Structure-related Toxicity

R. D. Haworth et al. have prepared series of compounds related to miotine and to prostigmine, and have used them to investigate the correlation of structure with toxicity in the two series. 

The contributions of QMs to the toxicities of the food additive BHT and structurally related alkylphenols in rats and mice have been investigated extensively over the past 25 years. This work has generated considerable insight into the relationships between toxicity and the metabolic formation and reactivity of these electrophiles. Most studies have focused on liver and lung damage is primarily observed in these organs due,... 

The fundamental chemistry, especially of the newer economic poisons, is of primary importance. The mechanism of action of the various types of economic poisons and the relation of structure to toxicity of insects are of fundamental interest. Chemical versus biological methods of evaluation should be presented. Performance methods of evaluation of these chemicals have been given careful consideration by several workers. Emphasis was placed by several workers on the need for much additional information on various aspects of the problem regarding the use of DDT, 2,4-D, and other pesticides. There is direct importance in studies on the metabolism of DDT. 

Bus, J.S., and J.A.Popp. 1987. Perspectives on the mechanism of action of the splenic toxicity of aniline and structurally-related compounds. Food Chem. Toxicol. 25 619-626. 

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... 

As noted under Mechanisms of Toxicity (Section 4.2), nitrate and nitrite esters are vasodilators with resulting hypotension (Nickerson 1975). Therapeutic doses of nitroglycerin for relief of angina are associated with headaches of vascular origin. Both PGDN and the structurally related ethylene glycol dinitrate produce headaches in humans and methemoglobinemia and hypotension in rats (Andersen and Mehl 1979). 

Another possible use of in vitro developmental toxicity tests would be to select the least developmentally toxic backup from among a group of structurally related compounds with similar pharmacological activity [use (2) in the list above], for example, when a lead compound causes malformations in vivo and is also positive in a screen that is related to the type of malformation induced. However, even for this limited role for a developmental toxicity screen, it would probably also be desirable to have a measure of the comparative matemotoxicity of the various agents and/or information on the pharmacokinetics and distribution of the agents in vivo. 

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. 

Regardless, it is important to carry out the safety evaluation for all flavoring substances. In many cases, it is possible to use pharmacokinetic or metabolic data on the substance in addition to toxicity data or other information on structurally-related compounds. 

Knowledge of chemical structure, pharmacokinetics, and metabolic pathways provides a method to assess the safety of flavoring substances that lack a full safety testing profile using data from structurally related substances which have been adequately tested for toxicity. 

In order to determine whether this increase in toxicity was necessarily bound up with the presence of two fluorine atoms in the molecule, a series of structurally related esters was prepared and examined.1... 

Additional factors may be applied if there are significant shortcomings in the available data that are a cause for concern. If, for example, data relating to the effects of a chemical during the developmental phase are absent, and there are reasons to suspect that the chemical could have such effects (it may, for example, be structurally related to a known developmental toxicant) an additional factor may be applied to the NOAEL. 

The intense interest in the discovery of potent biologically active compounds has prompted various attempts to relate toxicity to molecular structure and to codify the effects... 

For many of the drugs associated with hepatotoxicity, there are examples of structurally related drugs which are latent to bioactivation and toxicity because of the absence of the toxicophore or the existence of alternate metabolic pathways. For example, the hepatotoxicity associated with the use of the anti-Parkinson s agent tolcapone does not occur with the structurally related drug entacapone, despite administration at doses similar to tolcapone (200-1000 mg QD). This disparity may be explained in part by the observation that entacapone does not succumb to the bioactivation reactions of tolcapone in humans (Scheme 15.3) [35]. It is also noteworthy that tolcapone but not entacapone is a potent uncoupler of oxidative... 

The quaternary ammonium compounds paraquat and diquat are widely used non-selective contact herbicides, which are extremely toxic to humans. Fee et al. [112] established an HPLC-MS-MS procedure for the determination of these herbicides in whole blood and urine using ethyl paraquat as internal standard. After extraction with Sep-Pak C18 cartridges, analytes were separated using ion pair chromatography with heptafluorobutyric acid in 20 mM ammonium acetate and acetonitrile gradient elution. Detection was carried out in ESI MS-MS SRM mode. Using similar separation and detection conditions, paraquat, diquat, difenzoquat, and a number of structurally related quaternary nitrogen muscle relaxants (see Section 20.2.1.3) were determined in whole blood by Ariffin and Anderson [113]. 

Propoxyphene (dextropropoxyphene Darvon) is structurally related to methadone but is much less potent as an analgesic. Compared with codeine, propoxyphene is approximately half as potent and is indicated for the treatment of mild pain. It is not antipyretic or antiinflammatory like aspirin and is less useful than aspirin in most cases of mild pain. Toxicity from propoxyphene, especially in combination with other sedatives, such as alcohol, has led to a decrease in its use. Death following ingestion of alcohol in combination with propoxyphene can occur rapidly (within 20 minutes to 1 hour). The drug is not indicated for those with histories of suicide or depressive illnesses. 

This toxicity study is required if there is no evidence from available information on structurally related substances, from (quantitative) structure-activity relationship ((Q)SAR) estimates or from in vitro methods that the substance may be a developmental toxicant... 

Thalidomide was initially selected as Candidate K17. It was discovered from peptide research but promoted as being structurally related to barbiturate with hypnotic properties, beyond those of the classic barbiturate Luminal, but without toxicity. 

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