DOSE SPACING

For infants aged 7 to 11 months who have not been vaccinated, three doses of HbOC, PRP-OMP, and PRP-T should be given two doses, spaced 4 weeks apart, and then a booster dose at age 12 to 15 months (but at least 8 weeks since dose 2). For unvaccinated children aged 12 to 14 months, two doses should be given, with an interval of 2 months between them. In a child older than 15 months, a single dose of any of the four conjugate vaccines is indicated. 

Vermeire et al. (1999) pointed out that there is no scientific basis for any value of a default factor to account for uncertainty in the NOAEL, nor any distribution. The authors considered the use of LOAEL/NOAEL ratios to estimate a NOAEL from a LOAEL as questionable, since doses in toxicological tests are usually spaced at fixed intervals and the observed distribution of LOAEL/NOAEL ratios primarily reflects the historical frequency of use of various dose spacing. There is no guarantee whatsoever that extrapolation of a LOAEL with any factor will yield an estimate of the NOAEL. Therefore, this factor can only be assigned using expert judgment in which... 

ECETOC (2003) recommended that if an appropriate NOAEL is available, then no extrapolation and hence, no assessment factor is necessary. Where it is considered more appropriate to use the LOAEL, a default assessment factor of 3 was recommended however, the factor may need to be adjusted depending on the effects observed at the LOAEL and the slope of the dose-response curve. The BMD could be an alternative approach for defining or confirming a NOAEL depending on the data quality and dose spacing. 

In general, the use of LOAEL/NOAEL ratios to estimate a NOAEL from a LOAEL is questionable as these ratios reflect more the applied intervals between the dose levels in the studies (dose spacing, which is dependent on the study design), rather than the steepness of the dose-response relationship, i.e., the inherent toxicity. It has also been pointed out that there is no guarantee whatsoever that at one dose interval lower (extrapolation from a LOAEL to a NOAEL), the effect would be statistically nonsignificant. 

Three randomized clinical trials support the efficacy of bupropion in ADHD. The first used doses up to 6 mg/kg (98) the other two used doses of 100 to 300 mg per day in equally divided daily doses spaced at least 6 hours apart ( 99, 100). The concern with bupropion is its seizure risk, which requires that its daily dose stay below 450 mg per day in adults (i.e., approximately 6.5 mg/kg). Virtually no work has been done to determine the plasma concentrations of bupropion and its three active metabolites in children and adolescents. Hence, it is unknown whether a limit of 6.5 mg per kg is also appropriate for children. No data exist as to whether children are more or less sensitive to bupropion in terms of seizure risk at the same drug concentration. Also, little is known about pharmacokinetic drug-drug interactions that could reduce the clearance of bupropion. For these reasons, cautious dosing is advised when prescribing bupropion for children on other medications that can reduce oxidative drug metabolism (see Chapter 3 and Chapter 7 for more details). 

Ethylene—Dicarboxylic Acid Copolymers. Partial neutralization of copolymers containing carboxyls in pairs on adjacent carbons, eg, ethylene—maleic acid, has been described (11). Surprisingly, there is no increase in stiffness related to neutralization. Salts with divalent metal cations are not melt processible. The dose spacing of the paired carboxyl groups has resulted in ionic duster morphology which is distinct from that of the commercial ionomer family. 

Fig. 4.15 Cavity formation in siliconized silicon carbide, KX01. Cavities are always located at Si/SiC interfaces, most often between two dosely spaced SiC grains. As the cavities grew from the narrow space between the grains, they arrested on encountering a large pool of silicon. Applied tensile stress in vertical direction in the figure. From Hockey and Wiederhom.64...

Ultimately a derived no-effect level (DNEL) (in humans) or a predicted no-effect concentration (PNEC)20 (in ecosystems) is calculated for a substance, group of substances or chemical mixture. Assessment factors (AF) - sometimes referred to as uncertainty factors or safety factors - compensate for lack of data and assumptions resulting from dose spacing and other test model parameters (adapted from [124]) ... 

AFi accounts for variations between species AFii accounts for variations within the same specie AFd compensates for dose spacing... 

It is essential that a broad dose response relationship be established. The initial goal should be to estimate the threshold response. This typically is achieved by high-end dosing to establish frank effect and lowest observed effect levels. Subsequent experimentation should be designed to explore possible subthreshold responses with the threshold as part of the frame of reference. In order to study subthreshold responses it is advisable to explore a 1000-fold dose range below the threshold, with semi-log dose spacing. This would involve the use of at least six doses below the established threshold. 

Note 7—A dose-space reference electrode on a three electrode probe is assumed to be one that measures 5 X of solution resistance. 

Precaution Wear safety glasses with side shields nuisance dust mask if use causes dusting, and plastic or rubber gloves flamm. dust cone, as low as 0.017 oz/ft in air can bum, and if ignited in a dosed space, can incompat. with acids, bases and oxidizing agents... 

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