Dose-response relationships distribution

Ideal for studying the dose-response relationship for QT interval prolongation taking into account all the pharmacological properties of a compound The dog model is one of the most widely used anesthetized rabbits (especially female rabbits) have also been proposed for high sensitivity It provides complementary information with respect to in vitro tests (activity of metabolites, measurement of plasma drug concentrations, calculation of the volume of distribution) Possibility to induce experimental TdP... 

Further data on the effects of chronic inhalation exposure to 1,4-dichlorobenzene would be useful, especially because chronic exposures to 1,4-dichlorobenzene in the air, in the home, and the workplace are the main sources of human exposure to this chemical. Any further testing of the effects of chronic exposure to 1,4-dichlorobenzene via the oral route should probably be done at lower levels of 1,4-dichlorobenzene than those that have already been used in the NTP (1987) bioassay, and should focus on dose-response relationships involving the hepatic, renal, hematopoietic, central nervous system, and metabolic pathways. Data on the effects of chronic dermal exposure to 1,4-dichlorobenzene may be useful if dermal absorption and systemic distribution of 1,4-dichlorobenzene can be demonstrated from toxicokinetic studies, since chronic dermal exposure to 1,4-dichlorobenzene occurs as a result of bathing and showering in drinking water that contains low levels of this chemical in many U.S. communities. 

SSDs are being routinely used for the display and interpretation of effects data (Parkhurst et al. 1996 Posthuma et al. 2002). An SSD for atrazine (shown in Figure 7.3) displays the typical S-shaped curve associated with many chemical dose-response relationships. Each point on the curve represents an LC50 for a particular species exposed to atrazine under standard toxicity test protocols. The SSD approach uses only a single statistically derived endpoint from each available toxicity test (e.g., the LC50 or EC50). In contrast, all data collected during any specific toxicity test can be used in a hierarchical model. The ability to use all available data to make inferential decisions is a marked improvement over the standard SSD effects distribution. 

The likely range of the intersex indicator (ISI) for L. littorea was also calculated based on the dose-response relationship for L. littorea as published by Oehlmann (2002) and the spatial distribution of water concentrations. The range of possible ISI values from the 5 and 95 percentile of the exposure concentration distributions were calculated applying Formula 1. 

Another model, widely used in the past, is the Mantel-Bryan probit model (Mantel et al., 1975). This can be derived by assuming that the dose-response relationship for each individual has a threshold, and that the thresholds for different individuals in the population are distributed log-normally. This model gives a lower risk at low doses than does any power law and, therefore, a lower risk than the multistage or proportional models (Figure 8.5). Moreover, when backgroimd is included, Crump et al., (1976) and Pfeto (1977) have shown that it... 

NCRP (1980). National Council on diation Protection and Measurements. Influence of Dose and Its Distribution in Time on Dose-Response Relationships for Low-LET Radiations, NCRP Report No. 64 (National Council on Radiation Protection and Measurements, Bethesda, Maryland). 

Figure 2.5 Dose-response relationship expressed as a frequency distribution.

Thus, a large dose may be ineffectively distributed and remain at the site of administration as a depot. A large dose of a compound given orally, for instance, may not be all absorbed, depending on the rates of absorption and transit time within the gut. Saturable active absorption processes would be particularly prone to dose effects, which could result in unexpected dose-response relationships. 

The explanation of the pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination processes is a highly specialized branch of toxicology, and is beyond the scope of this chapter. However, here we introduce a few basic concepts that are related to the several transport rate processes that we described earlier in this chapter. Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to xenobiotics. In addition these studies are essential to provide information on the fate of the xenobiotic following exposure by a define route. This information is essential if one is to adequately interpret the dose-response relationship in the risk assessment process. In recent years these toxicokinetic data from laboratory animals have started to be utilized in physiologically based pharmacokinetic (PBPK) models to help extrapolations to low-dose exposures in humans. The ultimate aim in all of these analyses is to provide an estimate of tissue concentrations at the target site associated with the toxicity. 

In section 2.3 of this chapter the present approach to characterisation of dose-response relationships was described. In most cases it is necessary to extrapolate from animal species that are used in testing to humans. It may also be necessary to extrapolate from experimental conditions to real human exposures. At the present time default assumptions (which are assumed to be conservative) are applied to convert experimental data into predictive human risk assessments. However, the rates at which a particular substance is adsorbed, distributed, metabolised and excreted can vary considerably between animal species and this can introduce considerable uncertainties into the risk assessment process. The aim of PB-PK models is to quantify these differences as far as possible and so to be able to make more reliable extrapolations. 

Statistical models. A number of statistical dose-response extrapolation models have been discussed in the literature (Krewski et al., 1989 Moolgavkar et al., 1999). Most of these models are based on the notion that each individual has his or her own tolerance (absorbed dose that produces no response in an individual), while any dose that exceeds the tolerance will result in a positive response. These tolerances are presumed to vary among individuals in the population, and the assumed absence of a threshold in the dose-response relationship is represented by allowing the minimum tolerance to be zero. Specification of a functional form of the distribution of tolerances in a population determines the shape of the dose-response relationship and, thus, defines a particular statistical model. Several mathematical models have been developed to estimate low-dose responses from data observed at high doses (e.g., Weibull, multi-stage, one-hit). The accuracy of the response estimated by extrapolation at the dose of interest is a function of how accurately the mathematical model describes the true, but unmeasurable, relationship between dose and response at low doses. 

Dose-response data based largely on animal studies. It is noteworthy that rodent studies now used to predict the dose-response relationship in humans were never intended for that purpose (Barr, 1988). These studies were designed for purposes of hazard identification (see Section 3.1.4.1.2) and were not intended to be the basis for estimating human responses at low doses (Paustenbach, 1995). For example, there usually are significant differences between animals and humans with respect to the rate at which chemicals are metabolized, distributed, and excreted, and these are not taken into account when animal tests are designed. Also, animal tissues will frequently respond differently to toxicants than human tissue. 

Influence of Dose and Its Distribution in Time on Dose-Response Relationships for Low-LET Radiations (1980)... 

Data from in vivo (intraperitoneal) exposures of mice to aluminum chloride also indicate that this compound is clastogenic. Mice were injected intraperitoneally with 0.01, 0.05, or 0.1 molar aluminum chloride, and bone marrow cells were examined for chromosomal aberrations. There was a significant increase in chromatid-type aberrations over the controls, and these occurred in a nonrandom distribution over the chromosome complement (Manna and Das 1972). No dose-response relationship could be demonstrated, although the highest dose of aluminum chloride did produce the greatest number of aberrations. These data are supported by in vitro studies that show that aluminum chloride causes cross-... 

Diliberto JJ, Akubue PI, Luebke RW, et al. 1995. Dose-response relationships of tissue distribution and induction of CYP1A1 and CYP1A2 enzymatic activities following acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. Toxicol Appl Pharmacol 130 197-208. 

The use of Monte Carlo and other stochastic analytical methods to characterize the distribution of exposure and dose-response relationships is increasing (IPCS, 2001a). The Monte Carlo method uses random numbers and probability in a computer simulation to predict the outcome of exposure. These methods can be important tools in risk characterization to assess the relative contribution of uncertainty and variability to a risk estimate. 

There is a continuing need for validated biomarkers of exposure that provide information on the frequency, duration, and intensity of an exposure, as well as a better understanding of distribution, metabolism, and excretion within the individual. Likewise, continued development of analytical methods (e.g. Monte Carlo) that provide a broad characterization of exposure and dose-response relationships should be encouraged. 

Fig. 1.5 Illustration of the simulation and analysis of a virtual trial outcome. The solid line represent the true dose-response relationship based on a sampled set of parameters from the joint posterior distribution of the model parameters. The circles represent the simulated drug effects in the patients included in the trial on the basis of the true" model parameters and the errors bars...

A key element in decision making will be to understand the relationship between the level of chemical exposure and the consequent risks to health or the environment. There are two main ways in which we can understand this relationship through the species sensitivity distribution (SSD) or the dose-response curve. The SSD is perhaps the more useful for environmental assessment because it integrates all species, whereas the dose response describes the cause-effect relationship for only one species. Nevertheless, the dose-response relationship could be a valuable tool for environmental assessment when the species described is either particularly sensitive,... 

The individual tolerance concept has some unrealistic properties (Kooijman 1996 Newman and McCloskey 2000). Most importantly, if there is a distribution in sensitivities, this would imply that the survivors from an experiment are the less sensitive individuals. Experiments with sequential exposure show that this prediction fails (at least as the dominant mechanism) (Newman and McCloskey 2000 Zhao and Newman 2007). There is sufficient reason to conclude that the individual threshold model is not sufficient to explain the observed dose-response relationships, and that mortality is a stochastic process at the level of the individual... 

Distributed pharmacokinetics is characterized not only by spatially dependent concentration profiles but also by dose-response relationships that become spatially dependent. For example, biological responses such as cell kill are often quantified as functions of area under the concentration-vs.-time curve (ALIC). In compartment models, response is frequently correlated with the area under the plasma-concentration-vs.-time curve, where... 

The fundamental principle of toxicology is the concept that the sixteenth century physician Paracelsus articulated in the 1500s sola dosis facit venenum or the dose makes the poison . The modem version of this observation is the dose-response relationship, which is experimentally and theoretically supported through pharmacokinetic and pharmacodynamic experimentation. Pharmacokinetics is concerned with the study of the time course of the disposition of drugs, specifically absorption, distribution, metabolism and elimination, often referred to as ADME. In non-technical terms it can be thought of as what the body does to the chemical. An understanding of the pharmacokinetic (in the case of dmgs) or toxicokinetic (all chemicals) profile is critical to estimate the... 

Osteoporosis is a condition characterized by a loss of bone mass and density that has been causally related to exposure to cadmium, a toxic heavy metal that is widely distributed in the ambient environment. In a Chinese study, a dose-response relationship between cadmium exposure and osteoporosis was demonstrated. M Other studies have demonstrated that... 

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