Disruption of androgen regulation in the prostate by the environmental contaminant hexachlorobenzene

Hexachlorobenzene (HCB) is a persistent environmental contaminant that has the potential to interfere with steroid hormone regulation. The prostate requires precise control by androgens to regulate its growth and function. To determine if HCB impacts androgen action in the prostate, we used a number of methods. Our in vitro cell-culture-based assay used a firefly luciferase reporter gene driven by an androgen-responsive promoter. In the presence of dihydrotestosterone, low concentrations (0.5-5 nM) of HCB increased the androgen-responsive production of firefly luciferase and high concentrations of HCB (> 10 microM) suppressed this transcriptional activity. Results from a binding assay showed no evidence of affinity between HCB and the androgen receptor. We also tested HCB for in vivo effects using transgenic mice in which the transgene was a prostate-specific, androgen-responsive promoter upstream of a chloramphenicol acetyl transferase (CAT) reporter gene. In 4-week-old mice, the proportion of dilated prostate acini, a marker of sexual maturity, increased in the low HCB dose group and decreased in the high HCB dose mice. In the 8-week-old mice, there was a significant decrease in both CAT activity and prostate weight upon exposure to 20 mg/kg/day HCB. Therefore, in vitro and in vivo data suggest that HCB weakly agonizes androgen action, and consequently, low levels of HCB enhanced androgen action but high levels of HCB interfered. Environmental contaminants have been implicated in the rising incidence of prostate cancer, and insight into the mechanisms of endocrine disruption will help to clarify their role.

Empirical investigation of interactive highway safety design model accident prediction algorithm : Rural intersections

One major gap in transportation system safety management is the ability to assess the safety ramifications of design changes for both new road projects and modifications to existing roads. To fulfill this need, FHWA and its many partners are developing a safety forecasting tool, the Interactive Highway Safety Design Model (IHSDM). The tool will be used by roadway design engineers, safety analysts, and planners throughout the United States. As such, the statistical models embedded in IHSDM will need to be able to forecast safety impacts under a wide range of roadway configurations and environmental conditions for a wide range of driver populations and will need to be able to capture elements of driving risk across states. One of the IHSDM algorithms developed by FHWA and its contractors is for forecasting accidents on rural road segments and rural intersections. The methodological approach is to use predictive models for specific base conditions, with traffic volume information as the sole explanatory variable for crashes, and then to apply regional or state calibration factors and accident modification factors (AMFs) to estimate the impact on accidents of geometric characteristics that differ from the base model conditions. In the majority of past approaches, AMFs are derived from parameter estimates associated with the explanatory variables. A recent study for FHWA used a multistate database to examine in detail the use of the algorithm with the base model-AMF approach and explored alternative base model forms as well as the use of full models that included nontraffic-related variables and other approaches to estimate AMFs. That research effort is reported. The results support the IHSDM methodology.