The use of toxicologic data in mechanistic risk assessment: 1,3-butadiene as a case study

The National Research Council (NRC) recently published a report. Science and Judgment in Risk Assessment, that critiqued the current approaches to characterizing human cancer risks from exposure to chemicals. One issue raised in the report relates to the use of default options for quantitation of cancer risks. Default options are general guidelines that can be used for risk assessment when specific information about a chemical is absent. Research on 1,3-butadiene represents an interesting case study in which existing knowledge on this chemical indicates that two default options may no longer be tenable: (1) humans are as sensitive as the most sensitive animal species, and (2) the rate of metabolism is a function of body surface area rather than inherent species differences in metabolic capacity. Butadiene, a major commodity chemical used in the production of synthetic rubber, is listed as one of 189 hazardous air pollutants under the 1990 Clean Air Act Amendments. Butadiene is a carcinogen in rats and mice, with mice being substantially more sensitive than rats. The extent to which butadiene poses a cancer risk to humans exposed to this chemical is uncertain. Butadiene requires metabolic activation to DNA-reactive epoxides to exert its mutagenic and carcinogenic effects. Research is directed toward obtaining a better understanding of the cancer risks of butadiene in humans by evaluating species-dependent differences in the formation of the toxic butadiene epoxide metabolites, epoxybutene and diepoxybutane. The data include in-vitro studies on butadiene metabolism using tissues from humans, rats, and mice as well as experimental data and physiological model predictions for butadiene in blood and butadiene epoxides in blood, lung, and liver after exposure of rats and mice to inhaled butadiene. The findings suggest that humans are more like rats and less like mice regarding the formation of butadiene epoxides. The research approach employed can be a useful strategy for developing mechanistic and toxicokinetic data to supplant default options used in carcinogen risk assessments for butadiene.     

Swept Volume Approximation of Polygon Soups

We present a fast algorithm to approximate the swept volume (SV) boundary of arbitrary polygon soup models. Despite the extensive research on calculating the volume swept by an object along a trajectory, the efficient algorithms described have imposed constraints on both the trajectories and geometric models. By proposing a general algorithm that handles flat surfaces as well as volumes and disconnected objects, we allow SV calculation without resorting to preprocessing mesh repair nor deforming offsets. This is of particular interest in the domain of product lifecycle management (PLM), which deals with industrial computer aided design (CAD) models that are malformed more often than not. We incorporate the bounded distance operator used in path planning to efficiently sample the trajectory while controlling the total error. We develop a triangulation scheme that draws on the unique data set created by an advancing front level-set method to tessellate the SV boundary in linear time. We analyze its performance, and demonstrate its effectiveness both theoretically and on real cases taken from PLM.     

Local search: the Internet is the Yellow Pages

The proposed Internet-derived Yellow Pages aggregate, annotate, and certify Web content for use in geographically oriented searching. The IDYP provides a framework for combining Internet-derived content with the trust and fairness that characterize the printed Yellow Pages, still the predominant source of consumer-oriented local information.     

Dissolution kinetics of phenylbutazone

This study investigated the possible effects of simultaneous, noninstantaneous, reversible chemical ionization of carbon acids on the dissolution of a typical pharmaceutical carbon acid, phenylbutazone, and its deutero analog. The dissolution rate versus pH profile for phenylbutazone was consistent with phenylbutazone acting as if it were an acid where the ionization can be considered instantaneous. In view of the dissolution behavior of phenylbutazone under various conditions, it is unlikely that the noninstantaneous ionization kinetics demonstrated for this compound play a major role in determining the dissolution rate, either in vitro or in vivo, since the average residence time in a typical aqueous diffusion layer for phenylbutazone dissolution is longer than the reaction time for its ionization. Slowing the reaction time with a primary isotope effect by deuterium substitution for the ionizable proton caused significant deviation from classical behavior for d-phenylbutazone.     

The effects of a health promotion-health protection intervention on behavior change: the WellWorks Study

OBJECTIVES: This study assessed the effects of a 2-year integrated health promotion-health protection work-site intervention on changes in dietary habits and cigarette smoking. METHODS: A randomized, controlled intervention study used the work site as the unit of intervention and analysis; it included 24 predominantly manufacturing work sites in Massachusetts (250-2500 workers per site). Behaviors were assessed in self-administered surveys (n = 2386; completion rates = 61% at baseline, 62% at final). Three key intervention elements targeted health behavior change: (1) joint worker-management participation in program planning and implementation, (2) consultation with management on work-site environmental changes, and (3) health education programs. RESULTS: Significant differences between intervention and control work sites included reductions in the percentage of calories consumed as fat (2.3% vs 1.5% kcal) and increases in servings of fruit and vegetables (10% vs 4% increase). The intervention had a significant effect on fiber consumption among skilled and unskilled laborers. No significant effects were observed for smoking cessation. CONCLUSIONS: Although the size of the effects of this intervention are modest, on a populationwide basis effects of this size could have a large impact on cancer-related and coronary heart disease end points.     

Influence of gender and acetone pretreatment on benzene metabolism in mice exposed by nose-only inhalation

Benzene (BZ) requires oxidative metabolism catalyzed by cytochrome P-450 2E1 (CYP 2E1) to exert its hematotoxic and genotoxic effects. We previously reported that male mice have a two-fold higher maximum rate of BZ oxidation compared with female mice; this correlates with the greater sensitivity of males to the genotoxic effects of BZ as measured by micronuclei induction and sister chromatid exchanges. The aim of this study was to quantitate levels of BZ metabolites in urine and tissues, and to determine whether the higher maximum rate of BZ oxidation in male mice would be reflected in higher levels of hydroxylated BZ metabolites in tissues and water-soluble metabolites in urine. Male and female B6C3F, mice were exposed to 100 or 600 ppm 14C-BZ by nose-only inhalation for 6 h. An additional group of male mice was pretreated with 1% acetone in drinking water for 8 d prior to exposure to 600 ppm BZ; this group was used to evaluate the effect of induction of CYP 2E1 on urine and tissue levels of BZ and its hydroxylated metabolites. BZ, phenol (PHE), and hydroquinone (HQ) were quantified in blood, liver, and bone marrow during exposure and postexposure, and water-soluble metabolites were analyzed in urine in the 48 h after exposure. Male mice exhibited a higher flux of BZ metabolism through the HQ pathway compared with females after exposure to either 100 ppm BZ (32.0 2.03 vs. 19.8 2.7%) or 600 ppm BZ (14.7 1.42 vs. 7.94 + 0.76%). Acetone pretreatment to induce CYP 2E1 resulted in a significant increase in both the percent and mass of urinary HQ glucuronide and muconic acid in male mice exposed to 600 ppm BZ. This increase was paralleled by three- to fourfold higher steady-state concentrations of PHE and HQ in blood and bone marrow of acetone-pretreated mice compared with untreated mice. These results indicate that the higher maximum rate of BZ metabolism in male mice is paralleled by a greater proportion of the total flux of BZ through the pathway for HQ formation, suggesting that the metabolites formed along this pathway may be responsible for the genotoxicity observed following BZ exposure.     

Sustainable intensification: a multifaceted,systemic approach to international development

Sustainable intensification (SI) is a term increasingly used to describe a type of approach applied to international agricultural projects. Despite its widespread use, there is still little understanding or knowledge of the various facets of this composite paradigm. A review of the literature has led to the formalization of three principles that convey the current characterization of SI, comprising a whole system, participatory, agroecological approach. Specific examples of potential bottlenecks to the SI approach are cited, in addition to various technologies and techniques that can be applied to overcome these obstacles. Models of similar, succcessful approaches to agricultural development are examined, along with higher level processes. Additionally, this review explores the desired end points of SI and argues for the inclusion of gender and nutrition throughout the process. To properly apply the SI approach, its various aspects need to be understood and adapted to different cultural and geographic situations. New modeling systems and examples of the effective execution of SI strategies can assist with the successful application of the SI paradigm within complex developing communities. © 2016 Society of Chemical Industry