4%) men and 55,302 (16.6%) women who were apparently first-time trainees, 39.5% (n = 109,760) of men and 60.9% (n = 33,699) of women were injured during training based on over 2 million recorded medical encounters entries. The large cohort yielded statistically significant, small magnitude associations between injury and all individual and training-related covariates for men, and all but medical accession waivers and weight for women. After adjustment, largest magnitude effects among men were due to age > 25 yr vs. 17-18 yr (OR = 1.83, 95% CI: 1.75, 1.91); having been married in the past vs. being single (OR = 1.36, 95% CI: 1.24, 1.49); rank E4-E7 vs. E1 (OR = 0.56, 95% CI: 0.53. 0.59); training at Ft. Jackson (OR = 0.66, 95% CI: 0.64, 0.69), Ft. Leonard Wood (OR = 0.67, 95% CI: 0.65, 0.70), or Ft. Knox (OR = 0.69, 95% CI: 066, 0.72) vs. Ft. Benning. Odds of injury were highest during 2005, 2006, and 2007. After adjustment for weight and body mass index, taller men had higher odds of BCT injury than average height men (OR = 1.08, 95% CI: 1.05, 1.11). Among women, short stature (OR = 1.11; 95% CI: 1.04, 1.19), training at Ft Leonard Wood (OR = 1.10; 95% CI: 1.04, 1.16) and evidence of injury prior to training based on accession waiver (OR = 1.12; 95% CI: 1.00, 1.26) increased injury risk. Conclusions: This Army-wide analysis reveals higher BCT-related injury rates for both men and women than prior studies and identifies risk factors for injuries during BCT. The large data set allows adjustment for many covariates, but because statistical analysis may yield significant findings for small differences, results must be interpreted based on minimally important differences determined by military and medical professionals. Results provide information that may be used to adapt training or medical screening and examination procedures for basic trainees.

Assessing the Likelihood and Magnitude of a Population Health Benefit Following the Market Introduction of a Modified-Risk Tobacco Product: Enhancements to the Dynamic Population Modeler, DPM(+1).

Researchers and those responsible for evaluating and implementing policies intended to reduce population harm must assess the potential for both intended and unintended consequences associated with those policies. Such assessments should be based on the combined dimensions of magnitude, and thus likelihood, of shifts in exposure patterns needed to produce a population benefit or harm, and magnitude of the expected population benefit or harm. In response to this assessment need, we provide a conceptual description of the dynamic population modeler, DPM(+1), as well as illustrative analyses that estimate the effects on all-cause mortality, life expectancy, and quality of life-adjusted life expectancy if exposure patterns in the population shift from a higher risk product (e.g., cigarettes) to a lower, or modified, risk tobacco product (MRTP) in specified ways. Estimates from these analyses indicate that, within a single birth cohort, switching completely from cigarette smoking to MRTP use is more likely to lead to a population-level survival benefit than initiating tobacco use with an MRTP instead of cigarettes. This is because tobacco initiation rarely occurs beyond young adulthood, whereas continuing smokers exist in all subsequent age categories, leading to a greater cumulative effect. In addition, complete switching to MRTP use among a small proportion of smokers in each age category offsets the survival deficit caused by unintended shifts in exposure patterns, such as MRTP initiation among never tobacco users followed by transitioning to cigarette smoking and/or cigarette smokers switching to MRTP use instead of quitting.

Data on cardiovascular and pulmonary diseases among smokers of menthol and non-menthol cigarettes compiled from the National Health and Nutrition Examination Survey (NHANES), 1999-2012.

This Data in Brief contains results from three different survey logistic regression models comparing risks of self-reported diagnoses of cardiovascular and pulmonary diseases among smokers of menthol and non-menthol cigarettes. Analyses employ data from National Health and Nutrition Examination Survey (NHANES) cycles administered between 1999 and 2012, combined and in subsets. Raw data may be downloaded from the National Center for Health Statistics. Results were not much affected by which covariates were included in the models, but depended strongly on the NHANES cycles included in the analysis. All three models returned elevated risk estimates for three endpoints when they were run in individual NHANES cycles (congestive heart failure in 2001-02; hypertension in 2003-04; and chronic obstructive pulmonary disease in 2005-06), and all three models returned null results for these endpoints when data from 1999-2012 were combined.

Stroke risk among menthol versus non-menthol cigarette smokers in the United States: Analysis of the National Health and Nutrition Examination Survey (NHANES).

Though available evidence is relatively consistent in showing no additional health effects among smokers due to menthol in cigarettes, two studies reported conflicting results for stroke risk using different subsets of NHANES data. We investigated reasons for the differences in these reports by analyzing NHANES cycles conducted between 1999 and 2012, combined and in subsets. Adjusted odds ratios (AOR) and 95% confidence intervals (CI) from three different survey logistic regression models compare risk of reported stroke diagnoses among menthol and non-menthol cigarette smokers. Depending on timeframe, about 1150 to 8000 U.S. adults (aged ≥ 20 years) who smoked on ≥ 1 of the last 30 days had complete data for cigarette type and all covariates included in each model. Results were not much affected by which covariates were included in the models, but depended strongly on the NHANES cycles included in the analysis. Using NHANES 1999-2012 data combined, AORs and 95% CIs for stroke comparing menthol with non-menthol cigarette smokers were 0.95 (95% CI: 0.65, 1.37), 0.85 (95% CI: 0.59, 1.23) or 0.86 (95% CI: 0.59, 1.25). Collectively, findings illustrate the need for fully reporting research and analytical methods, especially when analyses are meant to develop evidence intended for regulatory decision-making.

A tissue dose-based comparative exposure assessment of manganese using physiologically based pharmacokinetic modeling-The importance of homeostatic control for an essential metal.

A physiologically-based pharmacokinetic (PBPK) model (Schroeter et al., 2011) was applied to simulate target tissue manganese (Mn) concentrations following occupational and environmental exposures. These estimates of target tissue Mn concentrations were compared to determine margins of safety (MOS) and to evaluate the biological relevance of applying safety factors to derive acceptable Mn air concentrations. Mn blood concentrations measured in occupational studies permitted verification of the human PBPK models, increasing confidence in the resulting estimates. Mn exposure was determined based on measured ambient air Mn concentrations and dietary data in Canada and the United States (US). Incorporating dietary and inhalation exposures into the models indicated that increases in target tissue concentrations above endogenous levels only begin to occur when humans are exposed to levels of Mn in ambient air (i.e. >10µg/m3) that are far higher than those currently measured in Canada or the US. A MOS greater than three orders of magnitude was observed, indicating that current Mn air concentrations are far below concentrations that would be required to produce the target tissue Mn concentrations associated with subclinical neurological effects. This application of PBPK modeling for an essential element clearly demonstrates that the conventional application of default factors to "convert" an occupational exposure to an equivalent continuous environmental exposure, followed by the application of safety factors, is not appropriate in the case of Mn. PBPK modeling demonstrates that the relationship between ambient Mn exposures and dose-to-target tissue is not linear due to normal tissue background levels and homeostatic controls.

Injury during U.S. Army basic combat training: a systematic review of risk factor studies.

CONTEXT: Approximately one quarter of men and half of women in U.S. Army basic combat training experience an injury. Preventing basic combat training-related injuries would reduce associated human and economic costs and discharges from the Army. Identification of risk factors for such injuries is a crucial step toward their prevention. Although some research has begun to address this need, prior studies of risk factors for training-related injury have not been reviewed systematically. This study systematically reviews the literature on risk factors for injury during U.S. Army basic combat training. EVIDENCE ACQUISITION: Original studies of risk factors for injury during U.S. Army basic combat training published since 1990 in peer-reviewed journals were identified using PubMed and manual searches of reference lists. This search was last performed in May 2013. Nineteen studies met the inclusion criteria. EVIDENCE SYNTHESIS: Methodologic quality and potential for bias were assessed. The findings of 11 studies deemed to be of high or medium quality were synthesized to determine the level of evidence supporting the association between each risk factor studied and risk of injury during basic combat training. Quality assessment and evidence synthesis were performed from June to September 2013. CONCLUSIONS: There is strong or moderate evidence supporting association of older age, history of smoking, and self-rated low physical activity level prior to basic combat training with increased risk of training-related injury among male trainees. There is limited, mixed, or insufficient evidence to identify risk factors for injury among female trainees.

Methodological challenges of using U.S. Army administrative data to identify a cohort of basic combat trainees and descriptive analysis of trends in characteristics that are potential risk factors for training-related injury.

OBJECTIVES: Training-related injury is a threat to military health and readiness. Prevalence of potential risk factors for training-related injury can change with U.S. Army recruitment goals and may influence basic combat training (BCT) injury rates. This article describes challenges of using administrative data to identify a trainee cohort and describes demographic and training characteristics across the five BCT locations. METHODS: Data from the Total Army Injury and Health Outcomes Database were used to identify a U.S. Army-wide cohort of first-time trainees from January 1, 2002 to September 30, 2007 and describe its characteristics. RESULTS: The cohort includes 368,102 first-time trainees. The annual number starting BCT increased from 52,187 in 2002 to 68,808 in 2004. The proportion of males increased from 81.57% in 2003 to 83.84% in 2007. Mean (SD) age increased from 20.67 (3.55) years in 2002 to 20.94 (3.65) years in 2007. Mean (SD) body mass index increased from 24.53 (3.56) kg/m(2) in 2002 to 24.94 (3.84) kg/m(2) in 2006. Other characteristics fluctuated by year, including proportions of race/ethnicity, accession waivers, and confirmed graduates. CONCLUSIONS: Fluctuations in trainee characteristics warrant further analysis of potential influence on BCT injury rates. For research uses, careful acquisition of administrative data is needed.

Measures of initiation and progression to increased smoking among current menthol compared to non-menthol cigarette smokers based on data from four U.S. government surveys.

There are no large-scale, carefully designed cohort studies that provide evidence on whether menthol cigarette use is associated with a differential risk of initiating and/or progressing to increased smoking. However, questions of whether current menthol cigarette smokers initiated smoking at a younger age or are more likely to have transitioned from non-daily to daily cigarette use compared to non-menthol smokers can be addressed using cross-sectional data from U.S. government surveys. Analyses of nationally representative samples of adult and youth smokers indicate that current menthol cigarette use is not associated with an earlier age of having initiated smoking or greater likelihood of being a daily versus non-daily smoker. Some surveys likewise provide information on cigarette type preference (menthol versus non-menthol) among youth at different stages or trajectories of smoking, based on number of days smoked during the past month and/or cigarettes smoked per day. Prevalence of menthol cigarette use does not appear to differ among new, less experienced youth smokers compared to established youth smokers. While there are limitations with regard to inferences that can be drawn from cross-sectional analyses, these data do not suggest any adverse effects for menthol cigarettes on measures of initiation and progression to increased smoking.

Evaluating the association between menthol cigarette use and the likelihood of being a former versus current smoker.

Menthol in cigarettes has been examined for its potential to affect smoking dependence, measured primarily as number of cigarettes smoked per day and time to first cigarette after waking; the ability to quit smoking constitutes an additional measure of dependence. Successful quitting among menthol compared to non-menthol cigarette smokers is difficult to determine from the literature, due in part to the various definitions of quitting used by researchers. Nevertheless, intervention and follow-up studies of smoking cessation treatments generally indicate no differences in quitting success among menthol compared to non-menthol smokers, while cross-sectional studies suggest some differences within race/ethnicity groups. The association between menthol cigarette use and likelihood of being a former versus current smoker was examined based on data from the National Health Interview Survey and Tobacco Use Supplement to the Current Population Survey. Analyses stratified by race/ethnicity and limited to smokers who had quit at least one year prior to survey participation provided inconsistent results with regard to menthol cigarette use and quitting, both within surveys (i.e., comparing race/ethnicity groups) and between surveys (i.e., same race/ethnicity group across surveys). Evidence suggesting the existence or direction of an association between menthol in cigarettes and quitting depended on the data source.

Patterns of menthol cigarette use among current smokers, overall and within demographic strata, based on data from four U.S. government surveys.

The National Health and Nutrition Examination Survey, National Survey on Drug Use and Health, National Health Interview Survey and Tobacco Use Supplement to the Current Population Survey provide estimates of the proportions of U.S. smokers who currently use menthol cigarettes, overall and within demographic strata. Among adult past-month, regular and daily smokers, menthol cigarette use ranges from 26% to 30%, with statistically higher proportions of female versus male smokers (8-11 percentage points higher) currently using menthol cigarettes. Compared to adult smokers overall, statistically higher proportions of non-Hispanic Black smokers (72-79%) and statistically lower proportions of non-Hispanic White smokers (19-22%) currently use menthol cigarettes, with no differences among smokers of other race/ethnicity groups (18-20% to 28-30%, depending on the survey). Higher proportions of younger adult past-month, regular and daily smokers (aged 18-25years) currently use menthol cigarettes compared to older adult smokers (aged 26-29years and/or ⩾30years); however, differences are small in magnitude, with the vast majority of adult smokers (70-75%) who currently use menthol cigarettes being aged ⩾30years. Comparisons between youth and adult smokers are provided, although data for youth smokers are less available and provide less consistent patterns of menthol cigarette use.

Primary measures of dependence among menthol compared to non-menthol cigarette smokers in the United States.

Previously published studies provide somewhat inconsistent evidence on whether menthol in cigarettes is associated with increased dependence. The National Health and Nutrition Examination Survey, National Survey on Drug Use and Health, National Health Interview Survey, and Tobacco Use Supplement to the Current Population Survey collect data on current cigarette type preference and primary measures of dependence, and thus allow examination of whether menthol smokers are more dependent than non-menthol smokers. Analyses based on combined data from multiple administrations of each of these four nationally representative surveys, using three definitions for current smokers (i.e., smoked ⩾1day, ⩾10days and daily during the past month), consistently demonstrate that menthol smokers do not report smoking more cigarettes per day than non-menthol smokers. Moreover, two of the three surveys that provide data on time to first cigarette after waking indicate no difference in urgency to smoke among menthol compared to non-menthol smokers, while the third suggests menthol smokers may experience a greater urgency to smoke; estimates from all three surveys indicate that menthol versus non-menthol smokers do not report a higher Heaviness of Smoking Index. Collectively, these findings indicate no difference in dependence among U.S. smokers who use menthol compared to non-menthol cigarettes.

A dynamic population model for estimating all-cause mortality due to lifetime exposure history.

We developed a comprehensive, flexible dynamic model that estimates all-cause mortality for a hypothetical cohort. All model input is user-specified. In the base case, members of the cohort may be exposed to a high risk product as they age. The counterfactual scenario includes exposure to both a high risk and a lower risk product. The model sorts the population into age and exposure categories, and applies the appropriate mortality rates to each category. The model tracks individual exposure histories, and estimates, at the end of each modeled age category, the number of survivors in the two exposure scenarios (base case and counterfactual), and the difference between them. Markov Chain Monte Carlo techniques are used to estimate the variability of the results. Model output was compared against US and Swedish life tables using population-specific tobacco exposure transition probabilities derived from the literature, and it produced similar survival estimates.

Disability among US Army Veterans vaccinated against anthrax.

CONTEXT: To protect troops against the use of anthrax as a biological weapon, the US Department of Defense began an anthrax vaccination program in 1998. 14 years after the inception of the vaccination program, there is no evidence suggesting vaccination against anthrax carries long-term health risks for Active Duty Soldiers. OBJECTIVE: To investigate the association between Anthrax Vaccine Adsorbed (AVA) received while on Active Duty and subsequent disability determined by the Veterans Benefits Administration. DESIGN, SETTING AND PARTICIPANTS: Case-control study nested in the cohort of all Active Duty personnel known to have separated from the US Army between December 1, 1997 and December 31, 2005. Cases were ≥10% disabled, determined either by the Army prior to separation (N=5846) or by the Veterans Benefits Administration (VBA) after separation (N=148,934). Controls (N=937,705) separated from the Army without disability, and were not receiving pensions from the VBA as of April 2007. Data were from the Total Army Injury and Health Outcomes Database and the VBA Compensation and Pension and Benefits database. MAIN OUTCOMES: Disability status (yes/no); for primary disability, percent disabled (≥10%, 20%, >20%) and type of disability. RESULTS: Vaccination against anthrax was four times more likely among disabled Veterans with hostile fire pay records (HFP, a surrogate for deployment). Vaccinated Soldiers with HFP had lower odds of disability separation from the Army 0.89 (0.80, 0.98); there was no association between vaccine and receiving Army disability benefits among those without HFP (OR=1.05, CI: 0.96, 1.14). Vaccination was negatively associated with receiving VA disability benefits for those with HFP (OR=0.66, CI: 0.65, 0.67), but there was little or no association between vaccine and receipt of VA disability benefits for those without HFP (OR=0.95, CI: 0.93, 0.97). CONCLUSIONS: Risk of disability separation from the Army and receipt of disability compensation from the VA were not increased in association with prior exposure to AVA. This study provides evidence that vaccination against anthrax is not associated with long term disability.