End-organ toxicities

The usual GLP 30- or 60-day repeat-dose toxicology study with a recovery group offers an opportunity to perform a more systematic investigation of the more subtle pharmacodynamic or toxicologic effects of biopharmaceuticals than those endpoints usually incorporated into such protocols. Some of these demand tissue samples, but many involve noninvasive biomarkers that can be carried forward into early phase human studies. These might include CNS assessments, inflammation and immune activation or suppression, cell proliferation or apoptosis in tissue samples, and end-organ toxicities. 

The most common adverse effects of infliximab are headaches, fever, chills, fatigue, diarrhea, pharyngitis, upper respiratory and urinary tract infections, and hypersensitivity reactions (urticaria, dyspnea, and hypotension). Infliximab has been also associated with infections and lymphoproliferative disorders. It is not associated with end-organ toxicity, and blood counts, liver enzyme levels, kidney function, and complement values can be expected to remain normal during treatment. This gives it a major advantage over other systemic psoriasis treatments. 

The individual unit of the nervous system is the neuron, a specialized cell that both receives and transmits information. The nervous system contains more than 100 billion neurons and is a major user of metabolic energy in the human body. It is also a region particularly susceptible to injury from toxic chemicals, lack of oxygen, and other assaults. Depending on the nervous region in which they reside, neurons may have different anatomical features and may use different chemical transmitters. Neurons communicate with each other and with their end organs by these chemical signals, which are released from the nerve terminal and interact with specific receptors on adjacent neurons or cells. 

Effluent Guidelines and Standards Electroplating--Definition of Total Toxic Organic Toxic Pollutant Effluent Limitation and Standards for Direct Discharge Point Sources That Use End-of-pipe >10 ng/L 40 CFR 413.02 EPA 1981 40 CFR 414.91 EPA 1987a... 

The extent and duration of drug exposure can also predispose to toxicity. This is particularly true for patients with end-organ dysfunction. An estimated... 

Azinphos-methyl requires bioactivation for its action. The parent compound is activated to the potent oxon by microsomal mixed-function oxidase enzymes, which in turn elicits toxicity by inhibiting acetylcholinesterase in synapse and neuromuscular junctions. AChE inhibition leads to overstimulation of cholinergic receptors on postsynaptic neurons, muscle cells, and/or end-organs and consequent signs and symptoms of cholinergic toxicity. 

Experience with acute toxicity is limited. A minimum toxic dose is not defined. Headache, dizziness, hypotension, tachycardia, sodium and water retention, and cardiac dysrhythmias may be seen following overdose. Severe hypotension may result in myocardial ischemia other end-organs may also be affected. 

The mechanism of toxicity for parathion is similar to that of chlorpyrifos. Following activation to the potent anticholinesterase paraoxon, acetylcholinesterase is inhibited within synapses and acetylcholine levels accumulate. This leads to overstimulation of cholinergic receptors of neurons, muscle cells, and end-organs culminating in cholinergic toxicity. 

Figure 3 A fiow chart depicting the various parameters or end points of toxicity to be monitored during the chronic study, both during and after treatment, as weii as those studied foiiowing euthanasia and necropsy. The routine, periodic assessment of chosen parameters may detect the onset of impending toxicity, proving invaiuabie for the detection of developing lesions and as predictors of target-organ toxicity.

Switch phenomenon. Switching refers to the changing of one end-organ response to another end-organ. For example, during a 24-h reaction the same toxic chemical exposure can start off as transient brain dysfunction and be followed by arthralgia, diarrhea, and then arrhythmia. 

Although CO2 is inhibitory to microbes, compressed hydrocarbon solvents may be appropriate for extractive bioconversions and extractions in biphasic (aqueous-compressed solvent) systems. Our laboratory investigated the metabolic activity of the anaerobic, thermophilic bacteria Clostridium ther-mocellum as a model system (45). Thermophilic bacteria have a distinct advantage over conventional yeasts for ethanol production in their ability to use a variety of inexpensive biomass feedstocks. Extractive fermentation using compressed solvents is an approach to address the end-product toxicity of these bacteria to ethanol and improve the economic viability of biofuel production by thermophilic organisms. 

IX. Specific Organ, Tissue, and Functional End-Point Toxicity.324... 

IX. SPECIFIC ORGAN, TISSUE, AND FUNCTIONAL END-POINT TOXICITY... 

Certain specific organ, tissue, and functional end-point toxic effects may be a direct consequence of CN exposure at the target site others are due to SCN metabohte exposure, and others are the result of pathophysiological consequences resulting from CN toxic effects. The more relevant of these for hazard assessment and clinical purposes are discussed briefly in the following sections. 

Ballantyne and Salem discuss the experimental and human clinical toxicology of cyanides with particular reference to their potential for apphcation as chemical warfare weapons and use by terrorists. They consider repeated exposure toxicity as well as specific organ, tissue, and functional end-point toxicity. Among the functional end-point toxicities, they review neurotoxicity, cardio-toxicity, vascular toxicity, developmental and reproductive toxicity, and genotoxicity. They conclude this review of the toxicology of cyanide by describing emergency first aid and poison-control... 

A nnmber of stndies have been reported on the repeated-dose toxicity of CR following dermal administration. Owens and co-workers studied the effects of CR following mnltiple dermal application in rabbits and monkeys. In the study by Marrs and co-workers, CR in acetone was applied to the skin of mice (5 days/wk for 12 wk). The animals were kept for an additional 80 weeks following the end of the application period. No abnormalities were noted that could be attributed to CR, but a high incidence of fatty infiltration of the liver was noted in one strain of mice, which was most likely due to acetone. These investigators concluded that the repeated dermal application of CR had little effect on the skin. They further postulated that in view of the absence of any specific organ toxicity, absorption of even substantial amounts of CR would have little effect. 

Tobramycin, like other aminoglycosides, causes both nephrotoxicity and ototoxicity. However, tobramycin may be less toxic to hair cells in the cochlear and vestibular end organs and cause less renal tubular damage than does gentamicin. 

Under anaerobic soil conditions, organic substrates are often not decomposed completely to carbon dioxide. Incompletely oxidized intermediates and end products toxic to plants often accumulate in waterlogged soils. These intermediates and end products include lactic acid, ethanol, acetaldehyde, and aliphatic acids such as formic, acetic, or butyric acid. Ethylene is also sometimes present in abnormally high concentrations in waterlogged or anaerobic soil. 

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