High Doses

A chief criterion for the selection of a correct hypothesis... seems to be the criterion of beauty, simplicity, 

FIGURE 6.12.3 Nutrients can also be toxic in large amounts. (From Russell, E.W., Soil Conditions and Plant Growth, John Wiley Sons, New York, 1961. With permission.) 

An example of a stimulant that is also a toxicant is the pesticide strychnine. This alkaloid works by neutralizing glycine, an amino acid responsible for transmitting inhibitory nerve impulses to muscles. Without inhibition, the muscles contract but do not relax. Skeletal muscles become hyperexcited and contract continuously. Limbs become stiff and respiration stops. Animals poisoned with strychnine suffocate and die. This poison is toxic to fish, insects, mammals, and birds. 

Some chemicals in the environment act as estrogen mimics they have effects similar to the female hormone estrogen when animals at many different levels are exposed to them. These effects include the promotion of certain types of cancers, sexual dysfunctions, genital defects, obesity, attention-deficit disorders, and the reduction of male secondary sexual characteristics (Hinterthuer, 2008). 

Bisphenol-A is frequently used in certain types of plastics and is one of these estrogen mimics. But, unlike more conventional toxics, hormones, and hormone mimics, are sometimes not more toxic at higher doses. The body s response to high doses of hormones is sometimes to stop responding. 

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Therefore it is reasonable to prepare already the data acquisition for a three dimensional evaluation in cone-beam-technique by means of two-dimensional detectors. The system is already prepared to integrate a second detector- system for this purpose. An array of up to four flat panel detectors is foreseen. The detector- elements are based on amorphous silicon. Because of the high photon energy and the high dose rates special attention was necessary to protect the read-out electronics. Details of the detector arrangement and the software for reconstruction, visualisation and comparison between the CT results and CAD data are part of a separate paper during this conference [2]. 

Measurements of ozone (O3) concentrations in the atmosphere are of particular importance. Ozone absorbs strongly in the ultraviolet region and it is this absorption which protects us from a dangerously high dose of ultraviolet radiation from the sun. The vitally important ozone layer lies in the stratosphere and is typically about 10 km thick with a maximum concentration about 25 km above the surface of the earth. Extreme depletion of ozone in a localised part of the atmosphere creates what is known as an ozone hole. 

Magnesia and aluminum suspension is useflil for the therapy of duodenal ulcers when given at high doses at frequent intervals. It is available in both hquid and tablet formulations. 

Hydraziae is toxic and readily absorbed by oral, dermal, or inhalation routes of exposure. Contact with hydraziae irritates the skin, eyes, and respiratory tract. Liquid splashed iato the eyes may cause permanent damage to the cornea. At high doses it can cause convulsions, but even low doses may result ia ceatral aervous system depressioa. Death from acute exposure results from coavulsioas, respiratory arrest, and cardiovascular coUapse. Repeated exposure may affect the lungs, Hver, and kidneys. Of the hydraziae derivatives studied, 1,1-dimethylhydrazine (UDMH) appears to be the least hepatotoxic monomethyl-hydrazine (MMH) seems to be more toxic to the kidneys. Evidence is limited as to the effect of hydraziae oa reproductioa and/or development however, animal studies demonstrate that only doses that produce toxicity ia pregaant rats result ia embryotoxicity (164). 

In experimental animals and in vitro, DHBs show a variety of biological effects including binding of metaboHtes to various proteins. Clastogenic effects have been observed in vitro and in some in vivo studies with the three compounds. No reproductive effects have been shown by conventional studies with either hydroquinone, catechol, or resorcinol (122). Hydroquinone has been shown to induce nephrotoxicity and kidney tumors at very high doses in some strains of rat (123) catechol induces glandular stomach tumors at very high dose (124). Repeated dermal appHcation of resorcinol did not induce cancer formation (125). 

Lead is toxic to the kidney, cardiovascular system, developiag red blood cells, and the nervous system. The toxicity of lead to the kidney is manifested by chronic nephropathy and appears to result from long-term, relatively high dose exposure to lead. It appears that the toxicity of lead to the kidney results from effects on the cells lining the proximal tubules. Lead inhibits the metaboHc activation of vitamin D in these cells, and induces the formation of dense lead—protein complexes, causing a progressive destmction of the proximal tubules (13). Lead has been impHcated in causing hypertension as a result of a direct action on vascular smooth muscle as well as the toxic effects on the kidneys (12,13). 

The accident at the Three Mile Island (TMI) plant in Pennsylvania in 1979 led to many safety and environmental improvements (4—6). No harm from radiation resulted to TMI workers, to the pubHc, or to the environment (7,8), although the accident caused the loss of a 2 x 10 investment. The accident at the Chernobyl plant in the Ukraine in 1986, on the other hand, caused the deaths of 31 workers from high doses of radiation, increased the chance of cancer later in life for thousands of people, and led to radioactive contamination of large areas. This latter accident was unique to Soviet-sponsored nuclear power. The Soviet-designed Chemobyl-type reactors did not have the intrinsic protection against a mnaway power excursion that is requited in the test of the world, not was there a containment building (9—11). 

Health and Safety Factors. Terephthahc acid has a low order of toxicity. Inhalation by rats for 6 h/d, 5 d/wk for 4 wk produced no fatahties at a dust exposure level of 25 mg/m. The mean acute oral toxicity for rats is over 18 g/kg (86), and for mice over 6 g/kg (87). When terephthahc acid was fed as 3% of the diet to rats, urinary calcuh formed in 90 d, some of which led to cancer. High doses of terephthahc acid lead to formation of calcium terephthalate at levels exceeding its solubihty in urine. This insoluble material leads to the calcuh and provides a threshold below which cancer is not observed (88). Normal precautions used in handling industrial chemicals should be observed with terephthahc acid. If ventilation is inadequate, a toxic-dust respirator should be used to avoid prolonged exposure. 

The demonstration that injected or force-fed neonatal rodents given extremely high doses of MSG showed evidence of brain lesions, has led to much additional research to determine any possible link between neurotoxicity and human use of MSG (33). However, no evidence from animal tests indicates that MSG in the diet causes brain damage in humans (34). 

Opioids. Morphine [57-27-2] C yH NO, (8) the most prevalent and analgesicaHy potent of the naturally occurring opium alkaloids (qv), has been used as an anesthetic premedication for over one hundred years (93). It has also been used as an iv analgesic for the last four decades, and, since 1969, in high doses as an anesthetic agent (117). 

In contrast to these protective effects, acute high dose (25 mg/kg) INDO injected ip 30 min prior to y-irradiation decreases the LD q of mice from... 

In 1969, a chronic toxicity study on a cyclamate saccharin (10 1) blend indicated bladder cancer problems in rats. Cyclamate was soon banned by the FDA, but saccharin remained an approved sweetener. In 1977, the FDA proposed a ban on saccharin because of the discovery of bladder tumors in some male rats fed with high doses of saccharin. Because no other nonnutritive sweetener was available at that time, the proposed ban faced strong opposition. 

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