Sequential exposures

The hetero-DA reaction with azadienes, a well known synthetic method for obtaining nitrogen heterocycles, suffers from some difficulties, because of the low reactivity of the diene. For example, azadiene 2 did not react with DMAD under the action of conventional heating [22], Sequential exposure to MW irradiation (30 W) for 10 min on a graphite support (Tmax = 171 °C) led to the adduct 7 with 60% conversion (50% in isolated product) [26, 27]. An equivalent yield was obtained by ultrasonic irradiation of the neat reaction mixture at 50 °C for 50 h [29]. 

Reinert et have suggested the use of the terms simultaneous" (mixtures of pollutants), "sequential" (one pollutant followed a second pollutant), and "intermittent" (when there is some period between sequential exposures) to refer to exposures in discussing studies of pollutant combinations. They also reconunended terminology for use in describing plant response to pollutant combinations less than additive, additive, 0 and greater than additive, +. 

Other combinations of pollutants with ozone, PAN, or both may be important, but have received little study. Matsushima reported additive foliar effects on pinto bean and tomato from a mixture of sulfur dioxide and PAN and a less than additive effect on tomato from mixtures of ozone and nitrogen dioxide. Fujiwara reported a greater than additive effect on pea from a mixture of ozone and nitrogen dioxide. Kress and Kohut studied the response of hybrid poplar to ozone-PAN mixtures. Kress used sequential exposures and found a greater than additive effect after most exposures after others, he reported mixed responses. Kohut used simultaneous exposure and found all three responses in three replicates of a study. The reasons for these variations are unclear. 

Kress, L. W. Response of Hybrid Poplar to Sequential Exposures of Ozone and PAN. Center for Air Environment Studies Publ. 259-72. University Park Pennsylvania State University. 1972. 39 pp. 

Plants respond in different ways to pollutant mixtures less than additive, additive, and greater than additive effects have been reported. Mixtures of ozone with sulfur dioxide and of nitrogen dioxide with sulfur dioxide can cause oxidantlike symptoms in some sensitive plants. Mixtures can cause effects below the threshold for either gas, although there is some disagreement here in r ard to ozone. Ratios of mixtures, intermittent exposures, sequential exposures to pollutants, and predisposition by one pollutant to the effects of a second pollutant may all be important in nature, but little research has been done. 

For a sequential exposure of these purposive deceptions, particularly the central myths of Duchamp s disinterestedness, indifference, and withdrawal, see Jones, 66-103. 

The initiator was purified, by distillation (19), sec-butyl-lithium (Lithco). The ethers and 1,1-diphenylethylene were purified by sequential exposure to , dibutyl magnesium (Lithco)... 

Figure 2-4 reflects that information exists for all three routes of exposure. However, all of these reports are limited because of the possibility of concurrent or sequential exposure to other potentially toxic substances present in the environment (workplace or home), such as other insecticides, or present as components of diazinon-containing formulations. In all cases, accurate information regarding levels and duration of exposure were not presented in these reports. Further, the health effects of human acute exposure to diazinon are much more fully characterized than those associated with intermediate and chronic exposures. 

The oxidative polymerization of pyrrole can also be induced in solvent-free systems and several papers have described synthesis via exposure of a matrix saturated with an Fe(III) salt to pyrrole vapour 90,91>. Mohammadi et al. 92> described synthesis on planar substrates by sequential exposure to FeCl3 and pyrrole and have also discussed a similar synthesis using H202 as the oxidant93). 

The refinement (2) proceeded in the same way as for the x-ray work, except that o and S q were refined as additional variables. We assumed that the scattering was kinematic. The cross sectional dimensions of the microfibrils are 200xl0C)X and our previous work on synthetic polymer single crystals showed that the kinematic approximation was adequate for such small crystallites. Intensity measurement presented considerable difficulty in that multiple film exposures could not be obtained. Sequential exposures of the same area of the specimen led to problems of beam damage, and patterns from different areas were not comparable due to differences in the preferred orientation. As a result, only the 28 strongest non-meridional intensities could be measured. These were all for reflections which could be indexed by the Meyer and Misch unit cell, and thus the two chain unit cell was used for the refinement. 

All mixture extrapolations considered so far have their focus on cases of simultaneous exposure to a set of toxicants, whereas organisms or species assemblages in the environment frequently face sequential exposure. Although extrapolative methods are available for sequential exposure to single compounds, this is not the case for mixtures. 

The individual tolerance concept has some unrealistic properties (Kooijman 1996 Newman and McCloskey 2000). Most importantly, if there is a distribution in sensitivities, this would imply that the survivors from an experiment are the less sensitive individuals. Experiments with sequential exposure show that this prediction fails (at least as the dominant mechanism) (Newman and McCloskey 2000 Zhao and Newman 2007). There is sufficient reason to conclude that the individual threshold model is not sufficient to explain the observed dose-response relationships, and that mortality is a stochastic process at the level of the individual... 

Bedaux and Kooijman 1994 Kooijman 1996 Newman and McCloskey 1996, 2000 Zhao and Newman 2007). This is not just an academic discussion the 2 theories lead to different time courses of mortality at constant exposure (Kooijman 1996) (see Figure 2.10) and have very different consequences for sequential exposure (Newman and McCloskey 2000 Zhao and Newman 2007). In reality, both sensitivity difference and stochasticity are likely to play a role in mortality. Individuals also differ in sensitivity, especially in field populations, but there is clearly a substantial stochastic component involved in mortality that cannot be ignored. The method to deal with stochastic events in time is survival analysis or time-to-event analysis (see Bedaux and Kooijman 1994 Newman and McCloskey 1996). For industrial practices, this method has a long history as failure time analysis (see, e.g., Muenchow 1986). Bedaux and Kooijman (1994) link survival analysis to a TK model to describe survival as a function of time (i.e., the hazard rate is taken proportional to the concentration above a threshold value). Newman and McCloskey (1996) take an empirical relationship between external concentration and hazard rate. 

Mixture Effects and Exposure Typology Sequential Exposures.107... 

The majority of experimental mixture studies have analyzed the effects that arise from simultaneous exposure to chemicals. Very few studies exist where sequential exposure to several chemicals was analyzed. Only a concept founded on an understanding of the relationship between dose or concentration and exposure duration, time to effect, and recovery can hope to deal with the effect of sequential exposures. Conceptual frameworks for descriptions of time-dependent toxicity from a mechanistic perspective are available (e.g., Rozman and Doull 2000 Ashauer et al. 2006). However, the link between existing dose-time response models and a framework for mixture effect analysis from sequential exposure has yet to be made. A recent example of an interesting study that looked at sequential exposures is from Ashauer et al. (2007b), who base their analysis on a 1-compartment model for substance uptake, plus additional parameters for effect propagation and recovery. Generalizations are not yet in sight. 

An extension of concepts of mixture toxicology to dealing with sequential exposures is timely. 

Several key issues in risk assessment of chemical mixtures were identified, that is, exposure assessment of mixtures (e.g., mixture fate and sequential exposure), the concept of sufficient similarity, mixture interactions, QSARs, uncertainty assessment, and the perception of mixture risks. Resolving these key issues will significantly improve risk assessment of chemical mixtures (see next section). 

Toxicity testing of mixtures should move beyond the standard tests for deviations from the default models of CA and RA, toward a more mechanistic understanding of the process involved in mixture toxicity. These studies should focus not only on the processes and effects involved in concurrent exposure to multiple substances (i.e., cocktails), but also on those involved in sequential exposure to multiple substances. 

National authorities should develop legislation that enables the assessment and management of potential high-risk situations caused by sequential exposures to different compounds and exposures through multiple pathways, with specific emphasis on a systems approach rather than on approaches focusing solely on chemicals, or on water or soil as compartments. 

In both human and ecological risk assessment, there is considerable scientific latitude to develop novel methods (e.g., those that exist in only one of the subdisciplines could be useful in the other one) and to refine approaches (e.g., by considering complex reaction networks and more specific attention for modes of action). The refinements are needed to improve the scientific evidence that is available for underpinning risk assessments. Several key issues in risk assessment of chemical mixtures were identified, that is, exposure assessment of mixtures (e.g., mixture fate and sequential exposure), the concept of sufficient similarity (requires clear criteria), mixture interactions, QSARs, uncertainty assessment, and the perception of mixture risks. Resolving these key issues will significantly improve risk assessment of chemical mixtures. 

Hazucha, M.J., L.J.Folinsbee, E.Seal, and P.A.Bromberg. 1994. Lung function response of healthy women after sequential exposures to NO > and OAm. J. Respir. Crit. Care Med. 150 (3) 642-647. 

From a chemical standpoint, simultaneous exposure is the only procedure to use. Any test substance can undergo cis-trans isomerism such as demonstrated by cinnamic acid and its derivatives or photochromism. Both of these phenomena can be reversible, presenting an equilibrium situation. If one uses sequential exposures—or even worse, separate samples—for each source, the results obtained may be biased. 

Mullins et al. have performed studies of the interaction of CO and NO using a model surface consisting of a low coverage of Rh and a ceria film of controlled oxidation state. Although the co-adsorption of these species is competitive, coadsorption by sequential exposures was performed using controlled sub-saturation doses of CO and NO. Since the adsorption of either CO or NO is strongly affected by the oxidation state of the ceria, it is not surprising that their interaction with each... 

Qiao GL, Riviere JE. Systemic uptake and cutaneous disposition of pen tachlorophenol in a sequential exposure scenario Effects of skin preexposure to benzo [a] pyrene. J Toxicol Environ Health A 2002 65(18)4307 31. 

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