Toxicity lesions

Some biomarker responses provide evidence only of exposure and do not give any reliable measure of toxic effect. Other biomarkers, however, provide a measure of toxic effects, and these will be referred to as mechanistic biomarkers. Ideally, biomarker assays of this latter type monitor the primary interaction between a chemical and its site of action. However, other biomarkers operating down stream from the original toxic lesion also provide a measure of toxic action (see Figure 14.3 in Chapter 14), as, for instance, in the case of changes in the transmission of action potential... 

In chronic studies, DMMP was administered by gavage in corn oil for up to 2 years at doses of 500 or 1000 mg/kg/day to rats and at doses of 1000 or 2000mg/kg/day to mice. " Survival in dosed male rats was reduced, due in part to renal toxicity. Lesions of the kidney included increased severity of spontaneous age-related nephropathy including calcification, hyperplasia of the tubular and transitional epithelium, tubular cell adenocarcinomas, and transitional cell papillomas and carcinomas. Similar lesions were not seen in female rats or in mice of either sex, although reduced survival in male mice prevented adequate analysis. The... 

AP sites, left unrepaired, impede the progression of DNA polymerases during DNA replication and can be mutagenic in the synthesis of both DNA and RNA. AP sites can also be converted to toxic lesions by spontaneous rearrangements that produce structures that can crosslink with proteins and lipids. They can also create toxic lesions by the activities of topoisomerase I and topoisomerase II. In addition, the processing of AP sites by the BER proteins can produce structures that are toxic. Hence, to prevent these deleterious events from occurring, the BER process is likely coordinated and each step involves a handing off from one enzyme in the pathway to the next. 

Mouse 10 Inhalation 78,257,711 6 h/d for 4-14 d No clinical signs of toxicity. Lesions of respiratory epithelium rhinitis with metaplasia and necrosis) observed at highest concentration. Severity increased NOAEL 257 LOAEL 711 Zissu et a). 1995... 

Markers that are concurrent with toxic lesion are diagnostic, whereas those indicative of late pathology are predictive. The latter is of greater value as it... 

Identification of novel biomarkers of toxicity Previously, the detection of novel biomarkers of toxic effect has mainly been serendipitous. However, it is now possible to use a combined NMR-expert systems approach to systematically explore the relationships between biofluid composition and toxicity and to generate novel combination biomarkers of toxicity. Pattern recognition maps can be examined for evidence of clustering of data according to site and type of toxic lesion. 

In order to test the NMR-PR approach further, the time course of metabolic urinary changes induced by two renal toxins has been investigated in detail. In this case, toxic lesions were induced in Fisher 344 rats by a single acute dose of the renal cortical toxin mercury(II) chloride and the medullary toxin 2-bromoethanamine. The rat urine was collected for up to 9 days after dosing and was analysed using NMR spectroscopy. The onset, progression and recovery of the lesions were also followed using histopath-... 

Rataboul, P, Vernier, P., Biguet, N.F., et al. 1989. Modulation of GFAP mRNA levels following toxic lesions in the basal ganglia of the rat. Brain Res. Bull. 22(1) 155-161. 

Histological Examination of Primary Toxic Lesions a) Flank... 

In applying a 1 % solution of DNCB on the flank without acanthosis, the primary toxic lesions already described are observed after 24 hours (sub-epidermal bullae, necrosis of the epidermis, infiltration), whereas on the flank with acanthosis there are practically no lesions (Fig. 4a and b). 

If a 1% solution of DNCB is applied on the nipple with acanthosis, there are no lesions (excision 24 hours after application). However if the same solution is applied on a nipple without acanthosis, the usual primary toxic lesions are observed (necrosis of the epidermis). 

DDTC can inhibit platinum nephrotoxicity without affecting activity (Chapter 2.2). In this case, studies with model compounds showed that the bis(guanosine) complexes were not affected by DDTC (10 mM, 37 C) whereas a mono(guanosine) complex and a bis(adenosine) complex reacted readily with the DDTC ligand [137]. These results confirm observations from studies on DNA, where very little platinum is removed by DDTC at low binding ratios, and allow the prediction that DDTC should not reverse the toxic lesion on DNA, as observed [137]. It would be interesting to correlate the various effects of the nephroprotective sulfur nucleophiles (Chapter 2.2) and their effects on antitumour activity of cisplatin with the behavior toward model compounds (see also Chapter 3.7). 

Frequent blood transfusions have to be given to children with severe aplastic anaemia or homozygous thalassaemia to allow for a normal growth pattern and a sufficient quality of life. After puberty, however, the clinical effects of iron deposition appear. Iron deposits are extensive in the ventricular myocardium, but toxic lesions occur also in other organs, particularly in the liver. The condition deteriorates progressively, causing death during adolescence or early adult life (17 ). 

In isolated hepatocytes the first toxic lesion is a change in cell shape. About 10 minutes after administration of phalloidin to the medium hepatocytes develop numerous blebs on their surface (11). We compared the kinetics of bleb formation in vivo with the kinetics of actin polymerization from the thymosin (34 complex in vitro, and found that the two processes develop at a comparable rate. Since polymerization occurs at a rate somewhat faster than the development of surface blebbing in vivo, the morphological lesions in the... 

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