Toxicity pathways

Pohl L, Gillette J. 1984-1985. Determination of toxic pathways of metabolism by deuterium substitution. Drug Metab Rev 15 1335-1351. 

Kleinstreuer NC et al (2011) Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics. Toxicol Appl Pharmacol 257 111-121... 

The success of such approaches critically depends on our ability to identify the essential mechanistic elements of toxicity pathways and to rebuild them in in vitro models, and on the possibility to conclude about cause and effect relationships between human exposures and diseases. Both these aspects provide significant challenges for research. 

Bhattacharya S et al (2011) Toxicity testing in the 21 century defining new risk assessment approaches based on perturbation of intracellular toxicity pathways. PLoS One 6(6) e20887... 

As discussed above, the risk of chemicals in the environment is dependent on both exposure and toxicity. Pathways through which organisms in the environment are exposed to chemicals are therefore key determinants of how safe (and therefore, how green ) a chemical is, and must be considered in moving towards a reduced risk or hazard approach to the production and use of chemicals. Fate in the environment is the principal determinant of exposure and designing chemicals for reduced hazard and risk to the environment involves consideration of processes that affect the chemical in the environment, in addition to toxicity. Assessment of environmental fate, including design of chemicals for nonpersistence, is discussed in detail in Chapter 16. 

Zewert T, Pliquett U, Vanbever R, Langer R, Weaver J. Creation of transdermal pathways for macromolecule transport by skin electroporation and a low toxicity, pathway-enlarging molecule. Bioelectrochem Bioenerg 1999 49 11-20. 

Biological systems possess a number of mechanisms for protection against toxic foreign compounds, some of which have already been mentioned. Thus, metabolic transformation to more polar metabolites, which are readily excreted, is one method of detoxication. For example, conjugation of paracetamol with glucuronic acid and sulfate facilitates elimination of the drug from the body and diverts the compound away from potentially toxic pathways (see chap. 7). Alternatively, a reactive metabolite may be converted into a stable metabolite. For example, reactive epoxides can be metabolized by epoxide hydrolase to stable dihydrodiols. 

Figure 7.77 The metabolism of halothane and its proposed involvement in the toxicity. Pathway 1 (oxidative) and pathway 2 (reductive) are both catalyzed by cytochrome P-450.

In summary, in studies of chemical toxicity, pathways and rates of metabolism as well as effects resulting from toxicokinetic factors and receptor affinities are critical in the choice of the animal species and experimental design. Therefore it is important that the animal species chosen as a model for humans in safety evaluations metabolize the test chemical by the same routes as humans and, furthermore, that quantitative differences are considered in the interpretation of animal toxicity data. Risk assessment methods involving the extrapolation of toxic or carcinogenic potential of a chemical from one species to another must consider the metabolic and toxicokinetic characteristics of both species. 

Fig. 1. Cleavage of APP via nontoxic and toxic pathways. Sequential cleavage of APP by a and y secretases results in the production of the nonpathological fragment, P3 (A). Cleavage by (3 and y secretases results in the production of toxic A(3 fragments (B). (From ref. 3.)...

A report by the National Academy of Sciences proposed that future toxicity screens not be organ-based as they are today, but that they instead focus on detecting specific mechanisms of toxicity.86 Thus, a suite of such assays may be used to determine what toxicity pathways are triggered by exposure to specific chemicals. Similar approaches may be applied to developmental toxicity tests. In this way, we need not know all the relevant developmental biology pathways... 

The National Academy of Sciences put together a symposium entitled "Toxicity Pathway-Based Risk Assessment Preparing for Paradigm Change." Presentations... 

This enzyme is present in the cytosolic fraction of rat liver and kidney and also in the microflora of the gut. Because thiols may be toxic and are more lipophilic than their cysteine conjugate precursors, jS-lyase is generally a toxication pathway. 

EPA will also benefit under the MOU from access to doe s Joint Genome Institute. Genomics is a new area of biology, derived from the large-scale DNA sequencing efforts of the human genome, and holds the potential to reveal molecular pieces of the toxicity pathway and improve chemical risk assessments and the evaluation of the health of ecosystems. 

Natsch A (2010) The Nrf2-Keapl-ARE toxicity pathway as a cellular sensor for skin sensitizers functional relevance and a hypothesis on innate reactions to skin sensitizers. Toxicol Sci 113 284-292... 

Jennings P (2013) Stress response pathways, toxicity pathways and adverse outcome pathways. Arch Toxicol 87(1) 13-14... 

---