Limit doses

Toxicity. Sugar alcohols are classified as relatively harmless. Acute oral toxicity values in mice for mannitol and sorbitol (5) are given in Table 4. The acute oral LD q value for xyUtol in mice is 25.7 g/kg (205). Ingestion of 10 g/d of either mannitol or sorbitol by a normal human subject for one month resulted in no untoward effects (206). XyUtol given to healthy humans for 21 d in increasing doses up to 75 g/d produced no adverse effects (207). The limiting dose of xyUtol for production of diarrhea in humans is 20—30 g (4), but tolerance usually develops on continued adrninistration (207). 

S1 C(R1) Dose Selection for Carcinogenicity Studies of Pharmaceuticals Limit Dose S2A Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals S2B Genotoxicity A Standard Battery for Genotoxicity Testing of Pharmaceuticals Toxicokinetics and Pharmacokinetics... 

Kumar D, Khan PK, Sinha SP. 1995. Cytogenetic toxicity and no-effect limit dose of pesticides. Food Chem Toxicol 33 309-314. 

Items marked with an asterisk may not be exclusions for mechanical thrombolysis with or without limited dose chemical agents. 

Electrophysiological changes take place in the human heart even under the influence of limited doses of caffeine. 

Reactor Tested HCHO (mg/L) Limiting Dose (mg HCHO/L) Formaldehyde Removal Efficiency (%) Reference... 

Limit dose to 4 tablets/day and usage to 2 days/week Maximum of 6 capsules/day and 20 capsule month... 

D-Phenothrin (I) Not likely to be carcinogenic to humans. Rat liver tumors occurred only at excessively toxic doses (limit dose) and mouse hepatocellular adenomas, which are common, did not achieve statistical significance (p < 0.01). Additionally, acceptable mutagenicity studies were negative for mutagenic potential [97] No tumorigenicity was observed [11]. 

SICa Guidance on Dose Selection for Carcinogenicity Studies of Pharmaceuticals Addendum on a Limit Dose and Related Notes Availability Notice Dec 97... 

Primates offer all of the possible dosing routes available in humans, but body size often limits dosing volumes. If volumes for subcutaneous or intramuscular injections exceed those suggested above, enzyme elevations [particularly alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] are frequently observed (unpublished results). Continuous infusion techniques in alert animals are available in some laboratories either through use of programmable backpack pumps or jacket-and-tether systems (Perkin and Stejskal, 1994). 

Dose selection for carcinogenicity stndies of pharmaceuticals limit dose... 

The high dose level should ideally induce a slight degree of maternal or developmental toxicity. Mortality should be avoided, and certainly should not exceed 10%. For nontoxic additives, a limit dose of 1,000 mg/kg/day or of 5% diet concentration may be applied, provided that these allow a sufficient margin of safety with respect to the anticipated human exposure. Otherwise, the maximum feasible dose may be limited by the physical properties of the test substance (e.g., maximum solubility in drinking water). 

Plasma brain natriuretic peptide concentrations, plasma aldosterone, heart failure hemodynamic measurements, clinical symptoms of heart failure, routine blood chemistries, blood pressure for hypotension and pulse rate for abnormalities (hypotension is dose-limiting/dose-dependent)... 

In most situations, only a small fraction of events traversing the cell is causative. For instance, only one 1 of 6000 electrons traversing a cell nucleus will produce a lethal lesion [32]. A possibly more meaningful definition of low dose ( biological low dose) can be made in terms of these causative events (hits) by asking that the contribution of the quadratic term in dose be less than a certain fraction, say 10%, of the total effect. Let A be this limiting dose. By definition ... 

Dicyclomine (Bentyl) [Anrimuscarinic, GI Anrispasmodic/ Anticholinergic] Uses Functional IBS Action Smooth-muscle relaxant Dose Adults. 20 mg PO qid T to 160 mg/d max or 20 mg EM q6h, 80 mg/d - qid then T to 160 mg/d, max 2 wk Feds. Infants >6 mo 5mg/dose tid-qid Children 10 mg/dose tid-qid Caution [B, -] Contra Infants <6 mo, NAG, MyG, severe UC, BOO Disp Caps, tabs, syrup, inj SE Anticholinergic SEs may limit dose Interactions T Anticholinergic effects W/ anticholinergics, antihistamines, amantadine, MAOIs, TCAs, phenothiazides T effects OF atenolol, digoxin X effects H7 antacids X effects OF haloperidol, ketoconazole, levodopa, phenothiazines EMS Avoid procainamide usage, may T adverse effects may T effects of digoxin, monitor... 

HPhe Fricke dosimeter (ferrous sulfate solutions) has been used to measure A the radiation intensity of various types of ionizing radiation sources since its development by Fricke and Morse in 1927 (2). It is widely accepted because it yields accurate and reproducible results with a minimum of care. This system meets many of the requirements specified for an ideal dosimeter (5, 9) however, it has a limited dose range, and for our applications it has been necessary to develop a dosimeter covering larger doses. Of the systems reviewed (6, 7), two (ferrous sulfate-cupric sulfate and ceric sulfate) showed the most promise for use with the radiation sources at the U. S. Army Natick Laboratories (8). Of these, the ferrous-cupric system has received the most use, and this paper describes our experience in using this system and suggests procedures by which it may be used by others with equal success. 

Norvir (ritonavir, ABT-538) by Abbott (Kalamazoo/MI, USA) in phase II demonstrated a 100-fold reduction of viral count, more than Crixivan and AZT. The threefold enhancement of CD4-T cell count after 12 weeks is also an improvement over AZT. However, even ABT-538 develops resistances, albeit more slowly than Crixivan. Hepatic side effects limit doses to 600 mg twice daily. Ritonavir has high oral bioavailability, about 78% in rats, good solubility (5.3 g IT1 (pH 7.4) to 6.9 g L-1 (pH 4.0)), and a plasma half-life of 1.2 h (Kempf, 1995). The molecule is difficult to produce in phase II, the overall yield in production was 2% ( ) in addition, the product was cherry-red. The combination of ritonavir and saquinavir has also been reported to dramatically increase saquinavir plasma concentrations (by as much as 50-fold). Ritonavir is believed to act by inhibiting cytochrome P450 (CYP 3A4), the enzyme responsible for saquinavir first-pass metabolism. 

Risk Index for Multiple Substances That Cause Deterministic Responses. The risk index for mixtures of substances that cause deterministic responses should be expressed in terms of dose, rather than risk, because risk is not proportional to dose and the goal of risk management is to limit doses to less than the threshold in the dose-response relationship (see discussion of Equation 6.2 in Section 6.3). As noted previously, deterministic responses from exposure to radionuclides should not be of concern in classifying waste, in which case only the risk index for chemicals that induce deterministic responses needs to be considered. 

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