Toxicological Modes of Action

As mentioned previously, the assessment of hazard and risk to humans from exposure to chemical substances is generally based on the extrapolation from data obtained in smdies with experimental animals. In the absence of comparative data in humans, a basic assumption for toxicological risk assessment is that effects observed in laboratory animals are relevant for humans, i.e., would also be expressed in humans. In assessing the risk to humans, an assessment factor is applied to take account of uncertainties in the differences in sensitivity to the test substance between the species, i.e., to account for interspecies variability (Section 5.3). If data are available from more than one species or strain, the hazard and risk assessment is generally based on the most susceptible of these except where data strongly indicate that a particular species is more similar to man than the others with respect to toxicokinetics and/or toxicodynamics. Two main aspects of toxicity, toxicokinetics and toxicodynamics, account for the namre and extent of differences between species in their sensitivity to xenobiotics this is addressed in detail in Chapter 5. 

It is generally accepted that the expression of toxicity in a mammalian system is dependent on a sequence of key events taking place, each of which is critical to the manifestation of the toxic endpoint. If at least one of these key events identified in experimental animals does not occur in humans, then it could be concluded that the toxic endpoint would not be observed in humans, and thus this effect is of limited relevance for the prediction of effects in humans. 

Therefore, information on the toxicological mode(s) of action as well as mechanistic data are essential in establishing the relevance to humans of the toxicological effects observed in experimental animals. The evaluation of the relevance for humans of data from smdies in animals is aided by use of data on the toxicokinetics, including metabolism, of a substance in both humans and the animal species used in the toxicity tests, when they are available, even when they are relatively limited. 

Certain effects in laboratory animals are known to be of limited relevance for the prediction of effects in humans. Clear, well-documented evidence for a species-specific effect/response (e.g., light hydrocarbon induced nephropathy in the kidney of male rats, peroxisome proliferation in the liver of rodents) should be used as justification for the conclusion that a particular effect is not expected to occur in humans exposed to the substance. 

Positive carcinogenic findings in animals require careful evaluation to determine their relevance to humans. Of key importance is the mechanisms/mode(s) of action of tumor induction. The WHO/IPCS has developed a conceptual framework to provide a strucmred and transparent approach for the assessment of the overall weight of evidence for a posmlated mode of induction for each mmor type observed (Sonich-Mullin et al. 2001). The framework promotes confidence in 

---

Bloomquist JR (1993) Toxicology, mode of action and target site-mediated resistance to insecticides acting on chloride channels. Comp Biochem Physiol C 106 301-314... 

ECETOC. 2006. Toxicological modes of action Relevance for human risk assessment. ECETOC Technical Report No. 99. Brussels ECETOC. 

The Geigy scientists developed several new research methods in the areas of biological evaluation of weed control and crop tolerance. They also developed new science methodologies to investigate areas of toxicology, mode of action, and dissipation in soils and plants. 

Recursive partitioning has successfully been used to develop models for various ADM ET properties, see Ref. [80], as well as for the elucidation of toxicological modes of action [103]. 

Gramatica, P., Vighi, M Consolaro, F., Todeschini, R., Finizio, A. and Faust, M. (2001) QSAR approach for the selection of congeneric compounds with a similar toxicological mode of action. Chemosphere, 42, 873-883. 

EFSA (2004) Opinion of the scientific panel on dietetic products, nutrition and allergies on a request from the commission related to the Tolerable Upper Intake level of silicon. EFSA J 60 1-11 Fruijtier-Polloth C (2012) The toxicological mode of action and the safety of synthetic amorphous silica - a nanostructured material. Toxicology 294 61-79 Gitelman HJ, Alderman FR, Perry SJ (1992) Silicon accumulation in dialysis patients. Am J Kidney Dis 19(2) 140-143... 

C. Tomlin, ed.. The Pesticides Manual A World Compendium, Incorporating the Agrochemicals Handbook, 10th ed.. The British Crop Protection Council and The Royal Society of Chemistry, Crop Protection PubHcations, Cambridge, U.K., 1994. Includes 725 entries by common name in alphabetic order, with chemical stmcture, chemical name(s), molecular formula, CAS Registry Number, physicochemical properties, commercialisation, mode of action, uses, trade names, analytical methods, mammalian toxicology, ecotoxicology, and environmental fate. 

Hodgson, E. and Levi, P. (1994). A multiauthor text dealing in depth with some aspects of biochemical toxicology highly relevant to the present topic. Examples of metabolism and mode of action of insecticides, and PAHs. 

Safe, S. (1984). Polychlorinated biphenyls and polybrominated biphenyls biochemistry, toxicology and mode of action CRC Critical Reviews in Toxicology 13, 319-395. 

Stronkhurst, J., Leonards, P., and Murk, A.J. (2002). Using the dioxin receptor Calux in vitro assay to screen marine harhour sediments for a dioxin-hke mode of action. Environmental Toxicology and Chemistry 21, 2552-2561. 

A mechanism of action describes the molecular sequence of events (covalent or non-covalent) that lead to the manifestation of a response. The complete elucidation of the reactions and interactions among and between chemicals, include very complex and varied situations including biological systems (macromolecular receptors, physical phenomena (thermodynamics of explosions) or global systems (ozone depletion). Unfortunately, this level of mechanistic detail is often unavailable but recent advances in molecular toxicology and others hazards, at the molecular level, have provided valuable information that elucidates key steps in a mechanism or mode of action. ... 

Borgert, C.J., QuiU, T.F., McCarty, L.S., Mason, A.M. (2004) Can Mode of Action Predict Mixture Toxicity for Risk Assessment Toxicology and Applied Pharmacology, 210, 85-96. 

In vitro tools could be used alone or in test batteries. Multiple endpoint batteries increase the power of the evaluation because they provide information of different cellular functions. This information can be useful to investigate the mode of action of toxicity and to provide data regarding the mechanistic nature of the toxicological effects of the chemical [8],... 

The platform includes different decision trees for the following endpoints the estimation of Threshold of Toxicological Concern (TTC), aquatic modes of action [44], skin and eye irritation and corrosion, mutagenicity and carcinogenicity [45], in vivo micronucleus assay, identification of Michael Acceptors and biodegradation potential [46]. 

Hildick-Smith [119] discussed the pharmacology, mode of action, therapeutic uses and toxicology of miconazole and other antifungal agents. 

Vos, J.G., E.I. Krajnc, P.K. Beekhof, and M.J. van Logten. 1983. Methods for testing immune effects of toxic chemicals evaluation of the immunotoxicity of various pesticides in the rat. Pages 497-504 in J. Miyamoto and PC. Kearney (eds.). Pesticide Chemistry, Human Welfare and the Environment. Vol. 3. Mode of Action Metabolisms and Toxicology. Pergamon Press, Oxford, UK. 

Soderlund DM (2010) Toxicology and mode of action of pyrethroid insecticides. In Krieger R (ed) Hayes handbook of pesticide toxicology. Academic Press, New York, pp 1665-1686... 

Soderlund DM (1995) Mode of action of pyrethrins and pyrethroids. In Casida JE, Quistad GB (eds) Pyrethrum flowers production, chemistry, toxicology and uses. Oxford University Press, New York, NY, pp 217-233... 

Since 1995 some new types of pyrethroids with high insecticidal potency have been developed for practical use. For this reason we decided to publish a volume written by experts in various fields to review the development of new pyrethroids and offer future perspectives. This volume includes chapters on the progress and the future of pyrethroids, the biosynthesis of natural pyrethrins, newly developed polyfluorobenzyl-type pyrethroids with potent insecticidal activity, the mode of action, mammal toxicology, biotransformation and enzymatic reactions, environmental behavior, and ecotoxicology of pyrethroids. We hope that this book will contribute greatly to the further development of pyrethroids. 

From a pharmacological point of view the first two strategies raise several distinct disadvantages. First, the exact structures of these fullerene-based systems in solution are usually unknown and, especially for polymeric materials inhomogeneous samples are frequently obtained. Furthermore, in many cases the amount of incorporated fullerene is not clearly determined. In addition, the presence of other molecules like the hosts or polymeric residues can cause unpredictable side effects and in no case the mode of action or activity can doubtlessly be associated with the fullerenes. However, for systematic investigations on structure-function relationships or extensive testings of toxicological or human availability properties, the use of structurally well-defined and characterized materials is mandatory. 

---