Duration adjustment

Approaches to duration adjustment are reviewed in Kimmel et al. (2006). Prior to derivation of NOAELs, LOAELs, or BMDs/ BMCs, the toxicity data are adjusted to a continuous exposure scenario. For oral studies, a daily exposure adjustment is made (e.g. a five days per week exposure is converted to seven days per week). For inhalation exposures, a concentration x time (c x t) adjustment is made. Traditionally, the inhalation exposure adjustment has not been done, because of concerns about peak versus integrated exposure and the likelihood of a threshold for effects. However, a review of the RfD and RfC processes by the USEPA recommended that inhalation developmental toxicity studies be adjusted in the same way as for other end-points (USEPA, 2002b). Derivation of a human equivalent concentration for inhalation exposures is intended to account for pharmacokinetic differences between humans and animals. 

Toxicokinetic data provide information on the absorption, metabolism, distribution (including placental transfer), and/or excretion (including via breast milk) of an agent. Chapter 3 (section 3.5) 

The exposure assessment characterizes the pathways, magnitude, frequency, and duration of human exposures from various sources. Chapter 5 provides an overview of these components and addresses the principles of exposure assessment in children. General principles of exposure assessment have been reviewed in a number of publications (USEPA, 1992a, 2005a IPCS, 1999a, 2000 Needham et al., 2005). This chapter will focus on the considerations that are important when applying the exposure data to a children s health risk assessment (see Box 2). 

---

Used to derive an acute-duration inhaiation Minimai Risk Levei (MRL) of 2 ppm for trichloroethylene 200 ppm duration-adjusted (7/24 hr) to 58.3 ppm, divided by an uncertainty factor of 30 (3 for use of a minimal LOAEL, 10 for human variability) = 1.9 ppm, rounded to 2 ppm. 

The inhalation RfC for naphthalene was 0.003 mg/m3, and this RfC was derived from a chronic (2-year) NTP inhalation study in mice using exposures of 0, 10, or 30 ppm (NTP, 1992). Groups of mice were exposed for 5 days a week and 6 hours a day. This study identified a LOAEL of 10 ppm. A dose-related incidence of chronic inflammation of the epithelium of the nasal passages and lungs was observed. This LOAEL concentration was normalized by adjusting for the 6-hour-per-day and 5-day-per-week exposure pattern. A LOAEL of 9.3 mg/m3 was obtained was derived by converting 10 ppm first to mg/m3 and then duration-adjusted levels for 6 h/day and 5 days/week for 103 weeks. An UP of 3000 was used, where 10 was for the interspecies (mice to humans) extrapolations, 10 for intraspecies variation in humans, 10 for using a LOAEL instead of a NOAEL, and 3 for database deficiencies. 

The oral RfD for naphthalene was 0.02 mg/kg/day, and a study by Battelle (1980) was used to calculate the RfD. Decreased body weight was the most sensitive end point in groups of Lischer 344 rats given 0, 25, 50, 100, 200, or 400 mg/kg for 5 days/week for 13 weeks. These doses were also duration-adjusted to 0, 17.9, 35.7, 71.4, 142.9, and 285.7 mg/kg/day, respectively. The NOAEL for a > 10% decrease in body weight in this study was 71 mg/kg/day. The UL of 3000 was based on 10 for rats to humans extrapolation, 10 for human variation, 10 to extrapolate from subchronic to chronic, and 3 for database deficiencies including lack of chronic oral exposure studies. 

Once an assessment has determined that the data indicate human risk potential for reproductive and developmental toxicity, the next step is to perform a quantitative evaluation. Dose-response data from human and experimental animal reproductive and developmental toxicity studies are reviewed to identify a no-observed-adverse-effect level (NOAEL) or a lowest-observed-adverse-effect level (LOAEL), and/or to derive a benchmark dose (BMD). Duration adjustments of the NOAEL, LOAEL, or BMD are often made, particularly for inhalation exposures when extrapolating to different exposure scenarios. Such adjustments have not been routinely applied to developmental toxicity data. The subcommittee recommends that duration adjustments be considered for both reproductive and developmental toxicity... 

The no-effect level from the NTP study has been used to calculate a safe oral dose for xylene in humans of 2 mgkg day This is 10 times higher than the oral reference dose published by the US EPA on its IRIS database, 0.2 mg kg day based on the rat no-observed-adverse-effect level of 250 mg kg day adjusted for duration of exposure and then divided by an uncertainty factor of 1000. The inhalation reference concentration for xylene is currently 0.1 mg m, derived from a duration adjusted rat lowest-observed adverse-effect level of 39mgm divided by an uncertainty factor of 300. 

The MRL was based on a NOAEL of 0.93 mg Hg/kg/day for renal effects in rats administered mercuric chloride 5 days a week for 2 weeks. The dose used in this study was duration-adjusted for a 5-day/week exposure and divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). Increased absolute and relative kidney weights were observed in male rats exposed to 1.9 mg Hg/kg/day as mercuric chloride (NTP 1993). At higher doses, an increased incidence and severity of tubular necrosis was observed. 

Questions such as the uses to which European bond futures can be put, contract specifications and trading volumes are discussed with illustrative examples. Technical issues, which surround the use of bond futures, are also examined and presented with numerical examples. The issues include the calculation of gross and net basis, identifying the cheapest-to-deliver (CTD) cash market bond, different approaches to measuring relative volatility, calculating hedge ratios, and portfolio duration adjustment. Bloomberg screen output is used to provide a real world flavour to the topics covered. 

The tested blade is flowed through either with hot or cold compressed air with a duration of max. 5 seconds The maximum heat temperature can be adjusted at 250 °C. 

Block 3 a device for management and synchronisation. Serves for adjusting the parameters of the system, gain factor, input impedance, amplitude and the duration of the initial pulse, as well as ensures a database communication for the further processing by the computer. 

Before creating a fault condition, to obtain the required /sc the impedance of the test circuit is adjusted so that the required fault current is obtained in all the phases on creating a short-circuit. To provide the required thermal effect (/sc /). the duration of test, /, is then adjusted accor-dingly. The relevant standards therefore stipulate that the test current may be higher or lower than required and can be compensated by adjusting its duration, i. 

However, due to the minor variations in the phase impedances, all the phases may not be subjected to identical severity of faults. For instance, in the above test each phase has recorded a different fault cunent. To evaluate the fault level from these test data, the general practice has been to consider the phase that has recorded the highest fault current as the base, which may occur in any of the phases. In the above test, it has occurred in phase Y. For this fault current, the test duration is adjusted to achieve the required severity of fault in terms of thermal effect (50 x 1 in the above case). 

Some users/consultants, however, are of the opinion that by this method the other phases are not subjected to the same severity. Accordingly, they prefer to consider the phase that is subjected to the least fault current as the base. Accordingly, the test duration should be adjusted for this phase. In the above case, the minimum severity has occurred in phase R, with only 39.6 kA. According to this philosophy the test duration should be enhanced to... 

In specifying the number of jacket zones and the aspect ratio for a full-scale reactor, there is a limitation on the temperature adjustment time. This implies that it must be of the same duration as experienced in the pilot plant reactor. Combining Equations 13-89 and 13-97 yields... 

There are several limitations to tliis approach that must be acknowledged. As mentioned earlier, tlie level of concern does not increase linearly as the reference dose is approached or exceeded because the RfDs do not luive equal accuracy or precision and are not based on the same severity of effects. Moreover, luizm-d quotients are combined for substances with RfDs based on critical effects of vaiy ing toxicological significance. Also, it will often be the case that RfDs of varying levels of confidence Uiat include different uncertainty adjustments and modifying factors will be combined (c.g., extrapolation from animals to hmnans, from LOAELs to NOAELs, or from one exposure duration to anoUier). 

If a carbonic anhydrase inhibitor is being given for absence or nonlocalized epileptic seizures, the nurse assesses the patient at frequent intervals for the occurrence of seizures, especially early in therapy and in patients known to experience seizures at frequent intervals. If a seizure does occur, the nurse records a description of the seizure in the patient s chart, including time of onset and duration. Accurate descriptions of the pattern and the number of seizures occurring each day helps the primary health care provider plan future therapy and adjust drug dosages as needed. 

From the contents of the teachers reflective diaries, the following differences in the lessons provided could be observed (1) Some teachers added extra exercises in knowledge consohdation, (2) some teachers left out particular activities, (3) some teachers adjusted the duration of particular sections (Fig. 13.2), (4) teachers used different motivational approaches to facilitate learning, e.g. students were rewarded with marks for their success in the Test of Gained Knowledge at the School N° 4. The duration of particular parts of the teaching plan is given in Fig. 13.2. 

The in vitro release profiles of many microsphere formulations including steroids can be determined by an ethanol/water model (74). By adjusting the ethanol/water ratio in the receiving fluid, the rate and duration of release can be optimized to afford a rapid evaluation tool for developmental and quality control purposes. The model is not intended to have one-to-one correlation with in vivo results. 

---