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PubMed1987

Potential use of cimetidine for treatment of acetaminophen overdose.

Acetaminophen, a drug frequently taken in intentional and accidental overdose, causes liver toxicity when concentration of the cytochrome P-450-derived metabolite exceeds the metabolic capacity of available glutathione. Present treatment of acetaminophen overdose involves oral N-acetylcysteine (NAC), which enhances liver glutathione synthesis. An alternative or additive approach to therapy would be to inhibit the formation of the toxic metabolite by inhibiting the cytochrome P-450 system. The H2-receptor antagonist cimetidine inhibits the cytochrome P-450 system, does not interfere with the administration or function of NAC, and therefore affords additive protection. Also, it has little effect on the nontoxic routes of elimination of acetaminophen and is itself quite nontoxic. That cimetidine protects against acetaminophen toxicity in animal models has been demonstrated on the basis of improved survival, as well as decreases in several critical elements used to monitor acetaminophen toxicity: classic histologic changes, aminotransferase activity, metabolite covalent binding, and liver glutathione depletion. Administration of cimetidine well after the overdose is also protective. In contrast, animal models of acetaminophen toxicity demonstrate that ranitidine does not afford protection from acetaminophen hepatotoxicity. Clinical data in well-done trials in humans will be needed to support the experimental animal data.

Acetaminophen↗
PubMed1999

Review of evidence for a novel model of cocaine-induced cardiovascular toxicity.

Cocaine is known to produce life-threatening cardiovascular complications in some but not all individuals. This review considers the premise that an appropriate animal model for cocaine-induced cardiotoxicity should be characterized by varying sensitivity in the population to the deleterious effects of cocaine. We have studied such a model in which physiological, biochemical, and pathological sensitivity to cocaine varies in rats. Our studies have identified a subset of rats that respond to cocaine with a decrease in cardiac output and a substantial increase in systemic vascular resistance (named vascular responders). In contrast, another group, designated mixed responders, is characterized by a smaller increase in systemic vascular resistance and a small increase in cardiac output. We reported that vascular responders are more likely to develop hypertension and cardiomyopathies with repeated cocaine administration. Under chloralose anesthesia, vascular responders have more profound pressor responses to cocaine and an initial brief spike in renal sympathetic nerve activity not usually noted in mixed responders. Vascular responders have higher resting and cocaine-induced dopamine turnover in the striatum. In addition, vascular responders have higher alpha-adrenergic vasoconstrictor tone, whereas mixed responders have higher adrenergic cardiac tone. The difference in cardiac output and systemic vascular resistance responses to cocaine in these two subsets of the population can be prevented by L-type calcium channel, muscarinic, or alpha-adrenergic blockade. Similar hemodynamic response variability is noted with other psychoactive agents and with acute stress, suggesting that the response patterns are not unique to cocaine. We propose that individual hemodynamic response variability is dependent on differences in CNS responsiveness and correlated with the incidence of cardiovascular disease.

Animals↗
PubMed2004

Comparison of pathways controlling toxicity in the eye and brain in Drosophila models of human neurodegenerative diseases.

Most human neurodegenerative diseases have a number of common features, including adult onset, progressive degeneration of selected neuronal populations and formation of abnormal protein aggregates. Although these shared characteristics raise the possibility of conserved pathogenic mechanisms, the diverse clinical and pathological features of each disorder indicate significant differences. As a number of human neurodegenerative diseases have now been modeled in Drosophila, and genetic modifiers identified, we have been able to perform a genetic comparison of pathways controlling toxicity in these models. By directly comparing modifiers isolated in the models of polyglutamine diseases and in a Drosophila model of tauopathy, we find a final common pathway of cell death involving apoptosis. Among the polyglutamine diseases, protein folding and histone acetylation are common key mediators. In addition, two novel modifiers suggest shared pathways of toxicity among all the disorders. Cell-type specificity is a salient feature of all neurodegenerative diseases; however, most work to date in the Drosophila models have been performed in the retina. Therefore, we determined whether similar pathways of toxicity operate in neurons of the Drosophila brain. Many, but not all, retinal modifiers also modify toxicity in postmitotic neurons in the brain. Analysis of polyglutamine toxicity in the adult brain facilitated the identification of nicotinamide (vitamin B3), a vitamin with histone deacetylase inhibiting activity, as a potent suppressor of polyglutamine toxicity. These findings outline common pathways of neurotoxicity, demonstrate disease- and cell-type specific pathways and identify a common vitamin as a potential therapy in polyglutamine disorders.

Animals↗
PubMed1994

Role of exogenous adenosine as a modulator of theophylline toxicity.

OBJECTIVE: In animal models, exogenous adenosine can reverse theophylline-induced neurologic toxicity. Thus, we examined the ability of adenosine to oppose the cardiovascular toxicity of theophylline. DESIGN: Open-label, dose-response trial. SETTING: Animal laboratory within a college of pharmacy. SUBJECTS: Ten chloral hydrate-anesthetized male Sprague-Dawley rats. INTERVENTIONS: Indwelling catheters were surgically inserted into the right carotid artery and right external jugular vein. Subsequently, escalating doses of adenosine (5 to 2000 micrograms) were given at theophylline doses of 0, 10, 20, 30, 40, and 50 mg/kg until a maximum slowing in heart rate occurred. MEASUREMENTS AND MAIN RESULTS: Left ventricular systolic pressure and maximum positive maximal change in pressure over time (+dP/dt) were determined at baseline and at the time of maximum heart slowing, during adenosine, for each theophylline dose (0 to 50 mg/kg). Escalating doses of adenosine resulted in progressive heart rate slowing until maximum slowing occurred. The adenosine doses required to reach maximum slowing of heart rate were 118 +/- 24, 410 +/- 197, 620 +/- 256, 855 +/- 264, 944 +/- 329 and 1062 +/- 463 (SD) micrograms at theophylline doses of 0, 10, 20, 30, 40, and 50 mg/kg, respectively, which were correlated (r2 = .57, p < .001). At baseline, increasing theophylline doses produced a progressive reduction in left ventricular systolic pressure. However, adenosine at maximum slowing doses reversed this effect where left ventricular systolic pressure at 0 mg/kg of theophylline was similar to left ventricular systolic pressure at 50 mg/kg of theophylline (p < .05). At baseline, 10 to 50 mg/kg of theophylline had no significant effect on +dP/dtmax. However, adenosine (at maximum slowing) decreased +dP/dtmax before theophylline administration (p < .01). Theophylline at doses of 10 to 50 mg/kg reversed adenosine's negative inotropic effect, where +dP/dtmax values at maximum slowing were greater than values at 0 mg/kg of theophylline (p < .05). CONCLUSIONS: Adenosine can reverse theophylline-induced electrophysiologic and hemodynamic instability, whereas theophylline can reverse the negative inotropic actions of adenosine. However, higher adenosine doses are needed to elicit these changes as the theophylline dose increases.

Adenosine↗
PubMed1994

Clinical studies with EO9, a new indoloquinone bioreductive alkylating cytotoxic agent. EORTC Early Clinical Trials Group.

EO9 [3-hydroxy-5-aziridinyl-1-methyl-2-(1H-indole-4,7-indione)-prop-be ta- en-alpha-ol] is a new bioreductive alkylating indoloquinone with a distinct antitumor activity against solid tumors, excellent activity under hypoxic conditions, and lack of bone marrow toxicity in preclinical models. Clinical phase I studies were performed to determine the toxicities, maximally tolerated dose, and pharmacology of EO9. The drug was administered as a 5-min IV infusion at intervals of 3 weeks or weekly to 59 patients with solid tumors. The starting dose of 2.7 mg/m2 was one-tenth of the mouse-equivalent dose lethal to 10% of mice. Doses were escalated according to a Fibonacci-like schedule. The pharmacokinetics of EO9 and its aziridine ring-opened metabolite EO5A were determined using a new high performance liquid chromatography method and noncompartmental calculation of kinetic parameters. The sigmoid maximal effects (Emax) model was used to fit pharmacokinetic parameters to toxicities. The 59 patients received in total 150 evaluable courses of EO9. The dose-limiting toxicity was proteinuria, which was accompanied by sodium and water retention. With the 3-weekly schedule, all symptoms were reversible on day 15 except in 2 patients, who developed acute renal failure. The renal function and proteinuria were quantitated and further evaluated by determining renal clearance ratios of immunoglobulin G/albumin and pancreatic/salivary amylase. The immunogobuline G/albumin and pancreatic/salivary amylase ratios pointed to a loss of glomerular negative charge consistent with a minimal change glomerulopathy. The maximum tolerated dose was 27 mg/m2, the recommended dose 22 mg/m2. The pharmacokinetics showed rapid elimination from the central compartment and wide interpatient variation in disposition.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Acquired ability of Staphylococcus aureus to produce toxic shock-associated protein and resulting illness in a rabbit model.

Staphylococcus aureus from patients with toxic shock syndrome (TSS) produce TSS toxin 1. We transferred, by a bacteriophage, the ability to produce TSS toxin 1 from a TSS toxin 1-positive to a TSS toxin 1-negative strain of S. aureus. This recombinant strain produced TSS toxin 1 as confirmed by isoelectric focusing, immunodiffusion, radioimmunoassay, and autoradiography. The recombinant produced TSS-like illness in rabbits, and was significantly (P less than 0.001) more lethal than the recipient strain. Both strains produced fever and diarrhea, but, in addition, rabbits challenged with the recombinant also developed lowered blood pressure (P = 0.002), conjunctival hyperemia, erythroderma, and respiratory distress. Histopathological findings in rabbits challenged with the recombinant strain were remarkably similar to those described for humans with TSS, e.g., erythrophagocytosis, liver "triaditis," and vasodilatation. This study demonstrates that this protein may contribute to the pathogenesis of the TSS.

Animals↗
PubMed2001

Factors influencing predictive models for toxicology.

Comparisons of different models to predict toxicity and evaluation of the predictive power of a model are affected by the variability of the data. We assessed this problem by considering experimental toxicity data and chemical descriptors. We evaluated several toxicological end-points (Oncorhynchus mykiss, Daphnia magna, Acceptable Daily Intake, Anas Platyrhynchos, Colinus virginianus and Muridae) in the case of pesticides and also considered the availability of toxicological data. We calculated hundreds of molecular descriptors (divided into constitutional, electrostatic, geometrical, quantum-chemical and topological ones) for the selected compounds using CODESSA, HyperChem and Pallas. Molecular descriptors may vary depending on the conformation of the molecules and on the software used. We evaluated the extent of this variability, and compared it with the variability of the experimental toxicological values.

Animals↗
PubMed1996

Ozone toxicity in the mouse: comparison and modeling of responses in susceptible and resistant strains.

Previous studies from this laboratory have demonstrated a concentration-related hypothermia and increases in bronchoalveolar lavage (BAL) fluid indexes of toxicity in the rat after exposure to environmentally relevant levels of ozone (O3). In similar studies with C57BL/6J (B6) and C3H/HeJ (C3) mice, other investigators have reported differential effects on BAL toxicity indexes between the two strains after O3 exposure. The present study investigated the relationship between the reported strain differences in BAL parameters in B6 and C3 mice exposed to O3 and the induced hypothermic response. Male 80-day-old mice (n = 94, 47/strain) were used for these studies. Subsets (n = 8/strain) of these animals were surgically implanted with radiotelemetry transmitters that permitted continuous monitoring of core body temperature and activity. All telemetry animals and an equal number of nontelemetry animals (n = 8/strain) were exposed to filtered air for 24 h followed by a 2-h exposure to 2 parts/million 16O3. With use of a similar protocol, groups of nontelemetry mice (n = 12/strain) were exposed to either filtered air or 2 parts/million 16O3 for 2 h. At 0 or 22 h postexposure, mice were anesthetized with halothane and intubated, and their lungs were lavaged with 37 degrees C saline. Although both strains of mice exhibited significant abrupt decreases in core body temperature on exposure to O3 and both recovered rapidly after cessation of the O3 exposure, the response of the C3 mice was more dynamic than that of the B6 mice. Similarly, both strains showed characteristic changes in biomarkers of O3 toxicity; however, the increases in BAL fluid protein and cells at 22 h postexposure were significantly greater and the percentage of neutrophils was significantly less in B6 mice than in C3 mice. It is possible that the strain differences in BAL constituents may be related to the differences in the hypothermic response.

Animals↗
PubMed2004

A toroid model for in vitro investigations of toxic shock syndrome toxin-1 production.

Human behaviours and consumer products may affect vaginal microbial ecology, thereby influencing women's health. Relevant experimentation systems are needed to understand such possible links. Here, we describe the development of a practical semi-solid in vitro model to assess the effects of interactions between vaginal environment and the presence of tampons, on bacterial communities, including the production of toxic shock syndrome toxin-1 (TSST-1) by Staphylococcus aureus.

Bacterial Toxins↗
PubMed1997

Antiviral efficacy and toxicity of ribavirin and foscarnet each given alone or in combination in the murine AIDS model.

The antiviral efficacy and toxicity of ribavirin, foscarnet (PFA), and combinations of both drugs at two different doses have been evaluated in the murine AIDS (MAIDS) model. Our results clearly demonstrated that infected mice treated with ribavirin at 100 mg/ kg/day were protected against splenomegaly, lymphadenopathy, and hypergammaglobulinemia whereas PFA alone at 180 or 360 mg/kg/day did not afford any protection. Treatment with drug combinations showed protective effects similar to those observed with ribavirin alone. Hyperplasia and deorganization of the lymphoid architecture were noted in spleen and lymph nodes of infected mice compared to those of the uninfected group. However, treatment with ribavirin restored the lymphoid tissue architecture and reduced the emergence of germinal centers. Electron microscopic examination of renal cortex of animals treated with PFA at 360 mg/kg/day revealed clear mitochondrial necrosis (bursting of mitochondria) of the distal tubules and vacuolization of the proximal tubules which was more striking with combination therapy. Regarding hematotoxicity, PFA did not cause significant hematotoxicity at both doses, whereas ribavirin was hematotoxic at both doses (50 and 100 mg/kg/day), this toxicity being more evident at the higher dose. In conclusion, treatment with ribavirin showed clear efficacy against MAIDS whereas PFA had no efficacy. Furthermore, ribavirin treatment caused hematoxicity and PFA treatment resulted in nephrotoxicity.

Animals↗
PubMed2001

A rat model of the cognitive impairment from Pfiesteria piscicida exposure.

Pfiesteria piscicida Steidinger & Burkholder, an estuarine dinoflagellate known to kill fish, has also been associated with neurocognitive deficits in humans. We have developed a rat model to determine the cause-and-effect relationship between exposure to Pfiesteria-containing water and cognitive impairment and to determine the neurobehavioral mechanisms underlying the Pfiesteria effect. The rat model of Pfiesteria toxicity can also provide important information concerning the toxin or toxins responsible for neurocognitive deficits resulting from Pfiesteria exposure. With the rat model we have repeatedly documented a Pfiesteria-induced choice accuracy impairment during radial-arm maze learning. The Pfiesteria-induced impairment was relatively specific to the acquisition phase of training. When rats were pretrained, Pfiesteria treatment did not affect performance. However, when these same rats were retrained on another task, the Pfiesteria-induced impairment became evident. Pfiesteria-induced effects were also seen in a locomotor activity test in the figure-8 apparatus and selected components of the functional observational battery. Pfiesteria effects on choice accuracy in the radial-arm maze in rats constitute a critical component of the model of Pfiesteria toxicity, as the hallmark of Pfiesteria toxicity in humans is cognitive dysfunction. Our finding that analysis of the first six sessions of radial-arm maze testing is sufficient for determining the effect means that this test will be useful as a rapid screen for identifying the critical neurotoxin(s) of Pfiesteria in future studies.

Animals↗
PubMed2005

Infliximab may reverse the toxic effects induced by tumor necrosis factor alpha in human spermatozoa: an in vitro model.

OBJECTIVE: To examine the toxic effects of tumor necrosis factor alpha (TNF-alpha) on ejaculated spermatozoa and evaluate the ability of infliximab to reverse these effects. DESIGN: Prospective controlled study. SETTING: Cleveland Clinic Foundation, Cleveland, Ohio. PATIENT(S): Thirty-one healthy sperm donors. INTERVENTION(S): Exposure of human spermatozoa to varying concentrations of TNF-alpha (100, 300, 400, 500 pg/mL, and 2.5 microg/mL) and infliximab (400 microg/mL). MAIN OUTCOME MEASURE(S): Sperm motility, functional integrity of plasma membrane, and DNA fragmentation. RESULT(S): Spermatozoa quality declined following incubation with TNF-alpha in a dose-dependent and time-dependent manner. Sperm motility and membrane integrity were higher in the samples incubated with TNF-alpha plus infliximab than in the samples treated with TNF-alpha only. These parameters improved significantly and were comparable with both controls and sperm incubated with infliximab alone. Similarly, the percentage of spermatozoa with DNA fragmentation improved significantly following incubation with TNF-alpha plus infliximab and again was comparable with both controls and sperm incubated with infliximab alone. CONCLUSION(S): Spermatozoa may be exposed to abnormal levels of TNF-alpha in the male reproductive tract or during their passage into the female reproductive tract (in cases of endometriosis). Exposing spermatozoa to pathological concentrations of TNF-alpha can result in significant loss of their functional and genomic integrity. Infliximab could potentially be used to help treat female infertility caused by endometriosis in those with elevated levels of TNF-alpha in their peritoneal fluid.

Analysis of Variance↗
PubMed2005

Toxic oil syndrome: genetic restriction and immunomodulatory effects due to adulterated oils in a model of HLA transgenic mice.

Toxic oil syndrome (TOS) was described in Spain in 1981, due to the ingestion of contaminated rapeseed oil denatured with 2% aniline. More than 20,000 persons were affected, causing over 2500 deaths. Immunological findings were: eosinophilia, mRNA for Th2 cytokines (IL-4 and IL-5) in lungs, elevated total IgE and sIL-2R and increase of DR2 HLA class II phenotypic frequency in patients died by TOS. Our objective is to test the genetic restriction found in humans using HLA transgenic mice. Results show that mice expressing human DR2 and DQ6 (both in linkage disequilibrium), had higher percentage of eosinophils (DQ6) and IgE (DR2) than other transgenic mice tested (DR3 and DR4). Also, a Th2 shift was found in DR2 transgenic mice when toxic oil was administered with OVA. This has been corroborated by the IL-5 mRNA expression in 4 out of 6 lung tissues from TOS oil treated BALB/c mice. These data indicate that an immunological response was induced as consequence of the toxic administration. These results correlate with those found in TOS patients and reinforce the implication of genetic restrictions in the acquisition of toxic-mediated disease.

Aniline Compounds↗
PubMed2006

A comparison of the cost-effectiveness of five strategies for the prevention of non-steroidal anti-inflammatory drug-induced gastrointestinal toxicity: a systematic review with economic modelling.

OBJECTIVES: To assess the relative effectiveness, patient acceptability, costs and cost-effectiveness of four strategies for the prevention of non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastrointestinal (GI) toxicity: (1) Cox-1 NSAIDs plus histamine-2 receptor antagonist (H2RA), (2) Cox-1 NSAIDs plus proton pump inhibitors (PPIs), (3) Cox-1 NSAIDs plus misoprostol, and (4) Cox-2 NSAIDs (later expanded to 4a Cox-2 coxibNSAIDs and 4b Cox-2 preferential NSAIDs). DATA SOURCES: Electronic databases up to May 2002. REVIEW METHODS: Relevant studies were selected, assessed and analysed. Pooled relative risk ratios (RR) from the systematic review were combined with up-to-date UK resource use and unit costs data in an incremental economic analysis. A probabilistic decision-analytic model was designed and populated with data to carry out incremental economic analysis. Incremental cost-effectiveness ratios (ICERs) were generated for the outcome measure, endoscopic ulcer or serious GI event averted, against total cost, and non-parametric bootstrapping was used to simulate variance of these ICERs. RESULTS: Of 118 selected trials, including 125 relevant comparisons (which included 76,322 participants) only 138 deaths and 248 serious GI events were reported. Seven comparisons were judged to be at low risk of bias. Comparing the gastroprotective strategies against placebo, there was no evidence of effectiveness of H2RAs against any primary outcomes (few events reported), PPIs may reduce the risk of symptomatic ulcers [RR 0.09, 95% confidence interval (CI) 0.02 to 0.47], misoprostol reduces the risk of serious GI complications (RR 0.57, 95% CI 0.36 to 0.91) and symptomatic ulcers (RR 0.36, 95% CI 0.20 to 0.67), Cox-2 'preferentials' reduce the risk of symptomatic ulcers (RR 0.41, 95% CI 0.26 to 0.65) and Cox-2 'coxibs' reduce the risk of symptomatic ulcers (RR 0.49, 95% CI 0.38 to 0.62) and possibly serious GI events (RR 0.55, 95% CI 0.38 to 0.80). All strategies except Cox-2 'preferentials' reduce the risk of endoscopic ulcers. There were only 12 direct comparisons between gastroprotective strategies. All they suggest is that Cox-2 preferentials are better than misoprostol for preventing GI complications. Indirect comparisons suggested that PPIs may prevent symptomatic ulcers better than Cox-2 coxibs, but this is very weak evidence. For prevention of endoscopic ulcers PPIs and misoprostol appear more successful than H2RAs and misoprostol is better than Cox-2 preferentials. There were no UK head-to-head published economic analyses with regard to the main gastroprotective strategies. There were generally insufficient data with regards to cardiac or renal outcomes, serious GI outcomes or life-years gained to populate the mode. Mean (2.5th and 97.5th percentile) costs per endoscopic ulcer averted compared with Cox-1 NSAIDs alone were as follows: Cox-1 plus H2RAs, -186 pounds (-555 to 804); Cox-1 plus PPIs, 454 pounds (251 to 877); Cox-1 plus misoprostol, 54 pounds (-112 to 238); Cox-2 selective NSAIDs, 263 pounds (-570 to 1280), or Cox-2 specific NSAIDs, 301 pounds (189 to 418). With regard to the prevention of endoscopic ulcers, Cox-1 NSAID plus H2RA is a dominant option. Cost-effectiveness acceptability analysis showed a 95% probability that this combination was less costly and more effective. Cost-effectiveness acceptability frontiers showed that if the decision-maker is willing to pay up to 750 pounds to avoid an endoscopic ulcer, then Cox-1 plus H2RA is the optimal strategy. If the decision-maker is willing to pay over 750 pounds, the optimal strategy is NSAID plus misoprostol. Between 1900 pounds and 3750 pounds, Cox-2 selective inhibitors are optimal, and over 3750 pounds, Cox-2 specific inhibitors become optimal. NSAID plus PPI is never the optimal strategy. Sensitivity and subgroup analyses suggest that Cox-1 NSAID plus H2RA and Cox-1 NSAID plus misoprostol become more cost-effective in the older age group. Some conclusions were associated with high levels of uncertainty. CONCLUSIONS: Although there is a very large body of evidence comparing Cox-2 NSAIDs with Cox-1 NSAIDs, this is not matched by studies of the other types of gastroprotectors or by studies directly comparing active gastroprotective strategies. This lack of direct comparisons led to the use of indirect comparisons to help understand the relative efficacy of these strategies. Indirect evidence in itself is weak and was also hampered by lack of evidence in the underlying studies (where the gastroprotectors were compared with placebo). Economic modelling suggests that Cox-1 NSAID plus H2RA or Cox-1 NSAID plus PPI are the most cost-effective strategies for avoiding endoscopic ulcers in patients requiring long-term NSAID therapy. All strategies other than Cox-2 selective inhibitors reduce the rate of endoscopic ulcer compared with Cox-1 alone. The economic analysis suggests that there may be a case for prescribing H2RAs in all patients requiring NSAIDs. Misoprostol is more effective, but is associated with a greater cost and GI side-effects which may be unacceptable for patients. However, when assessing serious GI events, the economic analysis is sufficiently weakened by the data available as to render clear practice recommendations impossible. Further large, independent RCTs directly comparing various gastroprotective strategies are needed. These should report items such as major outcomes, primary data, adverse events, assessment of practice and patient preference.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

Database mining with adaptive fuzzy partition: application to the prediction of pesticide toxicity on rats.

A data set of 235 pesticide compounds, divided into three classes according to their toxicity toward rats, was analyzed by a fuzzy logic procedure called adaptive fuzzy partition (AFP). This method allows the establishment of molecular descriptor/chemical activity relationships by dynamically dividing the descriptor space into a set of fuzzily partitioned subspaces. A set of 153 molecular descriptors was analyzed, including topological, physicochemical, quantum mechanical, constitutional, and electronic parameters, and the most relevant descriptors were selected with the help of a procedure combining genetic algorithm concepts and a stepwise method. The ability of this AFP model to classify the three toxicity classes was validated after dividing the data set compounds into training and test sets, including 165 and 70 molecules, respectively. The experimental class was correctly predicted for 76% of the test-set compounds. Furthermore, the most toxic class, particularly important for real applications of the toxicity models, was correctly predicted in 86% of cases. Finally, a comparison between the results obtained by AFP and those obtained by other classic classification techniques showed that AFP improved the predictive power of the proposed models.

Algorithms↗
PubMed2001

Mode of action and tissue dosimetry in current and future risk assessments.

Two fundamental concepts have emerged to organize contemporary approaches to chemical risk assessment - mode of action and tissue dosimetry. Mode of action specifies the nature of the interactions between the chemical and the body that lead to toxic responses and should, under optimal circumstances, also specify the form of the tissue dose that leads to these effects. This paper highlights recent development of biologically based dose response (BBDR) models for specific toxic endpoints that use knowledge on mode of action to specify measures of dose. These dose measures then are used to support low dose and interspecies extrapolations. We first focus on a series of dose response models developed for several compounds that produce nasal toxicity. These examples demonstrate a range of model structures from simple dosimetry models (methylmethacrylate) to linkage of dosimetry with specific biological processes involved in carcinogenesis (formaldehyde). Two BBDR models with dioxin illustrate the organization of biological and dosimetry information into specific testable hypotheses that could distinguish these different models and lead to a more uniform approach to risk assessment for this compound. A final section discusses the impact of molecular biology and the genomic revolution in relation to development of BBDR models for specific toxic endpoints.

Animals↗
PubMed1997

A transgenic mouse model for the detection of cellular stress induced by toxic inorganic compounds.

Transgenic mice for genotoxicity testing have been developed, although no such models have been produced for the evaluation of toxic, nongenotoxic chemical compounds. We have developed a transgenic mouse model for the analysis of toxic inorganic compounds. We engineered a mouse lineage with the human growth hormone (hGH) gene under the control of the human hsp70 promoter, in which a plasma-detectable hGH response can be elicited by exposure to heat shock. In primary cell cultures from these mice, hGH release was observed following treatment with several toxic inorganics. Transgenic mice injected intraperitoneally with sodium arsenite, cadmium chloride, copper sulphate, or methylmercurium chloride showed significant hGH levels in plasma.

Animals↗