Toxicity in Animals and Man

Rapid venous injection of potassium into the blood stream or intramminal infusion with some form of potassium is extremely toxic because of the rapid absorption. Pigs can tolerate up to 10-fold the potassium requirement, if plenty of drinking water is provided (Faries 1958). 

The human body has a limited capacity to increase body stores of potassium. The major causes of hyperkalemia are excess potassium intake and mixed doses of potassium and sodium electrolyte solutions (Mahfoud et al. 2003), reduced renal losses (acute renal failure, end-stage renal disease, mineralocorticoid deficiency, potassiumsparing diuretics) and redistributions of potassium (hemolyses, necrosis, muscle injury, catecholamine antagonists, insulin deficiency, abnormal skeletal muscle sodium channels) (Peterson 1997). Increased intake by itself is rarely the sole cause of significant hyperkalemia. However, sustained hyperkalemia usually indicates an underlying defect in renal potassium excretion or impaired potassium distribution (KCl supplements or salt substitutes). The 

The genetic defect knoivn as hyperkalemic periodic familial paralysis causes skeletal paralysis and hyperkalemia. In this disease, only one of the sodium channels is abnormal, and it has been suggested that a disease in ivhich all the sodium channels were affected would be nonviable (Peterson 1997). 

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Albertini, S.S.-D.L., Ruepp, S. andWeiser, T. (2004) Toxicogenomics How predictive is toxicogenomics for toxicity in animal and man 7th International Society forthe Study ofXenobiotics Meeting, Vancouver. 

Jenkins, M. Y., 1978, Effect of nutrient toxicities (excess) in animals and man vitamin A, "Effect of Nutrient Excesses and Toxicities in Animals and Man," M. Rechcigl, Jr., ed.,... 

Botham, RA. et al., Skin sensitization—a critical review of predictive test methods in animals and man, Fd. Chem. Toxic., 29, 275, 1991. 

The present volume of the series Methods and Principles in Medicinal Chemistry focuses on the impact of pharmacokinetics and metabolism in Drug Design. Pharmacokinetics is the study of the kinetics of absorption, distribution, metabolism, and excretion of drugs and their pharmacologic, therapeutic, or toxic response in animals and man. 

The rates of toxication or detoxication of drugs and xeno-biotics in animals and man are known to be influenced by age, sex, species, strain, disease and diet. One research report lists 10 factors (3a). It appears that for man, diet is most varied and therefore most complex as a variable in ascertaining its role in either enhancing toxicity or reducing untoward effects of therapeutic drugs or environmental chemicals. 

NagaoT, Golor G, Krowke R, Neubert D (1990), Organohalogen Compounds 1 317-319. Com-parison of cleft palate frequency induced by 2,3,7,8-tetrabromodibenzo-p-dioxin and 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice, Eco-Informa Press, Bayreuth Neubert D (1991), Chemosphere 23 1869-1893. Pecularities of the toxicity of polyhalogenated dibenzo-p-dioxins and dibenzofurans in animals and man ... 

Neubert D (1991), Chemosphere 25 1869-1893.. .Peculiarities of the toxicity of polyhalogenated dibenzo-p-dioxins and dibenzofurans in animal and man"... 

Intravenous vidarabine is effective in the treatment of kerato-uveitis in animals and man, and has been used intravenously to treat herpetic eye infections in man (1). It has also been used as an ointment for treating superficial keratitis that does not respond to idoxuridine, but it penetrates the eye poorly (2). It is no longer used because of unacceptable toxicity and inferior activity compared with newer drugs for Herpes simplex and Varicella zoster. Its rapid inactivation and poor solubihty are practical disadvantages. 

There are no apparent species differences in nicotine toxicity between animals and man. The toxic sequelae following chronic nicotine exposure to animals is similar to that in man including GI problems, cardiovascular effects, changes in neurochemistry, and reproductive effects such as decreased birth weight and length of gestation. 

Dr. Louis Friedman (U. S. Vitamin) In reference to Dr. McMahons report on the molecular modification in sulfonylureas, I think mention should be made of similar work in modification of biguanide, which, as you know, forms another clinical compound of utility in the treatment of diabetes. It is interesting to note, in commenting on the question of toxicity in man and animals, that Taubman and his associates in 1919 found that lower alkyl biguanides were too toxic in animals and recommended that they not be used in man. 

Aflatoxins have no beneficial uses for man — their importance lies in their economic and medical significance in terms of spoilage of foodstuffs and toxicity to animals and man. 

The many mineral interactions which influence the safe dietary levels of essential and toxic elements are partly represented in Figure 3.2. While interactions involving dietary elements may be either detrimental or beneficial, the major concern is that an antagonistic element may induce a deficiency of its counterpart nutrient whose concentration in the diet is borderline. The assessment of such in-vivo interactions will be considered here under the limits of bioavailability, which occurs at the site of absorption in the intestinal mucosa or the redistribution from one tissue to another one. Figure 3.2 illustrates the most important, quite different, species-specific interactions of metals, trace and macro elements, respectively, with net requirements in animals and man. Clearly, there are interrelationships in the metabolism of the mineral elements consumed. 

For nongenotoxic chemicals, risk assessment is based on the concept of threshold doses, below which no adverse effect results from exposure. From human or experimental animal data, one tries to establish the no observable adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL). In order to establish safe levels of exposure to potentially toxic agents, the NOAEL is divided by a safety factor (often named uncertainty factor). When the risk assessment is based on data from experimental animals, a default safety factor of 100 is usually applied. The safety factor constitutes a factor of 10 for potential differences in susceptibility between animals and man, and another factor of 10 for interindividual differences among humans. The factors are combinations of differences in toxicokinetics and toxicodynamics, both in animals and man. If true factors are known, the size of the safety factor may be changed accordingly. When risk assessment is based on human data, a safety factor of 10 is applied in most cases, for instance, for food additives. However, for natural toxins in food, smaller factors are usually applied. This is a risk management decision, often based on information on the absence of adverse health effects at intake levels close to the estimated LOAELs. 

Trlfluorothymidlne (F3T) has been found to be less toxic to corneal epithelium, in animals and man than are lUDR and cytosine arablnoside (Ara-C). The vitro and vivo spectrum of anti-DNA virus activity and the marked solubility in aqueous solution represent desirable properties. In a clinical trial comparing F3T and lUDR in HSV keratitis in man,58 there was more rapid healing in the F3T group than in the lUDR group, with a 1.5% versus a 39% failure rate, respectively. 

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