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.

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.

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.

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.

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.

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.

CYP1A1 and CYP1B1 genotypes, haplotypes, and TCDD-induced gene expression in subjects from Seveso, Italy.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is highly toxic in experimental animals, and is known to induce cytochrome P450 (CYP) gene expression. We investigated the effect of CYP1A1 and CYP1B1 variant genotypes and haplotypes on CYP1A1 and CYP1B1 mRNA expression and ethoxyresorufin-O-deethylase (EROD) activity in lymphocytes from 121 subjects from the Seveso population, Italy, accidentally exposed to TCDD in 1976. The 3'UTR 3801T>C and I462V variants of CYP1A1 were present in 16% and 6% of the subjects, respectively. The frequency of CYP1B1 variants was 85.2% for L432V, 49.6% for R48G and A119S, and 28.7% for N453S. There was complete linkage disequilibrium (LD) among the CYP1B1 variant loci (D'=-1) and high LD among the CYP1A1 loci (D'=0.86). Gene expression measured by RT-PCR did not vary by CYP1B1 genotype in uncultured lymphocytes. However, when lymphocytes were treated in vitro with 10 nM TCDD, CYP1B1 and CYP1A1 mRNA expression was strongly induced and modified by CYP variant alleles. Specifically, the CYP1B1*3 haplotype (L432V) was associated with increased CYP1B1 mRNA expression (P=0.03), following an additive model; the CYP1A1 I462V polymorphism was positively, although not significantly, associated with CYP1A1 expression. The CYP1B1*3 variant may have affected CYP1B1 expression in subjects highly and acutely exposed to dioxin at the time of the accident. Although based on small number of subjects, a slight increase in eczema (P=0.05, n=8) and urticaria (P=0.02, n=2) was observed 20 years after the accident in subjects carrying the CYP1B1*3 allele. Genetic variation in cytochrome P450 induction may identify subjects with variable responsiveness to TCDD and potentially increased risk of disease.

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.

The association between biomarker-based exposure estimates for phthalates and demographic factors in a human reference population.

Population-based estimates of environmental exposures using biomarkers can be difficult to obtain for a variety of reasons, including problems with limits of detection, undersampling of key strata, time between exposure and sampling, variation across individuals, variation within individuals, and the ability to find and interpret a given biomarker. In this article, we apply statistical likelihoods, weighted sampling, and regression methods for censored data to the analysis of biomarker data. Urinary metabolites for seven phthalates, reported by Blount et al., are analyzed using these methods. In the case of the phthalates data, we assumed the underlying model to be a log-normal distribution with the mean of the distribution defined as a function of a number of demographic variables that might affect phthalate levels in individuals. Included as demographic variables were age, sex, ethnicity, residency, family income, and education level. We conducted two analyses: an unweighted analysis where phthalate distributions were estimated with changes in the means of these distributions as a function of demographic variables, and a weighted prediction for the general population in which weights were assigned for a subset of the population depending on the frequency of their demographic variables in the general U.S. population. We used statistical tests to determine whether any of the demographic variables affected mean phthalate levels. Individuals with only a high school education had higher levels of di-n-butyl phthalate than individuals with education beyond high school. Subjects who had family income less than $1,500 in the month before sampling and/or only high school education had higher levels of n-butyl benzyl phthalate levels than other groupings. Di(2-ethylhexyl) phthalate was higher in males and/or in urban populations and/or in people who had family income less than $1,500 per month. Our findings suggest that there may be significant demographic variations in exposure and/or metabolism of phthalates and that health-risk assessments for phthalate exposure in humans should consider different potential risk groups.

Human consumption of methyleugenol and its elimination from serum.

Under a mandate from the U.S. Congress, the National Toxicology Program (NTP) of the U.S. Department of Health and Human Services conducts animal bioassays for carcinogenicity of potentially toxic chemicals to which the U.S. population might be exposed. Methyleugenol, a natural as well as synthesized substance, was nominated for study because it is structurally similar to safrole, a known animal carcinogen. Methyleugenol was found to be a very potent multisite carcinogen in male and female F344/N rats and B6C3F1 mice at all doses tested in 2-year NTP bioassays using gavage dosing. For this reason, human toxicokinetic studies were added to the traditional NTP protocol. A commercial brand of gingersnaps was found by chemists at the Centers for Disease Control and Prevention to contain a relatively high concentration of methyleugenol. After thorough scientific and clinical review, and approval by a National Institutes of Health institutional review board for the protection of human subjects, a study was conducted with nine healthy adult male and female human volunteers. The volunteers were given 12 gingersnaps for breakfast. Blood was drawn immediately before the meal and at 15, 30, 60, and 120 min afterward. The mean +/- SD fasting level of methyleugenol in serum was 16.2 +/- 4.0 pg/g wet weight. Peak blood levels were found at 15 min (mean +/- SD, 53.9 +/- 7.3 pg/g wet weight), followed by a rapid decline; the half-life of elimination was about 90 min. The peak levels were within the range of methyleugenol blood levels in the U.S. population, as measured concurrently in a subset of nonfasting participants in the Third National Health and Nutrition Examination Survey (NHANES III).

Aryl-hydrocarbon receptor-dependent pathway and toxic effects of TCDD in humans: a population-based study in Seveso, Italy.

Approximately 20 years after the Seveso, Italy accident, we conducted a population-based study to evaluate the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure upon immune and mechanistically based biomarkers of dioxin response in humans. TCDD toxic effects are known to be mediated by the aryl-hydrocarbon receptor (AhR). We randomly selected 62 study subjects from the highest exposed zones and 59 from the surrounding non-contaminated area. Current lipid-adjusted plasma TCDD concentrations in these subjects ranged from 3.5 to 90 ng/kg (or ppt) and were negatively associated with plasma IgG concentrations (r=-0.35; P = 0.0002). The expression of genes in the AhR-dependent pathway, including AhR, aryl-hydrocarbon receptor nuclear translocator (ARNT), CYP1A1, and CYP1B1 transcripts, and the CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity was measured in lymphocytes. AhR mRNA levels in uncultured lymphocytes were negatively associated with plasma TCDD (P=0.03). When mitogen-induced lymphocytes were cultured with 10nM TCDD, all AhR-dependent genes were induced 1.2- to 13-fold. In these cells, plasma TCDD was associated with decreased EROD activity. Markers within the AhR pathway were correlated with one another. Our findings suggest the presence of long-term effects in the subjects exposed to TCDD after the Seveso accident.

Characterization of dioxin exposure in residents of Chapaevsk, Russia.

Since 1967, a chemical plant in the town of Chapaevsk (Samara province, Russia) has produced large amounts of chlorinated compounds and is suspected to be a major source of local environmental dioxin contamination. Dioxins have been detected in the local air, soil, drinking water, vegetables, and cow's milk. Human exposure to dioxins is suspected as a factor in the deteriorating local public health. In an effort to characterize nonoccupational dioxin exposure among local residents, during the summer of 1998, 24 volunteers were recruited to donate blood and to provide information about their residence, employment, demographics, medical history, and dietary habits. Selected polychlorinated dibenzodioxins, dibenzofurans, and coplanar biphenyls were measured in blood serum samples. The mean concentration of total dioxin World Health Organization toxic equivalents (WHO-TEQ(98)) based on polychlorinated dibenzo-para-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and coplanar polychlorinated biphenyls (PCBs) was 61.2 (range 16.4-168.1) pg/g lipid. Subjects living in close proximity to the plant (less than 5 km) had significantly higher dioxin levels (mean WHO-TEQ(98), 75.7 pg/g lipid), as compared to subjects living more than 5 km from the plant (mean WHO-TEQ(98), 44.1 pg/g lipid) (P<0.04). Comparisons of the study results with available published data indicate that average blood dioxin levels were substantially higher in Chapaevsk residents than in nonoccupationally exposed populations of other parts of Russia, Europe, and North America. Chronic exposures of such magnitude may have appreciable adverse effects on public health.

The effectiveness of home-study driver education compared to classroom instruction: the impact on student knowledge and attitudes.

PROBLEM: Home-study driver education programs exist in several states, but none have been scientifically evaluated to determine if such courses are as effective as classroom courses for teaching driver education. METHOD: Over 1,300 students were randomly assigned to classroom instruction, or CD ROM, workbook, or Internet/workbook home-study courses and compared on proctored exit examination knowledge and attitude scores, and written knowledge test outcomes. RESULTS: Few differences were found on exit examination knowledge and attitude scores, but they tended to favor the CD and Internet/workbook home-study courses over the classroom or workbook courses. Differences favoring the classroom on written knowledge test outcomes likely reflect a bias in classroom courses toward teaching test-specific material. DISCUSSION: The findings present no compelling evidence that home-study courses are less effective than classroom courses for teaching driver education. IMPACT ON INDUSTRY: The findings could result in more widespread use of home-study courses. Also, the use of low-cost home-study courses as the first course of a two-stage driver education and training system could make integrating such programs with graduated driver licensing more feasible and acceptable to the public.

Evaluation of California's graduated driver licensing program.

PROBLEM: California's graduated driver licensing (GDL) program was implemented to reduce the high crash risk of teenage drivers. The program enhancements made in 1998 were evaluated in this study using methods that rule out the noticeable downward trend in California teen's fatal/injury crash rates as a possible explanation for any observed crash reductions that could otherwise be mistaken for program effects. METHOD: Monthly per capita fatal/injury crash rates for 15-to-17-year-olds and proportional representations of 16-17-year-olds' nighttime and passenger crashes were analyzed using intervention time series analysis. RESULTS: After removing trend, seasonality, and transition effects in the data, no overall reductions in fatal/injury crashes for 15-17-year-olds or 16-year-olds (separately) were found to be associated with the 1998 program enhancements, suggesting no overall exposure reduction effect of the longer instruction permit period nor increased competency associated with the higher number of required practice hours. However, the 12-month nighttime and 6-month passenger restrictions were found to be associated with annual savings of 55 and 816 fatal/injury crashes, respectively. DISCUSSION: Finding no overall impact of the 1998 GDL enhancements was not surprising given findings of an earlier survey suggesting that California teens and parents were largely already practicing program requirements prior to implementation and were not fully complying with the program requirements afterwards. Though the observed crash savings associated with the restrictions were of modest size, this is the first study to evidence a direct positive impact of the passenger restriction component of GDL programs. Larger reductions could be realized if the nighttime restriction started earlier and parents/law enforcement could be motivated to better enforce these restrictions. IMPACT ON INDUSTRY: The findings provide support for passenger and nighttime restriction components of GDL programs.

Problem driver remediation: a meta-analysis of the driver improvement literature.

PROBLEM: Given the public safety risk posed by violation and crash repeaters and the substantial costs for state driver improvement programs, it is important that their effectiveness be scientifically demonstrated and that intervention programs are based on sound research findings. METHOD: Crash and traffic violation standardized effect sizes (d) representing 106 individual interventions were coded from 35 methodologically sound studies and analyzed using meta-analysis. RESULTS: Driver improvement intervention in general was associated with small but significant reductions in both crashes (dw = 0.03) and violations (dw = 0.06). Significant effects were found on both measures for warning letters, group meetings, individual hearings, and license suspense/revocation. Of the driver improvement interventions studied, license suspension/revocation was by far the most effective treatment for both crashes and violations (dw = 0.11 and 0.19). Since one of the objectives of license suspension/revocation is to eliminate driving for the period of suspension, it is possible that much or all of the effect is due to reduced exposure and/or more careful driving during the suspension interval. Results were mixed for other types of interventions, although distributing educational or informational material was not associated with any reductions. Interventions associated with violation reduction tended to also be associated with crash reduction, although the relationship was not very strong (r = .30). DISCUSSION: Although interpretation of the effect size estimates was complicated by almost ubiquitous heterogeneity, the results do suggest an overall positive impact of driver improvement interventions in general. IMPACT ON INDUSTRY: The results support the continued use of driver improvement interventions, chiefly warning letters, group meetings, individual hearings, and especially license suspension/revocation. The results also suggest that court-triggered traffic violator programs are less effective than interventions triggered by drivers license agencies.