Structure and toxicity

It appeared to the author some years ago that, irrespective of the mechanism of the toxic action of DDT, there might be a correlation of structure and toxicity in analogous compounds. Hammett (13) has shown that the rate and equilibrium constants of over 50 side-chain reactions of meta and para substituted aromatic compounds may be correlated with the so-called substituent constant a, according to the equation log k — log k0 = pa, where k and k0 are rate (or equilibrium) constants for substituted and unsubstituted compounds, respectively, p is the reaction constant giving the slope of the linear relationship, and a is the substituent constant, which is determined by the nature and... 

Saxitoxin is a small tricyclic structure isolated from oceanic red tides it has attracted much interest for its peculiar structure and toxicity as a paralytic agent. The core structure that is related to a l-iminooctahydropyrrolo[l,2-f]-pyrimidine nucleus was prepared by rearrangement after oxidation of a double bond contained in a medium-size guanidine ring. This key intermediate in the synthesis was prepared from azide 376 with a judicious use of Mbs... 

Available information regarding surfactant toxicity is generally related to different surfactant groups (anionic and non-ionic) and, above all, to freshwater species, whereas toxicity in marine species is much less frequently described. A high number of investigations deal with the toxicity of commercial surfactants (homologue mixtures), but not much work has been done concerning the relationships between structure and toxicity. 

Munro et al. (1996) explored the relationship between chemical structure and toxicities through the compilation of a large reference database consisting of 613 chemical substances tested for a variety of noncarcinogenic toxicological endpoints in rodents and rabbits in oral toxicity tests, including subchronic, chronic, reproductive, and developmental toxicity. For many of the substances, more... 

The toxicology of a solvent is determined by many factors, such as bioavailabihty, metabolism, and the presence of structural features that may attenuate or enhance the reactivity of the parent molecule. Despite the structure-activity data available for many classes of commercial chemical substances, chemists have not recognized the use of structure-activity relations as a rational approach for choosing or designing new, less toxic commercial chemical substances. With qualitative structure-activity relationships, comparing the structures of the substances in the series with corresponding effects on the toxicity makes the correlation between toxic effect and structure. Through these, it may then be possible to predict a relationship between structure and toxicity... 

Structural and Toxic Mechanism-Based Approaches to Designing Safer Chemicals... 

With qualitative structure-activity relationships (SARs), the correlation of toxic effect with structure is made by visual comparison of the structures of the chemicals in a series of congeneric substances and the corresponding effects their structural differences have on toxic potency, for example, as represented by their LD50 values. From qualitative examination of structure-activity data the chemist may be able to see a relationship between structure and toxicity, and identify the least toxic members of the class as possible commercial alternatives to the more toxic members. 

Organonitriles are organic substances that contain the cyano (-C = N) group. Nitriles have wide commercial applications that include solvents, synthetic intermediates, pharmaceuticals, and monomers, to name just a few. As a class of substances, there are two types of toxicity associated with exposure to nitriles acute lethality and osteolathyrism. Some nitriles are known to cause both. The mechanisms by which nitriles cause these toxic effects, the corresponding relationships between nitrile structure and toxic potency for each effect, and the use of this information as a basis to design substances that may need to contain the functionality of the cyano group but will cause minimal toxicity have been discussed in detail [7]. Only the biochemical mechanism and SARs related to acute lethality of nitriles are discussed here. More detailed discussions are available [7, 8, 61]. 

The relevance of the QSAR shown in Equation 4.2 to this discussion is that since the logPe/w and kacorr values can be determined computationally, Equation 4.2 can be used to predict the acute toxicities of nitriles yet to be synthesized, or of existing nitriles for which measured toxicity data are not available. This examples also demonstrates the importance of first having a qualitative understanding of any existing relationships between structure and toxicity, and the mechanism of toxicity, before attempting to quantify the relationships. 

During his career, he made voluminous, critical, and lasting contributions to our understanding of the relationships between molecular structure and toxicity. He will be sadly missed by literally hundreds of professional scientists in government and industry in the United States and around the World. 

Humpf, H. U. and Voss, K. A. (2004). Effects of thermal food processing on the chemical structure and toxicity of fumonisin mycotoxins. Mol. Nutr. Food Res. 48(4), 255-269. 

Figure 16.16 Structure and toxicity data of most dangerous chemical warfare agents and their low-toxicity mimicking agents LD50-lethal dose...

From a practical point of view, the latter loss in speciation is less of a problem. In as much as the toxicity of As(III) and As(V) cannot be differentiated in terms of food safety reasons, their pooled concentrations can be used to assess the overall risk and the analyst can focus on the much less known As species to determine their structure and toxicity. This approach was followed by Parks et al. [133], who addressed the availability of As species from matrix components in difficult-to-extract seafood samples. TMAH was used, a highly basic compound formerly rejected for As speciation because of its incompatibility with chromatography [122], to create a three-step sequential extraction technique. TMAH was... 

Apart from toxicity tests involving the use of live animals, there are other ways of evaluating the toxic properties of chemicals that stem from an understanding of their mode of action. For example, the Ames test aids in the identification of substances that act as carcinogens or mutagens in mammals. Also, the study of the relationship between structure and toxicity (i.e., quantitative structure-activity relationships or QSARs) can provide support for the identification of toxic substances. These approaches will become more viable as molecular mechanisms of toxicity become better known, and they can lead to an understanding of the molecular characteristics that cause a chemical to interact adversely with cellular macromolecules. 

First toxicological studies with single toxaphene components were carried out in the 1970s to find important relations between structure and toxicity [244]. At that time, the toxic potential of components isolated from technical toxaphene was investigated. The compounds B7-515 (P-32 or Toxicant B) and B8-806/9 (P-42 or Toxicant A) were tested concerning their acute toxicity for fish, rats and insects. 

In this chapter we provide a historical perspective of the development of the field of computational toxicology. Beginning from the similarity-based grouping of elements into the periodic table, the chapter presents a chronology of developments from the simple observations of qualitative relations between structure and toxicity through LFER (linear free energy related) and QSAR (quantitative structure activity relationship) models, to the current... 

Pyrethroids may conveniently be classified into two groups based on the chemical structure and toxic action (1 -Z8). Type I pyrethroids do not possess an alpha-cyano group and include many conventional ones such as allethrin, tetramethrin, phenothrin and permethrin. Type II pyrethroids possess a cyano group at the a position and include cyphenothrin, cypermethrin, deltamethrin and fenvalerate. 

MCASE (Computer Automated Structure Evaluation MULTICASE, Cleveland, OH, US) correlates structures and toxicities. 

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