Toxicology of chemical mixtures: challenges for today and the future

A major challenge for the toxicologist involved in safety evaluation of chemical mixtures is to test the hypothesis that as a rule exposure to mixtures of chemicals at (low) non-toxic doses of the individual chemicals is of no health concern. A series of repeated dose studies in rats with defined mixtures of chemicals with the same or different target organs revealed that exposure to a combination of chemicals compared with exposure to the individual compounds did not constitute an evidently increased hazard, provided each chemical was administered at a level similar to, or slightly lower than, its own 'No-Observed-Adverse-Effect-Level'. The results of subacute oral toxicity studies in rats with defined mixtures of nephrotoxicants with similar mode of action underlined the applicability of the additivity assumption for a mixture of chemicals with simple similar action. Safety evaluation of complex chemical mixtures is a challenge that can be tackled as follows: first, identify the (e.g. ten) most risky chemicals in the mixture, and, second, assess the hazard and the potential health risk of the mixture of the most risky chemicals, using procedures developed for defined mixtures. To identify interactions between individual compounds, a most promising testing strategy appeared to be a statistical approach using a fractional two-level factorial design. A challenge for today and the future is to gradually substitute mixture-oriented (real life-oriented) standard setting for (unrealistic) single chemical-oriented standard setting.     

Are moment bounds on the recombination fraction between a marker and a disease locus too good to be true? Allelic association mapping revisited for simple genetic diseases in the Finnish population

In the past several years, allelic association has helped map a number of rare genetic diseases in the human genome. A commonly used upper bound on the recombination fraction between the disease gene and an associated marker is known to be biased downward, so there is the possibility that an investigator could be misled. This upper bound is based on a moment equation that can be derived within the context of a Poisson branching process, so its performance can be compared with a recently proposed likelihood bound. We show that the confidence level of the moment upper bound is much lower than expected, while the confidence level of the likelihood bound is in line with expectation. The effects of mutation at either the marker or disease locus on the upper bounds are also investigated. Results indicate that mutation is not an important force for typical mutation rates, unless the recombination fraction between the marker and disease locus is very small or the disease allele is very rare in the general population. Finally, the impact of sample size on the likelihood bound is investigated. The results are illustrated with data on 10 simple genetic diseased in the Finnish population.     

Efficiency Limits for Slip-on Type Buckle Arrestors for Offshore Pipelines

Slip-on buckle arrestors for offshore pipelines offer important advantages over other arrestor designs as they do not require welding. An additional advantage offered by the related concept of the two-part clamp-on arrestor is that it can be installed onto a continuous pipe. It has long been known that such devices often cannot reach higher arresting efficiencies. As a result, the use of slip-on arrestors in deepwater applications has been limited. The somewhat deficient performance is due to the fact that a propagating buckle can penetrate such devices via a folded-up U mode at pressures that are lower than the collapse pressure of the pipe. This can take place even for very rigid rings. A methodology for generating bounds on the maximum arresting efficiency that can be expected from slip-on arrestors is developed. An upper bound of their efficiency is related to the pressure at which a propagating buckle starts to penetrate a long and stiff circumferential confinement. A lower bound is established by relating the crossover pressure to the lowest pressure at which the buckle will propagate through the confinement. The parametric dependence of both of these pressures was established experimentally. The method developed yields the range of pipe D/t’s where degradation in arresting efficiency can be expected and predicts its extent. The arresting efficiency degradation was shown to depend on the yield stress of the pipe. Pipe of higher yield stress exhibits smaller degradation in arresting efficiency.     

The global burden of trachomatous visual impairment: I. Assessing prevalence

This paper summarizes primary epidemiologic studies of trachomatous blindness to develop age-/sex-/region-specific estimates of the global prevalence of trachomatous blindness and low vision. These studies are first examined for their validity and then employed to derive a 'minimum' prevalence of trachomatous visual impairment. This method yield a global total for 1990 of approximately 640,000 cases of trachomatous blindness, corresponding to a prevalence of 0.12/1,000 (lower and upper bounds, 0.10 to 0.14/1,000). When those with low vision due to trachoma are included, 1.5 million cases of visual impairment are estimated, corresponding to a prevalence of 0.28/1,000 (lower and upper bounds, 0.15 to 0.75/1,000). A second approach, labeled the 'projected' prevalence of trachomatous visual impairment, selects country-wide studies to derive representative regional prevalence values. A global total of 2,899,000 blind ("projected' prevalence of 0.55/1,000 with lower and upper bounds, 0.37 to 0.83/1,000) is estimated for 1990. With trachomatous low vision included, greater than 6.7 million individuals in 1990 have visual impairment from trachoma ("projected' prevalence of 1.28/1,000 with lower and upper bounds, 0.53 to 4.29/1,000). Analysis of the distribution of the global prevalence by age, gender, visual acuity and region provide direction for trachoma research and programme priorities. Attention is drawn to the limited studies and resulting wide variation in the estimates of trachomatous visual impairment prevalence as indicated by the lower and upper bound estimates. It is recommended that this epidemiologic uncertainty be reflected in global and regional estimates of trachomatous visual impairment prevalence in order to draw attention to how little is known and emphasize the need for further surveys. A second paper incorporates these findings in an assessment of the global burden of trachomatous visual impairment.     

Method to assist in the scheduling of add-on surgical cases--upper prediction bounds for surgical case durations based on the log-normal distribution

BACKGROUND: A problem that operating room (OR) managers face in running an OR suite on the day of surgery is to identify "holes" in the OR schedule in which to assign "add-on" cases. This process necessitates knowing the typical and maximum amounts of time that the case is likely to require. The OR manager may know previous case durations for the particular surgeon performing a particular scheduled procedure. The "upper prediction bound" specifies with a certain probability that the duration of the surgeon's next case will be less than or equal to the bound. METHODS: Prediction bounds were calculated by using methods that (1) do not assume that case durations follow a specific statistical distribution or (2) assume that case durations follow a log-normal distribution. These bounds were tested using durations of 48,847 cases based on 15,574 combinations of scheduled surgeon and procedure. RESULTS: Despite having 3 yr of data, 80 or 90% prediction bounds would not be able to be calculated using the distribution-free method for 35 or 49% of future cases versus 22 or 22% for the log-normal method, respectively. Prediction bounds based on the log-normal distribution overestimated the desired value less often than did the distribution-free method. The chance that the duration of the next case would be less than or equal to its 90% bound based on the log-normal distribution was within 2% of the expected rate. CONCLUSIONS: Prediction bounds classified by scheduled surgeon and procedure can be accurately calculated using a method that assumes that case durations follow a log-normal distribution.     

A comparison of muscular mechanical energy expenditure and internal work in cycling

The hypothesis that the sum of the absolute changes in mechanical energy (internal work) is correlated with the muscular mechanical energy expenditure (MMEE) was tested using two elliptical chainrings, one that reduced and one that increased the internal work (compared to circular). Upper and lower bounds were put on the extra MMEE (work done by net joint torques in excess of the external work) with respect to the effect of intercompensation between joint torques due to biarticular muscles. This was done by having two measures of MMEE, one that allowed no intercompensation and one that allowed complete intercompensation between joints spanned by biarticular muscles. Energy analysis showed no correlation between internal work and the two measures of MMEE. When compared to circular, the chainring that reduced internal work increased MMEE, and phases of increased crank velocity associated with the elliptical shape resulted in increased power absorbed by the upstroke leg as it was accelerated against gravity. The resulting negative work necessitated additional positive work. Thus, the hypothesis that the internal work is correlated with MMEE was found to be invalid, and the total mechanical work done cannot be estimated by summing the internal and external work. Changes in the dynamics of cycling caused by a non-circular chainring may affect performance and must be considered during the non-circular chainring design process.     

Evaluation of the electrical resistivity of steels

Literature data on the physical properties of steels have been collected and put into a database. The resistivity of steels has been analyzed as a function of composition and microstructure. An overview over former studies is given. The steels have been investigated in two groups, ferritic steels and austenitic steels. A thermodynamic analysis with ThermoCalc has been performed. Regression analysis on the influence of composition on the resistivity was then carried out. The results for ferritic steels are: Si and Al have the highest elemental resistivity, followed by Mn, Cu, Ni, Mo, and Cr. C precipitated in cementite shows a high coefficient in the analysis when the amount of Fe bound in cementite is not considered separately. C in solution with ferrite shows no significant effect. Cr bound in cementite shows a significant effect but Mn, though present in cementite in comparable amounts, has no significant effect on the resistivity. N and C have the highest elemental resistivity in austenite, followed by the substitutional solutes Nb, Si, Ti, Cu, Ni, Mo, and Cr. The carbides NbC and TiC appear with a higher coefficient in the regression model than can be explained by phase‐mixture models providing upper and lower bounds for the resistivity of two‐phase alloys. Cr₂₃C₆ shows no significant effect. The regression results can be used to predict the resistivity of steels with known composition. The model predicts the resistivity of ferritic steels with a maximum deviation between experimental and computed value of 12 nōm and a standard deviation of 5.6 nōm. For austenitic steels, the model prediction shows a maximum deviation of 52 μōcm and a standard deviation of 20 nōm.     

Undrained Limit States of Shallow Foundations Acting in Consort

There is no established procedure for the calculation of bearing capacity of a shallow foundation system comprising cojoined footings. Ad hoc approaches are relied on and may simply involve summing the ultimate limit states of the individual footings as if they acted independently; neglecting additional capacity of the system available from the kinematic constraint provided by the structural connection between the footings. In this study, the undrained capacity under general loading of rigidly connected two-footing systems at various separations has been investigated with finite-element analyses. Results are presented in terms of ultimate limit states under pure vertical (V), horizontal (H), and moment (M) loading, and failure envelopes defining limiting load states under combined VH, VM, HM, and VHM loads. Kinematic failure mechanisms observed in the finite-element analyses are presented and in cases used to provide the basis for upper bound solutions.     

Finite-Element Limit Analysis of Mohr–Coulomb Materials in 3D Using Semidefinite Programming

Semidefinite programming (SDP) provides a convenient framework for the solution of optimization problems involving the eigenvalues of symmetric matrices. The classical Mohr–Coulomb yield criterion for an isotropic cohesive-frictional continuum is most naturally expressed in terms of principal stresses (eigenvalues of the symmetric stress tensor), while the associated flow rule and plastic dissipation function can both be expressed in terms of principal strains (eigenvalues of the symmetric strain tensor). This suggests that SDP could be suitable for performing limit analysis of three-dimensional (3D) structures obeying the Mohr–Coulomb criterion, where the yield and flow rule constraints are difficult to enforce using other methods of optimization. In this paper it is demonstrated that SDP can indeed be used to obtain both lower and upper bounds on the exact collapse load for a Mohr–Coulomb continuum in 3D, though a novel derivation is needed to arrive at an efficient SDP formulation of the upper bound in terms of kinematic quantities only. Two numerical examples are studied, using finite-element discretizations of the stress and displacement fields that preserve the strictness of the lower and upper bound solutions. The arising optimization problems are solved using the general-purpose SDP solver SeDuMi, with no attempt to modify or tailor the code for this specific application. Even so, 3D analyses of moderate size (several thousand tetrahedral elements) are handled with encouraging efficiency.     

An association between air pollution and mortality in six U.S. cities

BACKGROUND: Recent studies have reported associations between particulate air pollution and daily mortality rates. Population-based, cross-sectional studies of metropolitan areas in the United States have also found associations between particulate air pollution and annual mortality rates, but these studies have been criticized, in part because they did not directly control for cigarette smoking and other health risks. METHODS: In this prospective cohort study, we estimated the effects of air pollution on mortality, while controlling for individual risk factors. Survival analysis, including Cox proportional-hazards regression modeling, was conducted with data from a 14-to-16-year mortality follow-up of 8111 adults in six U.S. cities. RESULTS: Mortality rates were most strongly associated with cigarette smoking. After adjusting for smoking and other risk factors, we observed statistically significant and robust associations between air pollution and mortality. The adjusted mortality-rate ratio for the most polluted of the cities as compared with the least polluted was 1.26 (95 percent confidence interval, 1.08 to 1.47). Air pollution was positively associated with death from lung cancer and cardiopulmonary disease but not with death from other causes considered together. Mortality was most strongly associated with air pollution with fine particulates, including sulfates. CONCLUSIONS: Although the effects of other, unmeasured risk factors cannot be excluded with certainty, these results suggest that fine-particulate air pollution, or a more complex pollution mixture associated with fine particulate matter, contributes to excess mortality in certain U.S. cities.     

Life-Cycle Costs of Commercial Roof Systems

The roofing industry in the United States generates annual revenues in excess of $23 billion. This represents a significant annual investment in infrastructure maintenance cost and the opportunity cost of these resources can significantly detract from an owner’s ability to invest in other areas. In addition, a failed or failing roof system represents a heightened opportunity for failure in the building envelope and inherently increases the risk of additional costs. Present roof asset management practice typically bases replacement decisions on fixed intervals, inspection results, maintenance issues, and, occasionally, failure risk. This paper develops a model for evaluating occupant costs and considering their impact in the roof management decision process through a total life-cycle cost (LCC) model that includes user/occupant cost model and correlates minimum total cost with improved intervention points in the asset deterioration cycle. The model is estimated from and applied to the extensive roof systems at Carnegie Mellon University in Pittsburgh, Pa. For these roofs, we find that the least cost roof service lives are roughly 30 years, but there can be considerable variation around this average for individual roofs.     

An approximate theory for calculation of roll torque during edge rolling of steel slabs

A roll torque model is derived for edge rolling. An upper bound solution assuming plain strain in the draught-spread plane is designed and the torque is derived. The torque and power calculated by the model is compared to power measurements in the edging stand of the hot strip mill at Fagersta Stainless AB. Slab shape after rolling is compared to estimated. The agreement between estimated and measured slab shape is very good. The calculated power is in good agreement with measurements for conventional stainless steel grade Fagersta R 350 (SS 2333), while the power is sligthly overestimated for the high alloy stainless steels Fagersta R 429 and R 560. The reason for this is probably the used flow-stress model. As the torque and power model is in good agreement with measurements it can be included in process control systems for width control.     

A unified theory for some effects of hydrogen source,alloying¦elements,and potential on crack growth in martensitic AISI 4340 steel

The effects of hydrogen on crack growth in martensitic AISI 4340 steel are shown to be fundamentally the same whether the hydrogen is supplied as molecular gas, through stress corrosion, or by electrolytic charging. At a given yield strength differences observed in the values of threshold stress intensity for crack growth are proposed to be linked to the degree of dissociation of the hydrogen near the crack tip, and hence to the concentration of hydrogen developed in the critical crack-tip region. Over a range of yield strength values, an upper bound of threshold stress intensity is developed in molecular hydrogen gas and a lower bound on exposure to atomic hydrogen from cathodic charging during or prior to testing. The open circuitK _Iscc values of the steel fall always within the upper and lower bounds, but the values ofK _Iscc may be moved to the lower bound by coupling to magnesium (cathodic charging) or to the upper bound by coupling to copper (anodic polarization). Variations in the concentration of carbon or manganese in the steel at a fixed yield strength produce effects on the value ofK _Iscc similar to the effects produced by cathodic or anodic polarization. With the lower concentrations of carbon or manganese the steel acts as if it were coupled to copper and at the higher concentrations as if coupled to magnesium. Carbon and manganese are therefore proposed to shift the positions of local anodes and cathodes and so influence the proportions of molecular and atomic hydrogen which reach the critical crack-tip region. The proposal is supported by data which show that only cathodic polarization affects the threshold stress intensity of the lowest carbon and manganese steelsK _Iscc is lowered) whereas only anodic polarization affects the higher carbon or manganese steels(K _Iscc is raised).     

Estimated intake of PCDDs, PCDFs and co-planar PCBs in individuals from Madrid (Spain) eating an average diet

The estimated intake of PCDD/Fs and co-planar PCBs associated with an average diet consumed in Spain was investigated. The estimated total average intake for PCDDs and PCDFs from an average spanish diet was found to be 142 pg I-TEQ/day (2.4 pg I-TEQ/Kg b.w./day, for a 60 Kg person). PCDDs provided almost 80% of the total dioxin equivalents. This represents the upper bound estimate. If concentrations less than the LOD are taken as equal to zero, then the estimated average intake would be 81 pg I-TEQ/day which is the lower bound estimate. Data reported are in good agreement with those reported for other countries.     

Theoretical estimation of the relation between the structure and volumetric properties of binary molten mixtures

The concentration behavior of the volumetric properties of model mixtures is described from a structural viewpoint. It is found that, apart from an energy factor, a geometric factor significantly contributes to the excess properties (molar volume, density) of a mixture. The geometric factor is caused by the difference in the geometric structures of the initial melts forming the mixture. The contribution of this factor to the relative excess volume of molten mixtures of alkali metal halides is separated and estimated.     

Religion, psychopathology, and substance use and abuse; a multimeasure, genetic-epidemiologic study

Agency for Toxic Substances and Disease Registry (ATSDR) utilizes chemical-specific minimal risk levels (MRLs) to assist in evaluating public health risks associated with exposure to hazardous substances. The MRLs are derived based on the data compiled from current worldwide literature searches and presented in ATSDR's toxicological profiles. These documents profile not only individual chemicals, but also groups of chemically related compounds and chemical mixtures. ATSDR took several approaches when developing MRLs for chemical mixtures. In some instances, toxicity equivalency factors were used to estimate the toxicity of the whole mixture; in other instances, the most toxic chemical was assumed to drive the health assessment for the whole mixture. Another approach was to treat the mixture as one entity and develop a health guidance value for the whole mixture. In yet another approach, each chemical of the mixture was evaluated separately and several health guidance values were developed. In the future, ATSDR will evaluate priority chemical mixtures found at hazardous waste sites. A weight-of-evidence approach, physiologically based pharmacokinetic modeling and bench-mark dose modeling, and quantitative structure-activity relationships will have an impact on the development of MRLs and the assessment of chemical mixtures.     

Environmental chemicals, respiratory hypersensitization and international chemical safety

Allergic hypersensitization to a variety of chemicals, natural and synthetic, is a worldwide health problem. Respiratory tract hypersensitization is responsible for significant morbidity and, in some cases, mortality. An important step in managing and controlling health risks, such as allergic hypersensitization, is to identify the chemical hazard, define dose-effect and dose-response relationships, evaluate exposure, and characterize risk. In practical terms, the risk and safety assessment processes lead to the designation of control limits for exposure to chemicals in air, food, water, and consumer products. The objective of exposure limits is to protect the whole human population, including the most susceptible individuals and 'at risk' groups. The existence of susceptible individuals is a factor that must be taken into account when quantitative chemical risk assessments are being made, and should be covered in the risk characterization. Within a population, individual susceptibility is influenced by genetic and environmental factors and these have regional and national differences. There may be cases where hypersusceptible individuals and groups, such as asthmatic children, are not fully protected by regulatory exposure limits. The International Programme on Chemical Safety, as the global programme on identifying and assessing chemical risks to human health and the environment in order to assist countries in effective management, is striving to elucidate the toxicological basis for chemically-associated disease and advance the basic science and methodology of chemical risk and safety assessment.     

Body mass index and alcohol consumption: Family history of alcoholism as a moderator.

Recent research suggests that excess food consumption may be conceptualized as an addictive behavior. Much of the evidence comes from neurobiological similarities between drug and food consumption. In addition, an inverse relation between alcohol consumption and body mass index (BMI) has been observed. Previous research has hypothesized that this inverse relation is attributable to competition between food and alcohol for similar neurotransmitter receptors. The current study explored this neurobiological hypothesis further by examining the influence of an indicator of biological risk associated with alcohol problems (family history of alcoholism) on the relationship between alcohol and food intake. Data from 37,259 participants in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) were included in the study. BMI, family history of alcoholism, gender, and race/ethnicity were assessed as predictors of typical drinking frequency and estimated blood alcohol concentration (BAC). An inverse relationship between alcohol consumption and BMI was demonstrated. An attenuation of family history effects on drinking behavior was evident for obese compared to nonobese participants. The results suggest a neurobiological link between alcohol use and food consumption, consistent with theories characterizing excess food consumption as an addictive behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

An attempt to define a just detectable effect for airborne chemicals on the respiratory tract in mice

We have attempted to define a just detectable effect (JDE) for three different types of reactions along the respiratory tract: (a) sensory irritation of the upper airways (S), (b) airflow limitation along the conducting airways (A), and (c) pulmonary irritation at the alveolar level (P1 or P). Each type of reaction, S, A, P1 or P, was recognized by analyzing the breathing pattern of unanesthetized mice held in body plethysmographs. A rule-based computer program analyzed each breath during a period of 3.75 h and classified each breath as normal (N) or falling in any of the above categories (i.e., S, A, P1 or P). Eight groups of four mice were used for sham exposures: exposed to water vapor. These data sets were used, as sham exposure data, to define the variation which can occur with time in order to define an expected range of normal variation. Once this range was established, we defined JDE values for each type of effect and used such values to evaluate the results obtained in exposed animals. Eight groups of four mice were exposed to a mixture of airborne chemicals, machining fluid G (MFG), at concentrations from 0.17 to 55 mg/m3. Data sets for individual animals and for each group of animals exposed to MFG were analyzed to determine if and when a particular effect occurred. It was possible to recognize the effects of low exposure concentrations on groups of exposed animals or individual animals within each group. This procedure will be valuable when investigating the effect of airborne chemicals and when it is impossible to generate high exposure concentrations to define concentration-response relationships.