Overview of Approach to Noncancer Risk Assessment
John C. Lipscomb, Edward V. Ohanian in Toxicokinetics and Risk Assessment, 2016
Toxicokinetic considerations can enter into the risk assessment paradigm at a number of points. In the hazard characterization phase, information on the degree of absorption and distribution of the chemical can provide information about likely and plausible targets. All aspects of TK (absorption, distribution, metabolism, and excretion) contribute to the determination of tissue dose, which ultimately determines the dose–response. Consideration of interspecies differences in TK can also provide information on the relevance to humans of effects observed in experimental animals. Finally, TK are relevant in relating external doses calculated as part of an exposure assessment to internal dose. It is important to use consistent approaches and assumptions for calculating internal dose in the dose–response and exposure phases of the risk assessment. Toxicokinetics can also be important in evaluating interactions between chemicals in mixtures. For example, certain solvents can increase the bioavailability of other chemicals. Chemicals that induce enzymes may increase the metabolism of other chemicals, leading to lower tissue dose if the parent chemical is the toxic form, or higher tissue dose if a metabolite is the toxic form. Conversely, inhibition of metabolic enzymes can increase a chemical’s activity. For example, piperonyl butoxide inhibits the activity of the enzyme cytochrome P450, and so can increase the biological half-life of P450 substrates, thereby increasing their potency. Because of this activity, piperonyl butoxide is often used as an insecticide synergist.
The Challenge of Parasite Control
Eric S. Loker, Bruce V. Hofkin in Parasitology, 2023
In some cases, less toxic compounds persist in the environment for a relatively short time and must therefore be applied more often. Pyrethroids, for instance, break down in only a few days under most environmental conditions. Although this rapid breakdown helps to limit their damage to aquatic environments, it indicates that these compounds must be used regularly to maintain vector control. The effective dose of these organic chemicals can, however, be reduced by combining them with piperonyl butoxide, which interacts synergistically with pyrethroids. Piperonyl butoxide has no insecticide activity by itself, but by inhibiting the invertebrate detoxification system involving cytochrome P450, the target vectors become less able to break down the insecticide. This means that less insecticide can be used to achieve the same outcome.
Rationale and technique of malaria control
David A Warrell, Herbert M Gilles in Essential Malariology, 2017
Pyrethrins are nerve poisons, acting through the insect cuticle, which is permeable to them. When sprayed, the droplets come into contact with the insect and their toxic action is fast. The addition of certain synergists increases the toxicity of pyrethrins to insects. Among these synergists, piperonyl butoxide is most commonly used.
Intensity of pyrethroid resistance in Anopheles culicifacies s.l. (Diptera: Culicidae) in Odisha State, India
Published in Pathogens and Global Health, 2020
Sudhansu Sekhar Sahu, Sonia Thankachy, Smrutidhara Dash, Gunasekaran Kasinathan, Ashwani Kumar
In view of increasing resistance in malaria vectors to SPs, many industries have started developing innovative products such as long-lasting non-pyrethroid for IRS with single insecticide or as mixtures and bi-treated nets [22]. However, implementing these newer tools depends on resistance strength in different vectors in different settings of the country which needs to be evaluated. Further, it is proven that piperonyl butoxide (PBO) is an effective synergist for natural pyrethrins and SPs [27]. Earlier, a study conducted in five southern districts of Odisha State showed that the deltamethrin susceptibility could be restored in phenotypic pyrethroid resistant An. culicifacies s.l., when exposed to PBO [5]. The involvement of mono-oxygenase as a major pyrethroid resistance mechanism in An. culicifacies s.l. was also observed as supported by other synergist bioassay study conducted recently in Chhattisgarh State [23].
The development and hepatotoxicity of acetaminophen: reviewing over a century of progress
Published in Drug Metabolism Reviews, 2020
Mitchell R. McGill, Jack A. Hinson
The first manuscript described the toxicity and showed the importance of drug metabolism (Mitchell et al. 1973). Importantly, the group found that mice are more susceptible to APAP hepatotoxicity than rats. Whereas a dose of 300 mg/kg was toxic to the mouse, a dose 8–10 times higher was required to produce a similar hepatotoxic effect in the rat. Moreover, they observed frequent lethality at these very high doses in the rat. They demonstrated the role of drug metabolism by pre-treating mice with inducers and inhibitors of drug metabolizing enzymes and then histologically evaluating the incidence of hepatic necrosis at 24 hours. Thus, following a dose of 375 mg/kg of APAP, saline pretreated mice had a 46% incidence of hepatic necrosis, whereas pretreatment of mice with the cytochrome P450 inducer phenobarbital increased the incidence of hepatic necrosis to 90%. In contrast, pretreatment with piperonyl butoxide or cobaltous chloride, two inhibitors of drug metabolizing enzymes, decreased the incidence of hepatic necrosis to 0%. These results pointed to a cytochrome P450-dependent mechanism of hepatotoxicity.
Metabolic and mitochondrial treatments for severe paracetamol poisoning: a systematic review
Published in Clinical Toxicology, 2020
Michael E. Mullins, Lauren H. Yeager, William E. Freeman
Since the earliest research, we learned that cytochrome P450 enzymes (later identified as CYP 2E1, CYP 1A2, and CYP 3A4) oxidize paracetamol and produce its characteristic liver injury [6]. In addition to the detoxifying action of endogenous glutathione and exogenous acetylcysteine, piperonyl butoxide – an inhibitor of metabolism by hepatic microsomes – reduced hepatic injury in rats [7]. In a later study, genetic knock-out mice expressing neither CYP 2E1 nor CYP 1A2 consistently survived with no elevation of ALT activity despite paracetamol doses twice the 100% lethal dose in wild-type mice [8]. Together these data suggest the possibility of adding a metabolic inhibitor as a potential treatment for paracetamol poisonings. Later research on the mechanisms of mitochondrial dysfunction in severe paracetamol poisoning has opened a new frontier in the treatment of severe paracetamol overdose. Three drugs represent the past, present, and likely future of metabolic or mitochondrial treatment (in addition to acetylcysteine) in cases of severe paracetamol poisoning.
Related Knowledge Centers
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