Dose level

At one time benzene was widely used as a solvent This use virtually disappeared when statistical studies revealed an increased incidence of leukemia among workers exposed to atmospheric levels of benzene as low as 1 ppm Toluene has replaced benzene as an inexpensive organic solvent because it has similar solvent properties but has not been determined to be carcinogenic m the cell systems and at the dose levels that benzene is... 

In laboratory tests, appHcation of DMAC to the skin of pregnant rats has caused fetal deaths when the dosages were close to the lethal dose level for the mother. Embryonal malformations have been observed at dose levels 20% of the lethal dose and higher. However, when male and female rats were exposed to mean DMAC concentrations of 31,101, and 291 ppm for 6 h per day over several weeks, no reproductive effects were observed (6). 

Polymers. Ion implantation of polymers has resulted in substantial increases of electrical conductivity (140), surface hardness (141), and surface texturing (142). A four to five order of magnitude increase in the conductivity of polymers after implantation with 2 MeV Ar ions at dose levels ranging from 10 -10 ions/cm has been observed (140). The hardness of polycarbonate was increased to that of steel (141) when using 1 MeV Ar at dose levels between 10 -10 ions/cm. Conductivity, oxidation, and chemical resistance were also improved. Improvements in the adhesion of metallizations to Kapton and Teflon after implantation with argon has been noted (142). 

Dietary Copper. Analytical data indicate that many diets contain less than the RDA for copper (109). Excessive copper has been reported to be fatal for oral dose levels of copper sulfate of 200 mg/kg body weight for a child and 50 mg/kg for adults. 

Insoluble Sulfur. In natural mbber compounds, insoluble sulfur is used for adhesion to brass-coated wire, a necessary component in steel-belted radial tires. The adhesion of mbber to the brass-plated steel cord during vulcanization improves with high sulfur levels ( 3.5%). Ordinary rhombic sulfur blooms at this dose level. Crystals of sulfur on the surface to be bonded destroy building tack and lead to premature failure of the tire. Rubber mixtures containing insoluble sulfur must be kept cool (<100°C) or the amorphous polymeric form converts to rhombic crystals. 

Subcutaneous injection of 100—750 mg/kg sulfolane at an ambient temperature of 10°C also caused a dose-dependent decrease in colonic temperature of rabbits. MetaboHc rate remained unchanged during the initial phase of the hypothermia for all dose groups but peripheral vasodilatation, as indicated by an increase in ear skin temperature, was seen at the higher dose levels (29). 

The LD q is calculated from data obtained by using small groups of animals and usually for only a few dose levels. Therefore, there is an uncertainty factor associated with the calculation. This can be defined by determining the 95% confidence limits for the particular levels of mortaUty of interest (Fig. 7). The 95% confidence limits give the dose range for which there is only a 5% chance that the LD q will be outside. 

Biotechnology. Particular attention must be paid to the detection of DNA in all finished biotechnology products because of the possibiUty that such DNA could be incorporated into the human genome and thus become a potential oncogene. The absence of DNA at the picogram-per-dose level should be demonstrated in order to assure the safety of biotechnology products (157). 

Two forms of lymphatic filariasis are found in India. The Bancroftian form is the most common and accounts for more than 90% of the disease whereas Bmgian filariasis accounts for the rest. In a study carried out in India (6) in 40 patients with Wuchereria Bancwfti filariasis treated with single oral doses, all of the dose levels chosen (25, 50, 100, and 200 mg/kg) were efficacious in clearing microfilariae from the blood of all patients treated. However, after three months some microfilaria recurred in the blood of most patients (Table 5). Further studies are planned and some are underway using different doses and regimens. Ivermectin still appears to hold promise as a new treatment for lymphatic filariasis. 

Vapors of both benzal chloride and benzotrichloride are strongly irritating and lacrimatory. Reported toxicides appear in Table 3. Also, for benzotnchlonde, the lowest pubflshed lethal dose (frog) is 2150 mg/kg (69) and the toxic dose level (inhalation rats) is 125 ppm/4 h (69). 

The second level of interaction, the intermediate-dose level, can result in measurable effects on forest ecosystems. These effects consist of a reduction in forest growth, change in forest species, and susceptibility to forest pests. Both laboratory investigations and field studies show SO2 to be an inhibitor of forest growth. When various saplings have been exposed to SO2 in the laboratory, they show reduction in growth compared with unexposed... 

Kulstad and Malmsten tested a number of derivatives of l,10-diaza-18-crown-6 (9) for toxicity in mice (intravenous). Compound 9 and the bis-N-2-hydroxyethyl,bis-N-2-carboxamidomethyl, and bis-N-2-carboxymethyl derivatives of 9 were tested and all were found to be toxic in the range of 5—50 mg/kg. At a dose level of 5 mg/kg of 9, the two mice tested were still alive after a week, but at a dose level of 25 mg/kg, the mice died in less than 24 h If these data could be translated directly to human beings, a 100 kg human would require something between 0.5—2.5 g of compound (i.v.) to produce a lethal effect. 

In risk characterization, step four, the human exposure situation is compared to the toxicity data from animal studies, and often a safety -margin approach is utilized. The safety margin is based on a knowledge of uncertainties and individual variation in sensitivity of animals and humans to the effects of chemical compounds. Usually one assumes that humans are more sensitive than experimental animals to the effects of chemicals. For this reason, a safety margin is often used. This margin contains two factors, differences in biotransformation within a species (human), usually 10, and differences in the sensitivity between species (e.g., rat vs. human), usually also 10. The safety factor which takes into consideration interindividual differences within the human population predominately indicates differences in biotransformation, but sensitivity to effects of chemicals is also taken into consideration (e.g., safety faaor of 4 for biotransformation and 2.5 for sensitivity 4 x 2.5 = 10). For example, if the lowest dose that does not cause any toxicity to rodents, rats, or mice, i.e., the no-ob-servable-adverse-effect level (NOAEL) is 100 mg/kg, this dose is divided by the safety factor of 100. The safe dose level for humans would be then 1 mg/kg. Occasionally, a NOAEL is not found, and one has to use the lowest-observable-adverse-effect level (LOAEL) in safety assessment. In this situation, often an additional un-... 

In recent years, developments in additives have been aimed at minimizing dose level, prolonging stabilizing... 

Clinical studies, available only for entacapone and tolcapone, support preclinical findings. A dose-dependent (100-800 mg) inhibition of the COMT activity of the erythrocytes can be seen after nitrocatechols. However, effective and sufficient dose levels of both entacapone and tolcapone, given concomitantly with L-dopa and DDC inhibitors to patients with Parkinson s disease, appear to be 100-200 mg. However, the treatment strategies of entacapone and tolcapone differ entacapone is a short-acting compound that is given with each dose of L-dopa, and COMT activity may even... 

Table IV shows the data on rigidity changes of the end-sealing compounds at two dose levels. Rigidity was determined by torsional braid analysis (5). These data indicate that the blend of cured and uncured isobutylene-isoprene copolymer was softened most by the irradiation treatment, the blend of polychloroprene and butadiene-styrene copolymer softened the least, and the blend of polychloroprene and the uncured isobutylene-isoprene copolymer was intermediate. Increasing the irradiation dose from 3-4 Mrad to 6-7.5 Mrad decreased the rigidity of the three end-sealing compounds. The irradiation temperature did not significantly influence rigidity.

Toxicity and Hazards. The odor cf ozone can be detected in concn as low as several parts per hundred million by vol (pphm). The threshold limit value (TLV) is O.lppmor 0.2mg/m3 its toxic dose level (TDL), 50% kill concn is 2ppm (Ref 6) Pure 100% liq ozone may be kept safely at 90°K (cooled by liq oxygen) for indefinite periods of time, but the smallest provocation, such as a spark or fast warming, even only up to bp (161°K), causes detonation. The evapn of liq ozone, for example, in the process of the prepn of pure gaseous ozone is, therefore, a dangerous procedure (Ref 3, p 224)... 

Pharmacokinetics concerns the fate of a dmg in the body at the approximate therapeutic dose range, while toxicokinetics assesses behaviour at the higher dose levels associated with toxic effects. The fate of a dmg is dictated by the rates of ... 

Most drugs can be expected to have potentially lethal effects, as their usefulness depends on their ability to infiuence physiological processes. However, the dose level at which toxic effects manifest should be significantly higher than those required to produce a pharmaceutical response, so that a good safety margin exists between therapeutic and toxic levels. 

The drug should be administered at three levels by the route proposed for humans. The high dose level should be set so as to have relevance in humans. For drugs that display significant toxic effects, this may be related to the maximally tolerated dose in the toxicity tests, for example, the dose causing less than 10% deviation in body weight versus controls. If there is little evidence of toxicity it may be more appropriate to base the dose level on a multiple (usually 25-fold) of the maximum therapeutic dosage recommended in humans. 

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