Species-specific effects

Primary endpoints Secondary endpoints In vivo model selection Species-specific effects Effects independent of species Animal model of disease... 

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. 

It should be noted that the cerebral edema produced by triethyltin can be regarded as a specific effect. However, the lesions of the bile ducts in rats and mice previously described for dibutyltin compounds appear to be a more species-specific effect. 

A number of zinc compounds with organic constituents (e.g., zinc salts of organic acids) have therapeutic uses. These include antidandruff zinc pyridinethione, antifungal zinc undecylenate used to treat athlete s foot, zinc stearate and palmitate (zinc soap), and antibacterial zinc bacitracin. Zinc naphthenate is used as a low-toxicity wood preservative, and zinc phenolsulfonate has insecticidal properties and was once used as an intestinal antiseptic. The inhalation of zinc soaps by infants has been known to cause acute fatal pneumonitis characterized by lung lesions similar to, but more serious than, those caused by talc. Zinc pyridine thione (zinc 2-pyridinethiol-l-oxide) has been shown to cause retinal detachment and blindness in dogs this is an apparently species-specific effect because laboratory tests at the same and even much higher dosages in monkeys and rodents do not show the same effect. 

Some common developmental effects attributed to 2,3,7,8-TCDD exposure in most laboratory mammals are thymic hypoplasia, subcutaneous edema, decreased prenatal growth, and prenatal mortality (Couture et al. 1990). In addition, there are other species-specific effects, such as cleft palate in mice. Any of... 

Simoneau, J-A., and D. Pette (1998). Species-specific effects of chronic stimulation upon tibialis anterior muscle in mouse, rat, guinea pig, and rabbit. Pflugers Arch. 412 86-92. 

Knowledge about metabolites and their activity is further an important criteria for the assessment of species-specific effects and differences, e.g. the search for the most human-like test model as the best predictor for human reactions, focuses on such differences. Metabolism can lead to pharmacologically active metabolites such knowledge is desirable early in development. In vitro metabolism studies normally precede in vivo preclinical safety assessments. 

Tang, K. W., and Taal, M. (2005). Trophic modification of food quality by heterotrophic protists Species-specific effects on copepod egg production and eg hatching.Exp. Mar. Biol. Ecol. 318, 85—98. 

Interferons (IFN) were discovered in England by A. Isaacs et al. in 1957. (39) They are low molecular weight glycoproteins acting as cytokines (so-called intercellular mediators) with clear species-specific effects. Interferon type I includes the subtypes IFN-a and IFN-p. They are formed by nearly all cells, whereby IFN-a is mainly produced by monocytes and B-lymphocytes, and IFN-fi mainly by fibroblasts. Both subtypes bind to the same receptor at the target cells and are taken up in the hepa-... 

However we also know that the test systems are not infallible they are subject to false positive outcomes (i.e., a false alert) or false negative outcomes (missing a human toxicity raises concern for all stakeholders). False positive outcomes may be the result of several factors, including occurrence of toxicity only at exaggerated dose levels (identifiable by determining safety margins based on comparative plasma exposure, or including biomarkers if available), or species-specific effects or toxic metabolites (as shown to not occur in humans). The consequence... 

Rusyn I, Peters JM, Cunningham ML. Modes of action and species-specific effects of di-(2-ethylhexyl)phthalate in the liver. Crit Rev Toxicol 2006 36 459-79. 

There are several plausible explanations for the species-specific effects of PPARa activators (1) Full-length PPARa protein is expressed at levels at least 10-fold greater in rodent liver than in human liver. (2) Humans but not rodents express an inactive form of PPARa in the liver which inhibits the active PPARa. 

In 1998, Sciuto and Stotts showed that post-treatment of guinea pigs with 5,8,11,14-eicosatetraynoic acid (ETYA) reduced pulmonary artery pressure after exposure to phosgene. ETYA is a competitive analogue of arachidonic acid and blocks the formation of arachidonic acid-derived mediators. Not all of the results of this study proved easy to interpret ETYA decreased lipid peroxidation (as measured by TBARS formation) and decreased oedema formation but increased leukotiene release. The authors account should be examined for details but the importance of possible species-specific effects is noted here. 

Rick There is. I believe, a species-specific effect in hypothermia and hyperthermia. This has been shown by Feldberg and Myers (1964) and others in their work with catecholamines. To what extent is this species-specific effect on thermoregulation present with anticholinesterases ... 

A typical recent example comes from some work on tryptase inhibitors, tryptase being a serine protease of interest for the treatment of asthma. Compound 44, shown in Figure 8.2, was found to be a 2.5 nM inhibitor of human tryptase, but a 365 nM inhibitor of the mouse enzyme, and a 400 nM inhibitor of monkey tryptase. Larger species specificity effects than this have been observed for some renin inhibitors, including zankiren (Figure 8.2) and the... 

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