Dose and Timing

With a single exposure to a toxic chemical or chemical mixture, the severity of the exposure is determined by the total amount of the exposure (the dose). The higher the dose, the greater the potential for harm. At low levels of exposure, the body is able to metabolize and/or eliminate the chemical(s) at rates rapid enough to prevent serious toxic effects. If the dose is high enough, however, the body s ability to rid itself of the toxin is overwhelmed threshold levels of toxin(s) are reached and symptoms of toxic exposure are observed. The threshold levels vary from chemical to chemical and from single chemical to mixture exposures. 

When toxic exposures are repeated, the timing as well as the dosage of the exposures is critical. The metabolism and excretion of xenobiotics proceed at finite rates. Stated another way, time is needed for the body to rid itself of the absorbed chemical and its metabolites. Let us consider a situation where the first exposure is at a level that the body can readily metabolize and excrete. If a second toxic exposure to the same chemical at the same level occurs before the body has had sufficient time to cleanse itself, a toxic buildup will occur with the onset of symptoms. 

The effects observed from exposure to toxic chemicals can be quite different if a dose is administered all at once or slowly over time. Repeated dosing with low levels of toxic chemicals can be tolerated even if the total exposure exceeds the threshold value, provided there is sufficient time between doses for the body to rid itself of the toxins. 

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Educating the Patient and Family To ensure accurate compliance with tiie prescribed drug regimen, tiie nurse carefully explains tiie dose and time intervals to tiie patient or a family member. Because... 

Corticosteroids a chronic painless myopathy associated with the long-term use of corticosteroids is a particularly common example of drug-induced muscle disorder. It is almost certain that mild cases are overlooked because steroids are so frequently used to treat inflammatory myopathies such as polymyositis. Fluorinated steroids are particularly frequently implicated, and the incidence of drug-induced muscle disease is dose and time-related. The presence of muscle weakness can even complicate topical steroid therapy. Corticosteroid-induced myopathy is mediated via intramuscular cytosolic steroid receptors. The steroid-receptor complexes inhibit protein synthesis and interfere with oxidative phosphorylation. The myopathy is associated with vacuolar changes in muscle, and the accumulation of cytoplasmic glycogen and mitochondrial aggregations. 

Overall the results reported in this review indicate that water scarcity might increase metal exposure (due to low dilution), metal uptake (due to higher retention under low flow), and metal toxicity and/or accumulation (depending on the dose and time of exposure), but also might cause opposite effects depending on the source of pollution. In addition, water scarcity will influence nutrient loads and will also modulate the fate and effects of metals. Thus, future studies addressing the role of environmental stress on the effects of toxicants at community scale are key to predict the impact of toxicants in the aquatic ecosystems. 

IFN-)il exhibits dose- and time-dependent inhibition of HCV rephcation in various models, independently of type I and IIIFN receptors and induced pathways (Marcello et al. 2006). A pegylated form of IFN-A, will soon enter clinical evaluation. 

Moreover, some studies have demonstrated that glycolic acid could cause an increase in the level of skin damage in a dose- and time-dependent manner. Lower doses (1 and 3 mg/cm ) of glycolic acid caused erythema and eschar at most, whereas higher doses (5 and 7 mg/cm ) of glycolic acid caused redness, edema and necrotic ulceration. 

The effects of implementing these modifications are dose- and time-dependent and could be greater for some individuals. 

CMV IgG and polyvalent IVIG The maximum recommended total dosage per infusion is 150 mg/kg beginning within 72 hours of transplantation Follow-up doses and time intervals depend on the type or organ transplanted Stomach upset (1 -6%) Fevers and chills (1-6%) Flushing (1-6%)... 

The available animal data suggest that diisopropyl methylphosphonate is not a hepatotoxin, at least in the doses and time courses studied. Therefore, exposure of persons living near the RMA is not expected to cause hepatic effects. 

Schwab BW, Richardson RJ. 1986. Lymphocyte and brain neurotoxic esterase Dose and time dependence of inhibition in the hen examined with three organophosphorus esters. Toxicol Appl Pharmacol 83 1-9. 

Ke, L., Eisenhour, C., Bencherif, M., Lukas, R. Effects of chronic nicotine treatment on expression of diverse nicotinic acetylcholine receptor subtypes. I. Dose- and time-dependent effects of nicotine treatment. J. Pharmacol. Exp. Ther. 286 825, 1998. 

To date, three pharmaceutical companies have entered clinical trials with PHD inhibitors for the treatment of anemia with the most advanced being FG-2216. In clinical studies, compound 2 (likely FG-2216) showed a dose- and time-dependent elevation of plasma erythropoietin after oral administration [66]. Healthy volunteers were orally administered various doses of compound 2 and serum erythropoietin (EPO) concentrations were measured at various times. Compound 2 increased serum EPO levels in a dose-dependent manner and, following administration of the 20 mg/kg dose, a 5-fold increase of EPO levels was observed after 12 h. In the same patent application, the effect of 2 on anemic predialysis patients with no previous rh-EPO exposure was also disclosed. Patients were treated with 2 three times/week for 4 weeks (no dose reported) and the hemoglobin levels were assessed on day 42. The patients who received treatment showed a mean increase in hemoglobin of 1.9 g/dL from baseline values, whereas subjects who received placebo showed a mean decrease of 0.35 g/dL from baseline levels. These data suggest for the first time that an oral PHD inhibitor could be effective for the treatment of anemia. 

Exposed to 19, 32 or 51 mg/L for up to 96 h Dose- and time-dependent increase in blood glucose and lactic acid concentrations liver glycogen decreased at all nickel levels and muscle glycogen decreased at the two higher levels high nickel concentrations were associated with elevated erythrocyte number, hemoglobin, and hematocrit. Nickel accumulated in blood, liver, muscle, and especially in kidney 41... 

Fed diets containing 0.3-3.0 mg/kg ration for 1-6 months Dose-and time-dependent increase in chloracne weight loss death and histopathology of sebaceous glands, thymus, and gastric mucosa 3... 

Generic Name Common Trade Names Oral Sedating Dose (mg) Physical Dependence Daily Dose and Time Needed to Produce Dependence Time Before Onset of Withdrawal (hours) Peak Withdrawal Symptoms (days)0... 

Littlefield, N. A., Farmer, J. H., Gaylor, D. W. and Sheldon, W. G. (1979). Effects of dose and time in a long-term, low-dose carcinogenic study. In Innovations in Cancer Risk Assessment (EDOlStudy) (Staffa, J.A. and Mehlman, M.A. Eds.). Pathotox Publishers, Chicago, IL, pp. 17-34. 

TABLE 15.3. Drugs Withdrawn from the Market Due to Dose- and Time-Unrelated Toxicity Not Identified in Animal Experiments... 

Some design options are shown in Tables 20.4 through 20.8, while the implications for going with one or other in terms of subject numbers, number of clinic visits, highest first dose given to a subject, biggest increment in dose, and time to complete the study are given in Table 20.9. 

Specific health effects resulting from an acute dose appear only after the victim exceeds a dose threshold. That is, the health effect will not occur if doses are below the threshold. (Note that this is significantly different from the LNT model used to predict stochastic effects.) After reaching the acute dose threshold, a receptor can experience symptoms of radiation sickness, also called acute radiation syndrome. As shown in Table 3.2, the severity of the symptoms increases with dose, ranging from mild nausea starting around 25-35 rad (0.25-0.35 Gy) to death at doses that reach 300-400 rad (3-4 Gy). Table 3.2 shows that the range of health effects varies by both total dose and time after exposure. 

Degeneration or neutrophil infiltration in vivo were exhibited around CNTs examined throughout the experimental period. Different sizes of CNTs cause different cell reaction (Goh et al., 2003). For example, SWCNTs inhibit HEK293 cell proliferation, decrease cell adhesive ability in a dose- and time-dependent manner (Grunlan et al., 2004) as shown in Fig. 9.7 and Fig. 9.8. 

Group 1 Dose-related reactions Group 2 Non-dose-related reactions Group 3 Dose- and time-related reactions Group 4 Time-related reactions Group 5 Withdrawal reactions Group 6 Treatment failure. 

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