Modes of chemical action

Biomarkers are defined as any cellular or molecular indication of toxic exposure, adverse health outcome or susceptibility (NAS, 1987). From this definition, three distinct biomarkers are evident, that of exposure, effects of exposure, and host susceptibility. As more extensively discussed by Maier et al. (2001), this field has progressed to a point where application to risk assessment is possible. For example, biomarkers of effects, exposure, and host susceptibility can give insights into mode of chemical action. These insights are likely to better inform the hazard... 

Thresholds exist for when and how insects respond to these chemical actions. These thresholds are governed by intrinsic factors related to the mode of action of the chemical and the insects susceptibility, as well as by extrinsic factors that modify those effects. Among the extrinsic factors, the physical environment, humidity, air movement, and temperature can affect the volatility of the active ingredient. The dose-dependent order in which thresholds are exceeded determines whether the primary mode of chemical action is repellent, irritant, or toxicant. Some pyrethroids can produce excitorepellency with possible mortality as a result of the exposure. Other pyrethroids with sufficiently high vapor phase concentration, for example, metofluthrin and transfluthrin, can result in a spatial repellent (barrier) effect regardless of knockdown and mortality of insects. 

Tables 2.6 and 2.7 give examples of the modes of action of pollutants in animals and in plants/fungi, respectively. It is noteworthy that many of the chemicals represented are pesticides. Pesticides are designed to be toxic to target species. On the other hand, manufacturers seek to minimize toxicity to humans, beneficial organisms and, more generally, nontarget species. Selective toxicity is an important issue. Regardful of the potential risks associated with the release of bioactive compounds into the environment, regulatory authorities usually require evidence of the mode of toxic action before pesticides can be marketed. Other industrial chemicals are not subject to such strict regulatory requirements, and their mode of action is frequently unknown.

Russom, C.L., Bradbury, S.R., Broderius, S.R., Hammermeister, D.E., Drummond, RA. (1997) Predicting Modes of Toxic Action from Chemical Structure Acute Toxicity in the Fathead Minniw (Pimephalespromelas). Environmental Toxicology Chemistry, 16(5), 948-967. 

Russom, C.L. et al. (1997) Predicting modes of toxic action from chemical structure acute toxicity in the fathead minnow (Pimephales promelas). Environ. Toxicol. Chem., 16 (5), 948-967. Henderson, R.F. (2001) Species differences in the metabolism of olefins implications for risk assessment. Chem.-Biol. Interact., 135, 53-64. 

Bradbury SP. 1994. Predicting modes of toxic action from chemical structure An overview, SAR QSAR. Environ Res 2 89-104. 

Whatever methods are employed to link assessment end points with measures of effect, it is important to apply the methods in a manner consistent with sound ecological and toxicological principles. For example, it is inappropriate to use structure-activity relationships to predict toxicity from chemical structure unless the chemical under consideration has a similar mode of toxic action to the reference chemicals. Similarly extrapolations from upland avian species to waterfowl may be more credible if factors such as differences in food preferences, physiology, and seasonal behavior (e.g., mating and migration habits) are considered. 

Substitution of foreign metals for the metals in metalloenzymes (those that contain metals as part of their structures) is an important mode of toxic action by metals. A common mechanism for cadmium toxicity is the substitution of this metal for zinc, a metal that is present in many metalloenzymes. This substitution occurs readily because of the chemical similarities between the two metals (for example, Cd2+ and Zn2+ behave alike in solution). Despite their chemical similarities, however, cadmium does not fulfill the biochemical function of zinc and a toxic effect results. Some enzymes that are affected adversely by the substitution of cadmium for zinc are adenosine triphosphate, alcohol dehydrogenase, and carbonic anhydrase. 

Which metallic element, though chemically not similar to radon, operates through a similar mode of toxic action What is the most likely route of exposure to this element ... 

Acute oral toxicity is the study of adverse effects occurring shortly after oral administration of a single chemical dose or multiple doses given to an animal within 24 hours. In the evaluation of chemical safety, determination of acute oral toxicity becomes important, since it normally forms the first study step. Acute toxicity is important in establishing dose regimen for subchronic and other studies, and may provide initial information on the mode of chemical toxic action, as well as a basis of for classification and labeling. 

Acute dermal toxicity is the study of adverse effects occurring within a short time of dermal application of a single-dose test chemical. In evaluating the safety of a chemical, determination of acute dermal toxicity is useful when exposure by the dermal route is likely and more predominant. It provides information on health hazards likely to arise from short-term exposure by the dermal route. Data from an acute dermal toxicity study may serve as a basis for chemical classification and labeling. It is an initial step in establishing a dose regimen in subchronic (and other) studies, and may provide information on dermal absorption as well as a chemical s mode of toxic action. 

The situation is different for aqueous species of humic substances, the organic matter in soil that is not identifiable as unaltered or partially altered biomass or as conventional biomolecules.21 Humic substances comprise organic compounds that are not synthesized directly to sustain the life cycles of the soil biomass. More specifically, they comprise polymeric molecules produced through microbial action that differ from biopolymers because of their molecular structure and their long-term persistence in soil. This definition of humic substances implies no particular set of organic compounds, range of relative molecular mass, or mode of chemical reactivity. What is essential is dissimilarity to conventional biomolecular structures and biologically refractory behavior. 

Many other phytotoxins not presented here have been structurally characterized and tested In some plant bioassay systems. Numerous other reported phytotoxin studies are In the "active fraction" stage and structure elucidation of the active components has not been achieved. Nevertheless, from the data presented. It can generally be concluded that diverse microbes produce a broad range of chemistries with phytotoxic activities chemical and biochemical synthesis of almost all of these compounds Is unknown (but derivitizatlon studies to alter phytotoxic activity have been used In a few Instances) knowledge of the spectrum of species susceptible to these compounds Is Incomplete (many weed and crop species have not been tested some compounds are toxic to organisms other than plants) and the molecular mode of phytotoxin action Is unstudied or unknown for most. The major exception Is the vast amount of data on blalaphos, phosalacine, and phosphinothricin, which have achieved commercial status. 

Bradbury, S.P. (1994). Predicting Modes of Toxic Action from Chemical Structure An Overview. SAR QSAR Environ.Res., 2,89-104. 

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