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This study investigated whether, in the absence of chronic noncancer toxicity data, short-term noncancer toxicity data can be used to predict chronic toxicity effect levels by focusing on the dose-response relationship instead of a critical effect. Data from National Toxicology Program (NTP) technical reports have been extracted and modeled using the Environmental Protection Agency's Benchmark Dose Software. Best-fit, minimum benchmark dose (BMD), and benchmark dose lower limits (BMDLs) have been modeled for all NTP pathologist identified significant nonneoplastic lesions, final mean body weight, and mean organ weight of 41 chemicals tested by NTP between 2000 and 2012. Models were then developed at the chemical level using orthogonal regression techniques to predict chronic (two years) noncancer health effect levels using the results of the short-term (three months) toxicity data. The findings indicate that short-term animal studies may reasonably provide a quantitative estimate of a chronic BMD or BMDL. This can allow for faster development of human health toxicity values for risk assessment for chemicals that lack chronic toxicity data.

The goal of this study was to systematically evaluate the choices made in deriving a chronic oral noncancer human health reference value (HHRV) for a given chemical by different organizations, specifically those from the U.S. Environmental Protection Agency, Health Canada, RIVM (the Netherlands), and the U.S. Agency for Toxic Substances and Disease Registry. This analysis presents a methodological approach for comparing both the HHRVs and the specific choices made in the process of deriving an HHRV across these organizations. Overall, across the 96 unique chemicals and 171 two-way organizational comparisons, the HHRV agreed approximately 26% of the time. A qualitative method for identifying the primary factors influencing these HHRV differences was also developed, using arrays of HHRVs across organizations for the same chemical. The primary factors identified were disagreement on the critical or principal study and differential application of the total uncertainty factor across organizations. Of the cases where the total UF was the primary factor influencing HHRV disagreement, the database UF had the greatest influence.

Environmental and public health organizations, including the World Health Organization (WHO) and the U.S. Environmental Protection Agency (USEPA), develop human health reference values (HHRV) that set "safe" levels of exposure to noncarcinogens. Here, we systematically analyze chronic HHRVs from four organizations: USEPA, Health Canada, RIVM (the Netherlands), and the U.S. Agency for Toxic Substances and Disease Registry. This study is an extension of our earlier work and both closely examines the choices made in setting HHRVs and presents a quantitative method for identifying the primary factors influencing HHRV agreement or disagreement.(1) We evaluated 171 organizational comparisons, developing a quantitative method for identifying the factors to which HHRV agreement (that is, when both organizations considering the same data set the identical HHRV values) is most sensitive. To conduct this analysis, a Bayesian belief network was built using expert judgment, including the specific science policy choices analysis made in the context of setting an HHRV. Based on a sensitivity of findings analysis, HHRV agreement is most sensitive to the point of departure value, followed by the total uncertainty factor (UF), critical study, critical effect, animal model, and point of departure approach. This analysis also considered the specific impacts of individual UFs, with the database UF and the subchronic-to-chronic UF being identified as primary factors impacting the total UF differences observed across organizations. The sensitivity of findings analysis results were strengthened and confirmed by frequency analyses evaluating which choices most often disagreed when the HHRV and the total UF disagreed.

Federal and other regulatory agencies often use or claim to use a weight of evidence (WoE) approach in chemical evaluation. Their approaches to the use of WoE, however, differ significantly, rely heavily on subjective professional judgment, and merit improvement. We review uses of WoE approaches in key articles in the peer-reviewed scientific literature, and find significant variations. We find that a hypothesis-based WoE approach, developed by Lorenz Rhomberg et al., can provide a stronger scientific basis for chemical assessment while improving transparency and preserving the appropriate scope of professional judgment. Their approach, while still evolving, relies on the explicit specification of the hypothesized basis for using the information at hand to infer the ability of an agent to cause human health impacts or, more broadly, affect other endpoints of concern. We describe and endorse such a hypothesis-based WoE approach to chemical evaluation.

Integrating occupational safety and health (OSH) into life cycle assessment (LCA) may provide decision makers with insights and opportunities to prevent burden shifting of human health impacts between the nonwork environment and the work environment. We propose an integration approach that uses industry-level work environment characterization factors (WE-CFs) to convert industry activity into damage to human health attributable to the work environment, assessed as disability-adjusted life years (DALYs). WE-CFs are ratios of work-related fatal and nonfatal injuries and illnesses occurring in the U.S. worker population to the amount of physical output from U.S. industries; they represent workplace hazards and exposures and are compatible with the life cycle inventory (LCI) structure common to process-based LCA. A proof of concept demonstrates application of the WE-CFs in an LCA of municipal solid waste landfill and incineration systems. RESULTS from the proof of concept indicate that estimates of DALYs attributable to the work environment are comparable in magnitude to DALYs attributable to environmental emissions. Construction and infrastructure-related work processes contributed the most to the work environment DALYs. A sensitivity analysis revealed that uncertainty in the physical output from industries had the most effect on the WE-CFs. The results encourage implementation of WE-CFs in future LCA studies, additional refinement of LCI processes to accurately capture industry outputs, and inclusion of infrastructure-related processes in LCAs that evaluate OSH impacts. Language: en

Pollutant release and transfer registers (PRTRs) are becoming a popular measure for addressing industrial pollution in many countries. PRTRs require reporting of emissions from specific industrial sectors and making the information publicly available. This article suggests a framework for comparing PRTRs in order to determine whether they attain their declared goals and which factors, if any, influence their effectiveness. The challenges to such a comparison can be divided into three groups. The first refers to changes that are directly linked to the characteristics of PRTRs: both the changes within a specific system over time and variations among different systems. The second refers to parameters that affect the outcomes of the systems without being directly a part of them. The third involves the relations between the emissions reported to the PRTRs and the associated environmental risk. We suggest an approach that relies on relative comparison, commensurate with the unique characteristics of each PRTR, that compares their actual outcomes. Such an approach is necessary both due to significant variations among current PRTRs as well as for following the unique policy objectives that are manifested in different PRTRs. Application of this comparative approach in the United States, England, Canada, and Australia demonstrates significant differences in PRTR systems across countries and suggests that the mere presence of a PRTR may not lead to reduced industrial emissions. The analysis also demonstrates that emission reductions do not correlate with reductions in risk-related measures. The article proposes several simple modifications to the composition of current PRTR databases that may facilitate more accurate analysis of results and effective oversight of implementation.

Compression measurements were conducted on three explosive formulation binders, extruded Estane, plasticized Estane, and plasticized hydroxyl-terminated polybutadiene, as a function of temperature and strain rate. The mechanical response of the Estane was found to exhibit the strongest dependency on strain rate and temperature and higher flow strength for similar test conditions of the three materials tested. Plasticized Estane was less sensitively dependent on strain rate and temperature, followed by the plasticized HTPB. The visco-elastic recovery of all three binders is seen to dominate the mechanical behavior at temperatures above the glass transition temperature (Tg). There is a pronounced shift in the apparent Tg to higher temperatures as the strain rate is increased. Two distinct behaviors are observed in the binders below the Tg. At low strain rates, the binders exhibit a yield behavior, followed by a drop in the flow stress, which may or may not recover. At high strain rates, the load drop does not occur and the flow stresses either gradually increase, as in plasticized HTPB, or it levels out as seen in the Estane-based binders. POLYM. ENG. SCI., 46:812–819, 2006. © 2006 Society of Plastics Engineers

In December 2000 the EPA initiated the Voluntary Children's Chemical Evaluation Program (VCCEP) by asking manufacturers to voluntarily sponsor toxicological testing in a tiered process for 23 chemicals selected for the pilot phase. The tiered nature of the VCCEP pilot program creates the need for clearly defined criteria for determining when information is sufficient to assess the potential risks to children. This raises questions about how to determine the "adequacy" of the existing information and assess the need to undertake efforts to reduce uncertainty (through further testing). This article applies a value of information analysis approach to determine adequacy by modeling how toxicological and exposure data collected through the VCCEP may be used to inform risk management decisions. The analysis demonstrates the importance of information about the exposure level and control costs in making decisions regarding further toxicological testing. This article accounts for the cost of delaying control action and identifies the optimal testing strategy for a constrained decisionmaker who, absent applicable human data, cannot regulate without bioassay data on a specific chemical. It also quantifies the differences in optimal testing strategy for three decision criteria: maximizing societal net benefits, ensuring maximum exposure control while net benefits are positive (i.e., benefits outweigh costs), and controlling to the maximum extent technologically feasible while the lifetime risk of cancer exceeds a specific level of risk. Finally, this article shows the large differences that exist in net benefits between the three criteria for the range of exposure levels where the optimal actions differ.

The North American Free Trade Agreement (NAFTA) and the General Agreement on Tariffs and Trade (GATT) have focused attention on risk assessment of potential insect, weed, and animal pests and diseases of livestock. These risks have traditionally been addressed through quarantine protocols ranging from limits on the geographical areas from which a product may originate, postharvest disinfestation procedures like fumigation, and inspections at points of export and import, to outright bans. To ensure that plant and animal protection measures are not used as nontariff trade barriers, GATT and NAFTA require pest risk analysis (PRA) to support quarantine decisions. The increased emphasis on PRA has spurred multiple efforts at the national and international level to design frameworks for the conduct of these analyses. As approaches to pest risk analysis proliferate, and the importance of the analyses grows, concerns have arisen about the scientific and technical conduct of pest risk analysis. In January of 1997, the Harvard Center for Risk Analysis (HCRA) held an invitation-only workshop in Washington, D.C. to bring experts in risk analysis and pest characterization together to develop general principles for pest risk analysis. Workshop participants examined current frameworks for PRA, discussed strengths and weaknesses of the approaches, and formulated principles, based on years of experience with risk analysis in other setting and knowledge of the issues specific to analysis of pests. The principles developed highlight the both the similarities of pest risk analysis to other forms of risk analysis, and its unique attributes.

Since cancer risk at very low doses cannot be directly measured in humans or animals, mathematical extrapolation models and scientific judgment are required. This article demonstrates a probabilistic approach to carcinogen risk assessment that employs probability trees, subjective probabilities, and standard bootstrapping procedures. The probabilistic approach is applied to the carcinogenic risk of formaldehyde in environmental and occupational settings. Sensitivity analyses illustrate conditional estimates of risk for each path in the probability tree. Fundamental mechanistic uncertainties are characterized. A strength of the analysis is the explicit treatment of alternative beliefs about pharmacokinetics and pharmacodynamics. The resulting probability distributions on cancer risk are compared with the point estimates reported by federal agencies. Limitations of the approach are discussed as well as future research directions.

Fourteen novel side-chain polysiloxanes 2 and their alkene precursors 1 containing methylene-cyclohexane, cyclohexane, benzene, bicyclooctane, 3-oxobicyclooctane, bicyclohexane and biphenyl moieties in the mesogenic core, and with (CH2)n spacer lengths of n = 3, 6 and 11 are reported. The order of efficiency of these cyclic moieties in promoting liquid-crystal properties in the polymers is the same as that observed for the precursor alkenes, indicating that similar qualitative structural rules govern mesophase type and thermal stability in both monomeric and macromolecular systems. The apparent occurrence of smectic C properties for two of the polymers is particularly interesting.

Etude des temperatures de transition vitreuse et nematique-isotrope d'homo- et de copolymeres [−SiO(Me)([CH 2 ] 4 −OR)] x n=5,11 R=C 6 H 3 (OC 8 H 17 )−CO 2 −Ph−Ph−R 1 (R 1 =CN, C 5 H 11 ) en fonction de leur composition

Proton and 13C NMR parameters have been determined for phenyldibenzophosphole and its oxide, sulfide, selenide and W(CO)5 complex from high-resolution one- and two-dimensional (COSY, HETCOR and 2DJ) experiments at 4.7, 7.1 and 9.4 tesla. Assignments of chemical shifts and coupling constants have been made and verified by computer simulation of the proton spectra. The data are discussed in relation to the geometry and electron density at phosphorus and the diamagnetic anisotropy of the W(CO)5 group.

Description d'une approche alternative pour augmenter la stabilite de couche multimoleculaire: incorporation d'un groupe chromophore dans la chaine laterale d'un polysiloxane

Natural abundance 13C NMR studies have been carried out on a series of phospholes and dibenzophospholes. The systems were analyzed with respect to ring conformation and substituent orientation. Assignments of all chemical shifts have been made by investigating partially relaxed inversion-recovery spectra and by investigating the field dependence of the spectra. A nonplanar (6-membered central ring) tricyclic phosphine was also examined. Here, the value of the two bond coupling constant 2J(PC) allowed determination of the orientation (axial) of the phosphorus-substituted phenyl ring. Conclusions regarding cyclic conjugation in phospholes are presented.

Preparation par polyhydrosilylation de poly(hydrogenomethylsiloxane avec une chaine laterale terminal alcenique en presence d'acide hexachloroplatinique dans le propanol-2

The polypeptide carbobenzoxy-glycyl-L-prolyl-L-leucyl-L-alanyl-L-proline (0.2 M in DMSO-d6) was investigated using 13C, 1H and 15N NMR in natural abundance at 4.7 tesla. The existence of cis–trans-Gly-Pro and -Ala-Pro bonds permits up to four isomers, and all four were observed (in a 60:30:7:3 ratio). 13C shifts of the proline β-CH2 resonances are consistent only with the 60% form being trans–trans. The 30% form is either trans–cis or cis–trans (order as above) and was tentatively assigned as cis-trans on the basis of relaxation behavior. Refocused INEPT studies aided the 13C assignments. The 15N data were obtained using both NOE and INEPT excitation, with signals evident for the three major isomers. The spectra were analysed by starting from the 13C data, which were assigned based on known regularities in peptide spectra. A 13C1H heteronuclear two-dimensional chemical shift correlation experiment allowed direct assignment of proton shifts for major and minor isomers. The NH proton shifts were assigned by running a homonuclear two-dimensional chemical shift correlation experiment and noting the correlation with the previously assigned α-CH protons. The 15N resonances were then assigned from a 15N1H heteronuclear two-dimensional chemical shift correlation experiment, relating the 15N signals directly to the NH proton resonances. Isomer interconversion between the two major isomers was demonstrated by performing a magnetization transfer homonuclear 2D experiment. Off-diagonal intensity was noted relating the major and minor isomer alanine NH proton, as well as for the major and minor isomer leucine NH protons.

Natural abundance 13C and 15N nuclear magnetic resonance studies have been carried out on a series of sodium tetrazolate salts, 1,5- and 2,5-disubstituted tetrazoles, bitetrazoles, and cobalt(III) tetrazolate complexes of the type (PBu3n)Co(DH)2(5-R-tetrazolate), where DH is the monoanion of dimethylglyoxime. The 15N chemical shifts have been analysed with respect to structure, substituent effects, electron density as determined by molecular orbital calculations, Bronsted acidity, Lewis basicity and nucleophilicity of the nitrogen atoms in the ambidentate tetrazoles.

An infant with Klippel Trenaunay Syndrome (KTS), a disorder of embryonic development characterized by hemangiomas and hypertrophy of lower extremities, had bilateral nephroblastomatosis diagnosed at 1 year of age. Although the natural course of these tumors is uncertain, lesions of this kind have been suggested as the source of Wilms' tumor. In addition, foci of primitive cells suggested malignant potential. The more extensively involved kidney was removed and the contralateral lesion was treated by irradiation, actinomycin D, and vincristine, resulting in disappearance of the lesions 6 months later. The association of nephroblastic tumors with soft tissue growth disorders is extended to include KTS, and the possible relationship of nephroblastomatosis to Wilms' tumor is discussed.

Nuclear DNA content of paraffin-embedded tissue from 48 adrenocortical neoplasms, 18 histologically normal control adrenal glands, and five hyperplastic adrenal glands was analyzed retrospectively using flow cytometry. Aneuploidy was compared with morphologic criteria as a predictor of recurrence. All 18 controls, five hyperplastic glands, and 39 neoplasms were diploid. Nine neoplasms were aneuploid. Compared with their diploid counterparts, aneuploid neoplasms were more likely to weigh more than 50 g (P less than 0.0001) and to have three or more histologic features of carcinoma (P less than 0.0001). Thirty-six neoplasms were followed clinically for at least 2 years (range 24 to 120 months, mean = 64.6 months) or until local recurrence, metastasis, or death. Five were clinically malignant. Neoplasms which recurred or metastasized were more apt to be aneuploid (P less than 0.005) than those showing no evidence of further disease during the follow-up period. They were also more likely to weigh more than 50 g (P less than 0.005) and to have three or more histologic features of carcinoma (P less than 0.0025). However, neither aneuploidy, large size, nor unfavorable histology result was a consistent feature in every malignant neoplasm. Flow cytometric DNA content analysis appears to be as effective a predictor of clinical outcome as size and histology and may be of particular value when the morphologic features are ambiguous.

BALB/c 3T3 cells infected with a temperature-sensitive mutant (LA90) of RSV have been used to investigate possible heterologous interactions between the pp60v-src tyrosyl kinase and the epidermal growth factor (EGF) and bradykinin receptors. The LA90 pp60v-src exhibits a very rapid activation t1/2 (less than 5 min) of protein kinase activity on decreasing the temperature from 40 degrees C to 35 degrees C. This change in temperature was also found to induce a very rapid decrease in the affinity for 125I-EGF of receptors on the RSV-LA90-infected cells but not of those on control parental cells. However, no significant changes were detected in the binding of 3H-bradykinin to either cell line. Two separable processes control the desensitization of the EGF receptor by pp60v-src, both of which are independent of protein kinase C. The first is rapid and transient, while the second is sensitive to cycloheximide and persists long after inactivation of pp60v-src.

Two samples of a statistical siloxane copolymer 1 having two different pendant side-chains have been investigated in the liquid-crystalline state using dielectric relaxation spectroscopy. Samples 1a and 1b differed only in the number of precipitations (3 and 12, respectively) used in the purification procedure. Sample 1a, contained side-chain precursor, whereas this contaminant was not detectable in sample 1b. It was found that the dielectric absorption curves for homeotropically-aligned and unaligned specimens of sample 1a, were far broader than those observed for corresponding specimens of sample 1b, and there was evidence of an extra highfrequency shoulder. In addition, the frequency-temperature locations of the overall loss peak differed between the two samples, being consistent with a plasticization effect caused by residual side-chain precursor in sample 1a. It is shown that dielectric relaxation spectroscopy provides a convenient method for monitoring local phase separation and overall plasticization in liquid-crystalline polymers caused by side-chain precursor contamination.

The removal of the alkene side-chain precursor from liquid-crystal (1.c.) polysiloxanes during their isolation by precipitation has been monitored by thin-layer chromatography. The commonly used procedure involving only three precipitations has been shown to be frequently insufficient to remove the alkene completely from the 1.c. polymer. Using 8 to 10 precipitations and monitoring the removal of alkene to

Vanadate can activate the uptake of Ca in A431 epidermal carcinoma cells by two- to fivefold with no detectable lag period. Preincubation with epidermal growth factor (EGF) to down-regulate the EGF receptor prevents subsequent stimulation by EGF but not that by vanadate. Ca uptake is sodium-independent and is not activated by depolarization in high KCl. On the contrary, vanadate-stimulated uptake is completely inhibited by decreasing the plasma membrane potential from about -65 to -30 mV. These results demonstrate that the EGF receptor is not itself functioning as a Ca channel, that vanadate is not acting at the level of EGF receptor, and that the Ca transport system exhibits an unusual potential sensitivity in that it is inhibited by depolarization of the plasma membrane.

Hemangioendothelial sarcoma of the penis in a 44-year-old man was treated by preoperative radiation, penectomy, and chemotherapy. The patient was free of evident disease 2 years later. Electronmicroscopy showed differentiated vascular structures at the periphery of the lesion and anaplastic cells throughout the remainder of the tumor.

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Reactions of (vinylphosphine) 2 MX 2 complexes with (1-R-3,4-dimethylphosphole) 2 MX 2 complexes (where vinylphosphine=Ph 2 VyP, PhVy 2 P, Et 2 VyP; R=Ph, Bzl, t-Bu; X=Cl, Br, I; M=Pd, Pt) produce dihalo [2-(R',R″-phosphino)-5,6-dimethyl-7-R-7-phosphabicyclo [2.2.1] hept-5-ene] metal(II) complexes via an intramolecular Diels-Alder [4+2] cycloaddition

Three types of ester incorporating the 1,4-disubstituted bicyclo[2.2.2]octane ring have been prepared and found to exhibit wide-range nematic phases at higher temperatures than those of analogous mesogens containing the 1,4-disubstituted phenylene or trans-1,4-disubstituted cyclohexane ring.