Genetic toxicology in silico protocol.

In silico toxicology (IST) approaches to rapidly assess chemical hazard, and usage of such methods is increasing in all applications but especially for regulatory submissions, such as for assessing chemicals under REACH as well as the ICH M7 guideline for drug impurities. There are a number of obstacles to performing an IST assessment, including uncertainty in how such an assessment and associated expert review should be performed or what is fit for purpose, as well as a lack of confidence that the results will be accepted by colleagues, collaborators and regulatory authorities. To address this, a project to develop a series of IST protocols for different hazard endpoints has been initiated and this paper describes the genetic toxicity in silico (GIST) protocol. The protocol outlines a hazard assessment framework including key effects/mechanisms and their relationships to endpoints such as gene mutation and clastogenicity. IST models and data are reviewed that support the assessment of these effects/mechanisms along with defined approaches for combining the information and evaluating the confidence in the assessment. This protocol has been developed through a consortium of toxicologists, computational scientists, and regulatory scientists across several industries to support the implementation and acceptance of in silico approaches.

A scoping review of the health and toxicological activity of bisphenol A (BPA) structural analogues and functional alternatives.

Recent studies report widespread usage or exposure to a variety of chemicals with structural or functional similarity to bisphenol A (BPA), referred to as BPA analogues or derivatives. These have been detected in foodstuffs, house dust, environmental samples, human urine or blood, and consumer products. Compared to BPA, relatively little is known about potential toxicity of these compounds. This scoping review aimed to summarize the human, animal, and mechanistic toxicity data for 24 BPA analogues of emerging interest to research and regulatory communities. PubMed was searched from March 1, 2015 to January 5, 2019 and combined with the results obtained from literature searches conducted through March 23, 2015, in The National Toxicology Program's Research Report 4 (NTP RR-04), "Biological Activity of Bisphenol A (BPA) Structural Analogues and Functional Alternatives". Study details are presented in interactive displays using Tableau Public. In total, 5748 records were screened for inclusion. One hundred sixty seven studies were included from NTP RR-04 and 175 studies were included from the updated literature search through January 2019. In total, there are 22, 117, and 221 human epidemiological, experimental animal, or in vitro studies included. The most frequently studied BPA analogues are bisphenol S (BPS), bisphenol F (4,4-BPF), and bisphenol AF (BPAF). Notable changes in the literature since 2015 include the growing body of human epidemiological studies and in vivo studies conducted in zebrafish. Numerous new endpoints were also evaluated across all three evidence streams including diabetes, obesity, and oxidative stress. However, few studies have addressed endpoints such as neurodevelopmental outcomes or impacts on the developing mammary or prostate glands, which are known to be susceptible to disruption by BPA. Further, there remains a critical need for better exposure information in order to prioritize experimental studies. Moving forward, researchers should also ensure that full dose responses are performed for all main effects in order to support hazard and risk characterization efforts. The evidence gathered here suggests that hazard and risk characterizations should expand beyond BPA in order to consider BPA structural and functional analogues.

In silico toxicology protocols.

The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information.

Systematic review of community health impacts of mountaintop removal mining.

BACKGROUND: The objective of this evaluation is to understand the human health impacts of mountaintop removal (MTR) mining, the major method of coal mining in and around Central Appalachia. MTR mining impacts the air, water, and soil and raises concerns about potential adverse health effects in neighboring communities; exposures associated with MTR mining include particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs), metals, hydrogen sulfide, and other recognized harmful substances. METHODS: A systematic review was conducted of published studies of MTR mining and community health, occupational studies of MTR mining, and any available animal and in vitro experimental studies investigating the effects of exposures to MTR-mining-related chemical mixtures. Six databases (Embase, PsycINFO, PubMed, Scopus, Toxline, and Web of Science) were searched with customized terms, and no restrictions on publication year or language, through October 27, 2016. The eligibility criteria included all human population studies and animal models of human health, direct and indirect measures of MTR-mining exposure, any health-related effect or change in physiological response, and any study design type. Risk of bias was assessed for observational and experimental studies using an approach developed by the National Toxicology Program (NTP) Office of Health Assessment and Translation (OHAT). To provide context for these health effects, a summary of the exposure literature is included that focuses on describing findings for outdoor air, indoor air, and drinking water. RESULTS: From a literature search capturing 3088 studies, 33 human studies (29 community, four occupational), four experimental studies (two in rat, one in vitro and in mice, one in C. elegans), and 58 MTR mining exposure studies were identified. A number of health findings were reported in observational human studies, including cardiopulmonary effects, mortality, and birth defects. However, concerns for risk of bias were identified, especially with respect to exposure characterization, accounting for confounding variables (such as socioeconomic status), and methods used to assess health outcomes. Typically, exposure was assessed by proximity of residence or hospital to coal mining or production level at the county level. In addition, assessing the consistency of findings was challenging because separate publications likely included overlapping case and comparison groups. For example, 11 studies of mortality were conducted with most reporting higher rates associated with coal mining, but many of these relied on the same national datasets and were unable to consider individual-level contributors to mortality such as poor socioeconomic status or smoking. Two studies of adult rats reported impaired microvascular and cardiac mitochondrial function after intratracheal exposure to PM from MTR-mining sites. Exposures associated with MTR mining included reports of PM levels that sometimes exceeded Environmental Protection Agency (EPA) standards; higher levels of dust, trace metals, hydrogen sulfide gas; and a report of increased public drinking water violations. DISCUSSION: This systematic review could not reach conclusions on community health effects of MTR mining because of the strong potential for bias in the current body of human literature. Improved characterization of exposures by future community health studies and further study of the effects of MTR mining chemical mixtures in experimental models will be critical to determining health risks of MTR mining to communities. Without such work, uncertainty will remain regarding the impact of these practices on the health of the people who breathe the air and drink the water affected by MTR mining.

Evaluation of 4-methylcyclohexanemethanol (MCHM) in a combined irritancy and Local Lymph Node Assay (LLNA) in mice.

4-Methylcyclohexanemethanol (MCHM) is a flotation reagent used in fine coal beneficiation. On January 9, 2014, crude MCHM, a mixture containing predominantly MCHM, was inadvertently released into the Elk River, a municipal water source that serves about 300,000 people in the Charleston, WV area, resulting in temporary contamination of 15 percent of the state's tap water and causing significant dermal exposure. The current studies were undertaken to determine whether crude MCHM or MCHM has the potential to produce dermal irritancy and/or sensitization. BALB/c female mice were treated daily for 3 consecutive days by direct epicutaneous application of 25 µL of various concentrations of crude MCHM or MCHM to the dorsum of each ear. A mouse ear-swelling test was used to determine irritancy potential and was undertaken in combination with the standardized Local Lymph Node Assay (LLNA) to determine skin sensitizing potential. MCHM was found to produce skin irritation at concentrations above 20% and did not produce sensitization. Crude MCHM also produced irritation, although weaker, and in addition was found to be a weak to moderate skin sensitizer. The results are discussed in terms of potential human health hazard.

Integrating Health Research into Disaster Response: The New NIH Disaster Research Response Program.

The need for high quality and timely disaster research has been a topic of great discussion over the past several years. Recent high profile incidents have exposed gaps in knowledge about the health impacts of disasters or the benefits of specific interventions-such was the case with the 2010 Gulf Oil Spill and recent events associated with lead-contaminated drinking water in Flint, Michigan, and the evolving health crisis related to Zika virus disease. Our inability to perform timely research to inform the community about health and safety risks or address specific concerns further heightens anxiety and distrust. Since nearly all disasters, whether natural or man-made, have an environmental health component, it is critical that specialized research tools and trained researchers be readily available to evaluate complex exposures and health effects, especially for vulnerable sub-populations such as the elderly, children, pregnant women, and those with socioeconomic and environmental disparities. In response, the National Institute of Environmental Health Science has initiated a Disaster Research Response Program to create new tools, protocols, networks of researchers, training exercises, and outreach involving diverse groups of stakeholders to help overcome the challenges of disaster research and to improve our ability to collect vital information to reduce the adverse health impacts and improve future preparedness.

Consensus Report of the 2015 Weinman International Conference on Mesothelioma.

On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the group's efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos-like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA-exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin-3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM.

The problem of suspended and revoked drivers who avoid detection at checkpoints.

OBJECTIVE: Although driver license suspension and revocation have been shown to improve traffic safety, suspended or revoked (SR) drivers who continue to drive-which appears to be the majority-are about 3 times more likely to be involved in crashes and to cause a fatal crash. In California and many other U.S. states, drivers are typically mailed notices requesting that they surrender their licenses when they are SR for reasons other than driving under the influence of alcohol or drugs (DUI), yet they frequently do not comply. Typical procedures at DUI checkpoints in California and other U.S. states include inspecting driver licenses and checking for signs of intoxication during brief contacts with law enforcement officers. Hence, these checkpoints are in fact DUI/license checkpoints in California and many other states. The purpose of this study was to estimate the extent to which SR drivers avoid being detected at DUI/license checkpoints for SR driving, because they illegally retained possession of their license cards. METHOD: Law enforcement officers used electronic license card readers at DUI/license checkpoints in Sacramento, California, to record data for 13,705 drivers. The SR status of all contacted drivers was determined after the checkpoints and compared to law enforcement citation records from the checkpoints. RESULTS: Although only 3% of the drivers contacted at the checkpoints were SR, about 41% of SR drivers were able to pass through undetected because they presented license cards that they illegally retained. Drivers SR for DUI-related reasons were more likely to be detected, whereas those SR for failure to provide proof of financial responsibility (insurance) were less likely to be detected. CONCLUSION: The fact that many SR drivers are able to pass through DUI/license checkpoints undetected weakens both the specific and general impacts of checkpoints for deterring SR driving and may diminish the effectiveness of suspension and revocation actions for reducing the crash risk posed by problem drivers. Using license card readers that can quickly identify SR drivers in real time during routine traffic stops and at DUI/license checkpoints warrants further consideration.

Non-compliance with graduated driver licensing (GDL) requirements: changes in GDL-related conviction rates over time among 16-17-year-old California drivers.

INTRODUCTION: Self-reports by novice teen drivers in California and elsewhere suggest that many violate graduated driver licensing (GDL) nighttime and passenger restrictions, and to a lesser extent, drive on learner permits without being supervised. Is this corroborated by their traffic conviction records? METHOD: We examined historical aggregated conviction rates for GDL-related violations before and after GDL, and Poisson regressions of conviction rates over time among 16-17-year-old California novices. RESULTS: During the year before they received their provisional licenses, <1% of 16-year-old novices and <2% of 17-year-old novices were convicted of driving unlicensed or unsupervised on their learner permits. Statewide historical conviction rates for these offenses were not higher after GDL was implemented, despite the longer holding period. Convictions for violating GDL nighttime or passenger restrictions were highest almost immediately after provisional licensure, though only about 3% of 16-year-old novices and 2% of 17-year-old novices were ever convicted of violating either restriction. DISCUSSION: California 16-17-year-old novice drivers were very rarely convicted of GDL-related violations. The contradictive, large differences between the current findings and self-report surveys are likely due in part to the fact that most self-reports assessed only whether teens had ever violated a GDL-related requirement, which exaggerates prevalence. Our conviction findings are more similar to estimates of non-compliance with GDL-related requirements from naturalistic driving studies that monitor actual driving behavior and take exposure into account, but are lower likely due to issues related to detection, enforcement, and adjudication of violations, as well as limitations of existing naturalistic studies.

Changes in driver cannabinoid prevalence in 12 U.S. states after implementing medical marijuana laws.

OBJECTIVE: To determine if cannabinoid prevalence increased among fatal-crash-involved drivers in 12 U.S. states after implementing medical marijuana laws. METHODS: Time series analyses of 1992 to 2009 driver cannabinoid prevalence from the Fatality Analysis Reporting System. RESULTS: Increased driver cannabinoid prevalence associated with implementing medical marijuana laws was detected in only three states: California, with a 2.1 percentage-point increase in the percentage of all fatal-crash-involved drivers who tested positive for cannabinoids (1.1% pre vs. 3.2% post) and a 5.7 percentage-point increase (1.8% vs. 7.5%) among fatally-injured drivers; Hawaii, with a 6.0 percentage-point increase (2.5 vs. 8.5) for all drivers and a 9.6 percentage-point increase (4.9% vs. 14.4%) among fatally-injured drivers; and Washington, with a 3.4 percentage-point increase (0.7% vs. 4.1%) for all drivers and a 4.6 percentage-point increase (1.1% vs. 5.7%) among fatally-injured drivers. Changes in prevalence were not associated with the ease of marijuana access afforded by the laws. DISCUSSION: Increased prevalence of cannabinoids among drivers involved in fatal crashes was only detected in a minority of the states that implemented medical marijuana laws. The observed increases were one-time changes in the prevalence levels, rather than upward trends, suggesting that these laws may indeed provide marijuana access to a stable population of patients as intended, without increasing the numbers of new users over time. Although this study provides some insight into the potential impact of these laws on public safety, differences between states in drug testing practices and regularity, along with the fairly recent implementation of most medical marijuana laws, suggest that the long-term impact of these laws may not yet be known. PRACTICAL APPLICATIONS: It is recommended that nationwide standardization of drug testing procedures and criteria be considered to improve the consistency of testing both between and within jurisdictions.

Crash and traffic violation rates before and after licensure for novice California drivers subject to different driver licensing requirements.

INTRODUCTION: How do crash and traffic violation rates for novice 16-17-year-old drivers change over the months before and after licensure under a graduated driver licensing (GDL) program relative to those for older novices who are not subject to GDL? METHOD: Plots and Poisson regression comparing overall rates and subtypes of crashes and traffic violations among California novice drivers ages 16 to 35 years over time before and after unsupervised licensure. RESULTS: Majorities of 16-year-olds (57%) and 17-year-olds (73%) actually hold their learner permits longer than the required 6 months; majorities (67%-81%) of age 18 or older novices hold their learner permits less than 6 months. Crash rates of novice 16- and 17-year-olds-as well as most other age groups-are highest almost immediately after they are licensed to drive unsupervised, after which their rates decline quickly during their first year of licensure and at a slower rate for the second and third years. Novice 16- and 17-year-olds' traffic violation rates reach their zenith long after their total crash rates peak and decline, whereas violation rates for older novices peak during their first year of licensure. Over 70% of 16- and 17-year-old novices are crash-free for the first 3 years of licensure. CONCLUSIONS: While novice 16- and 17-year-olds' highest crash rates occur almost immediately after they are licensed, their peak traffic violation rates are delayed until around the time they turn age 18. Both pre-licensure crash rates and post-licensure crash peaks were more pronounced for some older age groups of novices than was the case for 16-17-year-olds. PRACTICAL APPLICATIONS: Extending learner permit holding periods for 16-17-year-old novices appears consistent with their actual behavior; requiring older novices-particularly those ages 18 to 20-to hold permits for minimum periods may reduce their initial crash rates.

Graduated driver licensing program component calibrations and their association with fatal crash involvement.

Graduated driver licensing (GDL) programs are specialized licensing systems for beginner drivers adopted in all U.S. states, Australia, Canada, and New Zealand. GDL programs reduce novice drivers' exposure to high-risk driving situations while they gain driving experience. Several studies document the success of GDL programs overall in reducing young teen crash rates. However, little is known about which specific components of these programs (e.g., nighttime driving restrictions) and which calibrations of these components (e.g., 10 PM, 11 PM, 12 AM, or 1 AM), are associated with the largest crash reductions. The goal of this study was to identify the GDL component calibrations associated with the largest reductions in fatal crash involvements for 16-17-year-olds. Driver fatal crash involvements for all U.S. states from 1986 to 2007 were analyzed using Poisson regression models to estimate the association of various GDL component calibrations with 16- and 17-year-old driver fatal crash incidence, after adjusting for potential confounders. We found clear evidence that (a) a minimum learner permit holding period of 9-12 months and (b) a passenger restriction allowing only one teen passenger for 6 months or longer are the calibrations for the learner permit holding period and passenger restriction components associated with the largest reductions in 16-17-year-old driver fatal crash involvements. Additionally, the data suggest that (a) disallowing learner driving until age 16, (b) disallowing intermediate licensure until age 16½ to 17, and (c) a nighttime driving restriction starting at 10 PM or earlier are the calibrations for these components associated with the largest reductions in 16-year-old driver fatal crashes. There was no clear evidence to support particular calibrations for supervised driving hours or unrestricted license ages.

Supervised hours requirements in graduated driver licensing: Effectiveness and parental awareness.

Most states require teens to complete a certain number of hours of supervised driving practice to obtain a license to drive unsupervised. Although widely implemented, the effect of requiring supervised practice is largely unknown. Using auto-regressive integrated moving average (ARIMA) interrupted time-series analysis, we found no change in fatal and injury crash involvement of 16-17-year-old drivers in Minnesota following enactment of a 30h supervised driving requirement. To supplement and provide insight into these findings, we conducted telephone interviews with parents of newly licensed teenage drivers in five states with varying amounts of required supervised driving, including Minnesota. Interviews revealed awareness of supervised driving requirements was limited. Only a third of parents (32%) overall could correctly identify the number of hours their state required. In Minnesota only 15% of parents could identify the amount of supervised driving their teen was required to complete. Awareness of the number of hours required was substantially higher (55%) in Maryland. Unlike the other states, Maryland requires submission of a driving log detailing the hours of supervised driving. The findings suggest states need to develop more effective mechanisms to ensure parents are aware of supervised hours requirements.

Bisphenol A and other compounds in human saliva and urine associated with the placement of composite restorations.

BACKGROUND: Bisphenol A (BPA) and other related chemical compounds may be components used in the manufacturing process of resin-based composite dental restorative material. The purpose of the authors' study was to assess salivary and urinary concentrations of BPA and other compounds before and after placement of resin-based composite dental restorations. METHODS: The authors collected saliva and urine from 172 participants receiving composite restorations before and as long as 30 hours after placement of composite restorations. The authors analyzed saliva specimens from 151 participants and urine specimens from 171 participants for concentrations of BPA and five related compounds by using liquid chromatography/mass spectrometry (LC/MS). RESULTS: Salivary concentrations of BPA and some related compounds increased immediately (within one hour) after composite placement. Salivary concentrations of BPA and most study compounds returned to prerestoration levels within eight hours after composite placement. With the exception of a 43 percent increase in BPA, concentrations of the study compounds in urine returned to prerestoration levels nine to 30 hours after restoration placement. Concentrations in saliva were lower when a rubber dam was used; however, rubber dam use appeared to have no effect on urinary concentrations of the measured compounds during the study period. The authors observed similar changes in study compound levels in both saliva and urine between participants who received anterior restorations and those who received posterior restorations. CONCLUSIONS: Placement of resin-based composite restorations was associated with detectable increases in saliva of BPA and other study compounds within one hour after restoration placement and an increased concentration of BPA in urine nine to 30 hours after restoration placement. Rubber dam use did not reduce the absorption of BPA (measured as BPA level in urine) during the study. CLINICAL IMPLICATIONS: Additional studies are needed to address how long BPA levels in urine associated with composite placement remain elevated to aid in better understanding of the clearance rates of BPA and other study compounds.

Graduated driver licensing and fatal crashes involving 16- to 19-year-old drivers.

CONTEXT: In the United States, graduated driver licensing (GDL) systems allow full, unrestricted licensure for drivers younger than 18 years only after an initial period of supervised driving and an intermediate period of unsupervised driving that limits driving at night, transporting multiple young passengers, or both. OBJECTIVE: To estimate the association of GDL programs with involvement in fatal crashes among 16- to 19-year-old drivers. DESIGN, SETTING, AND PARTICIPANTS: Pooled cross-sectional time series analysis of quarterly 1986-2007 incidence of fatal crashes involving drivers aged 16 to 19 years for all 50 states and the District of Columbia combined. MAIN OUTCOME MEASURES: Population-based rates of fatal crash involvement for 16-, 17-, 18-, and 19-year-old drivers. Rate ratios and 95% CIs comparing state-quarters with stronger (restrictions on both nighttime driving and allowed passengers) or weaker (restrictions on either nighttime driving or allowed passengers) GDL programs with state-quarters without GDL. RESULTS: Fatal crash incidence among teen drivers increased with age, from 28.2 per 100,000 person-years (16-year-old drivers) to 36.9 per 100,000 (17-year-olds), before reaching a plateau of 46.2 per 100,000 (18-year-olds) and 44.0 per 100,000 (19-year-olds). After adjusting for potential confounders, stronger GDL programs were associated with lower incidence of fatal crashes for 16-year-old drivers, compared with programs having none of the key GDL elements (rate ratio, 0.74 [95% CI, 0.65-0.84]). However, stronger GDL programs were associated with higher fatal crash incidence for 18-year-old drivers (rate ratio, 1.12 [95% CI, 1.01-1.23]). Rate ratios for 17-year-olds (0.91 [95% CI, 0.83-1.01]), 19-year-olds (1.05 [95% CI, 0.98-1.13]), and 16- to 19-year-olds combined (0.97 [95% CI, 0.92-1.03]) were not statistically different from the null. CONCLUSIONS: In the United States, stronger GDL programs with restrictions on nighttime driving as well as allowed passengers, relative to programs with none of the key GDL elements, were associated with substantially lower fatal crash incidence for 16-year-old drivers but somewhat higher fatal crash incidence for 18-year-old drivers. Future studies should seek to determine what accounts for the increase among 18-year-old drivers and whether refinements in GDL programs can reduce this association.

Meeting report: mode(s) of action of asbestos and related mineral fibers.

BACKGROUND: Although asbestos in general is well known to cause a range of neoplastic and non-neoplastic human health effects, not all asbestos fiber types have the same disease-causing potential, and the mode of action (MOA) of specific types of asbestos and related fibers for various health outcomes are not well understood. OBJECTIVES: A workshop was held to discuss the state of the science of the MOA for asbestos-related disease. The objective was to review the range of asbestos-induced health effects (including those at sites remote to the respiratory tract). We sought to identify existing knowledge gaps and define what research is needed to address these gaps and advance asbestos research. DISCUSSION: Discussions centered on areas of uncertainty in the field, including the ways asbestos is defined and characterized, the role of different fiber characteristics (e.g., length and mineralogy) in disease, and the impact of low-dose exposures on human health. Studying the dosimetry and mode of action of multiple fiber types would enhance our understanding of asbestos-related disease. To better elucidate the MOA of specific asbestos fibers, the risk assessor requires data as to specific characteristics of asbestos in determining fiber toxicity (e.g., surface area, mineral type), which may inform efforts to assess and control exposures and prevent adverse human health outcomes for the diverse range of fiber types. Specific research aims were defined for these topics and for overarching issues to be addressed, including the use of standardized terminology, test materials, and better experimental models to aid in data extrapolation to humans. CONCLUSION: To resolve these and other issues, participants agreed that diverse scientific disciplines must coordinate to better understand the MOA leading to the various asbestos-related disease end points.

Long-term effect of the North Carolina graduated driver licensing system on licensed driver crash incidence: a 5-year survival analysis.

Several studies document the success of graduated driver licensing (GDL) systems in reducing young teen crash rates, but it is not yet clear whether any portion of the crash reduction is achieved by producing more capable drivers. The purpose of this study was to determine whether young teen drivers licensed under the North Carolina GDL system remain crash-free longer than those licensed prior to GDL, independent of the crude reductions in exposure (i.e., decreasing and delaying licensure) that may be responsible for most documented effects of GDL. Survival analysis was used to compare retrospective cohorts of 16-17 year olds before (n=105,569) and after (n=327,054) the North Carolina GDL system was implemented. The crash incidence of GDL-licensed 16-17 year olds (combined) was 10% lower than that for pre-GDL teens for at least 5 years after being licensed to drive independently (hazard ratio [HR]=0.90; 95% confidence interval [CI]=0.89, 0.91). However, more refined analysis revealed the reductions to only be among females (7%; HR=0.93; CI=0.91, 0.94) and males (15%; HR=0.85, CI=0.84, 0.87) licensed at age 16 and not among females (0%; HR=1.00; CI=0.95, 1.06) and males (0%; HR=1.00; CI=0.92, 1.09) licensed at age 17. Sixteen-year-old drivers licensed under the North Carolina GDL system experienced lower first-crash incidence during the first 5 years of unsupervised driving than did those licensed under the previous system. The benefits are greater for males, who tend to have higher crash rates. The findings contradict conventional wisdom that the entire benefit of GDL results merely from decreasing or delaying licensure among young drivers.

Do states upgrading to primary enforcement of safety belt laws experience increased daytime and nighttime belt use?

As of 1 January 2007, 26 states and the District of Columbia have enacted primary enforcement of their safety belt laws, which allows law enforcement to stop motorists and cite them solely when they observe a vehicle occupant who is not wearing a safety belt. Interrupted time series analyses were used to determine whether six states which upgraded to primary enforcement laws experienced changes in nighttime (9:00 p.m. to 4:59 a.m.) and daytime (5:00 a.m. to 8:59 p.m.) safety belt use based on proxy estimates from fatal crash-involved vehicle occupants. Nighttime and daytime safety belt use increased in five of the six states after the primary enforcement laws were enacted. Because the methods used in these analyses reduced the likelihood that these increases resulted from preexisting secular trends towards increased belt use, the results provide strong support that upgrading from secondary to primary enforcement increases occupant safety belt use during both daytime and nighttime periods.

The effects of graduated driver licensing on hospitalization rates and charges for 16-and 17-year-olds in North Carolina.

OBJECTIVE: To mitigate the high risk of motor vehicle crashes for young beginning drivers, over 40 states and the District of Columbia have implemented graduated driver licensing (GDL) systems that gradually and systematically ease teen drivers into higher risk driving conditions. Evaluations of GDL programs using motor vehicle crash data have demonstrated marked declines in crashes. The objective of this study is to examine the association between the implementation of the North Carolina GDL program and the rate of hospitalization, as well as hospital charges, for 16-and 17-year-old drivers. METHODS: Data were obtained from the North Carolina Hospital Discharge Database for the 26 months before and 46 months after the December 1, 1997, implementation of the GDL program. ARIMA interrupted time series analyses were used to model monthly hospitalization rates, controlling for the hospitalization rates of 25-to 54-year-old drivers. ARIMA analyses were also used to determine whether changes occurred in monthly total hospital charges. RESULTS: Among the 568 16-year-old hospitalized drivers, GDL was associated with a 36.5% decline in the hospitalization rate per population and a 31.2% decline in the total monthly driver hospitalization charges. Although a 12% reduction in the rate of hospitalizations was observed among the 615 17-year-old drivers, the analysis lacked sufficient power to be statistically reliable. No consistent change was observed in the 16-year-old driver total monthly hospital charges. CONCLUSIONS: The North Carolina GDL program was associated with a marked decline in the rate of hospitalizations and hospital charges for 16-year-old drivers. Following the implementation of GDL, over $650,000 in hospital charges have been averted each year for 16-year-old drivers. Analyses suggest these reductions were primarily the result of reduced exposure rather than an improvement in teen driving.