Toxic Dose

In the aforementioned example, relief from pain was the desired response, which is often termed the beneficial effect. As dosages of the drug continue to be increased, however, adverse or toxic effects may become apparent. To continue the earlier example, higher doses of the same medication may be associated 

FIGURE 1-4 Cumulative dose-response curve. The median effective dose CED5tl) is 10 mg, and the median toxic dose (TD50] is 320 mg. The therapeutic index (Tf) for this drug is 32. 

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Infants maybe sensitive to doses of vitamin A [11103-57-4] in the range of 75,000—200,000 lU (22.5—60 mg), although the toxic dose in adults is probably 2—5 million lU (90.6—1.5 g). Intakes in this range from normal food suppHes without oral supplements are simply beyond imagination (79). Vitamin D [1406-16-2] toxicity is much more difficult to substantiate clinically. Humans can synthesize active forms of the vitamin in the skin upon irradiation of 7-dehydrocholesterol. Toxic symptoms are relatively nonspecific, and dangerous doses seem to He in the range of 1000—3000 lU/kg body wt (25—75 flg/kg body wt) (80). Cases of toxicity of both vitamins E and K have been reported, but under ordinary circumstances these vitamins are considered relatively innocuous (81). 

The lowest dose reported to produce any toxic effect (toxic dose low). 

Health, Safety, and Environmental Factors. Sulfur dioxide has only a moderate acute toxicity (183). The lowest pubHshed human lethal concentration is 1000 ppm for 10 months. The lowest pubHshed human toxic concentration by inhalation is 3 ppm for 5 days or 12 ppm for 1 hour. The lowest pubHshed human lethal concentration is 3000 ppm for 5 months. In solution (as sulfurous acid), the lowest pubHshed toxic dose is 500 flg/kg causing gastrointestinal disturbances. Considerable data is available by other modes of exposure and to other species NIOSH standards are a time-weighted average of 2 ppm and a short-term exposure limit of 5 ppm (183). 

Health nd SMety Factors. The lowest pubhshed human oral toxic dose is 430 mg/kg, causing nervous system disturbances and gastrointestinal symptoms. The LD q (rat, oral) is 750 mg/kg (183). Thiocyanates are destroyed readily by soil bacteria and by biological treatment systems in which the organisms become acclimatized to thiocyanate. Pyrolysis products and combustion products can include toxic hydrogen cyanide, hydrogen sulfide, sulfur oxides, and nitrogen oxides. 

Manufacture, Shipment, and Analysis. In the United States, sodium and potassium thiocyanates are made by adding caustic soda or potash to ammonium thiocyanate, followed by evaporation of the ammonia and water. The products are sold either as 50—55 wt % aqueous solutions, in the case of sodium thiocyanate, or as the crystalline soHds with one grade containing 5 wt % water and a higher assay grade containing a maximum of 2 wt % water. In Europe, the thiocyanates may be made by direct sulfurization of the corresponding cyanide. The acute LD q (rat, oral) of sodium thiocyanate is 764 mg/kg, accompanied by convulsions and respiratory failure LD q (mouse, oral) is 362 mg/kg. The lowest pubhshed toxic dose for potassium thiocyanate is 80—428 mg/kg, with hallucinations, convulsions, or muscular weakness. The acute LD q (rat, oral) for potassium thiocyanate is 854 mg/kg, with convulsions and respiratory failure. 

The acute toxicities of various sulfates have been reported (126). Generally, dimethyl sulfate (LD q 440 mg/kg in rats) is more toxic than diethyl sulfate (LD q 880—1412 mg/kg in rats), which is more toxic than dibutyl sulfate (lowest observed toxic dose, 9500 mg/kg in rats). Ethylene sulfate is more toxic than dimethyl sulfate (40). 

The threshold of a toxic dose in adult humans is about 0.2—0.5 g Ba the lethal dose in untreated cases is 3—4 g Ba, LD q about 66 mg/kg (47). The fatal dose of barium chloride for humans is reported to be between 0.8 and 0.9 g (0.55—0.60 g of Ba) (50). However, for most of the acid-soluble salts of barium, doses greater than 1 g have been tolerated (51). Lethal doses are summarized in Table 5. Dusts of barium oxide are considered potential dermal and nasal irritants (52). 

Value is toxic dose low. TD q, the lowest dose of a substance introduced by any route other than inhalation, over any given period of time to which humans or animals have been exposed and reported to produce any nonsignificant toxic effect in humans or to produce nonsignificant tiimorigenic or reproductive effects in animals or humans. 

Calcium chloride is found in the marine environment. The elemental composition of seawater is 400 ppm calcium, 18,900 ppm chlorine, and many organisms and aquatic species are tolerant of these concentrations. Toxicity arises either from the invasion of freshwater in otherwise saltwater environments or possible toxic doses of calcium chloride from spills, surface mnoff, or underground percolation into typically freshwater streams or aquifers. Various agencies have guidelines for calcium and chloride in potable water (41). The European Economic Community (EEC) is the only agency to have a minimum specification for calcium in softened water. 

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). 

Hazard characterization, or dose-response characterization, by using experimental animals to reveal target organs and toxic doses, and the shape of the dose-response curve... 

According to Powell and Chen, gramine, used as the unstable hydrochloride, m.p. 191° (dec.), raises the blood pressure in anaesthetised cats in Small doses, but lowers it in doses of 30 to 40 mgm. per kilo., with a secondary rise. It reduces the chief effects of adrenaline without reversal. The toxic dose for rats is about 63 mgm./kilo. Supniewski and Serafinowna state that gramine excites the central nervous system in mammals, but in large doses causes paralysis. At 1 in 25,000 it causes contraction of the isolated uterus. 

Depending on the dose and temperature regime, the screening effect azomopine is observed after intoxication by chlorophos. The survival of white rats injected with this preparation is 50% higher than that of control rats. When toxic doses of copper sulfate were injected for 7 days, 70 and 36% of the rats survived. After the simultaneous injection of azomopine, their survival increased to 100 and 70% (74MI1). 

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)... 

Because the minimal lethal or toxic dose of LSD is not well established, assessment ofseverity of intoxication should always be made on clinical grounds. The... 

Trihexyphenidyl (Artane) and benztropine (Cogentin) are prescription drugs used in the treatment both of Parkinson s disease and the extrapyramidal side effects produced by neuroleptic medication. They are occasionally abused for their mind-altering properties, which occur at toxic doses (Perry et al. 1978). Abusers often try to obtain these drugs by false representation of extrapyramidal symptoms, which are claimed to result from the use of phenothi-azines or other neuroleptics (Rubinstein 1978). 

Merkord J, Weber H, Kroning G, Henningshausen G (2001) Repeated administration of a mild acute toxic dose of di-n-butyltin dichioride at intervals of 3 weeks induces severe lesions in pancreas and liver of rats. Human and Experimental Toxicology, 20(8) 386-392. 

The LC50 values of methyl parathion have been established in rats. A 1-hour LC50 of 200 mg/m and a 4-hour LC50 of 120 mg/m for males were determined by Kimmerle and Lorke (1968). One-hour LC50 values of 257 mg/m for male rats and 287 mg/m for female rats were determined for 70-80% pure methyl parathion by EPA (1978e) the rats were exposed to aerosols of respirable size. Survivors of toxic doses recovered clinically by 10-14 days postexposure. Sex-related differences in acute mortality of rodents have also been observed after exposure to methyl parathion by other routes (Murphy and Dubois 1958). 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

TD50 toxic dose, 50% specific toxic effect... 

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