Dose-response relationships components

Having established a suitable timepoint for the component of interest, the researcher may find it useful to examine the dose-response relationship for the agonist under study. 

The linear component of the LMS model, qi (i.e., one of the parameters of the polynomial), is approximately equivalent to the slope at low doses of the dose-response relationship between the tumor incidence and the dose. This linearity at low dose is a property of the formulation developed for the multistage model and is considered by proponents to be one of its important properties. This linear component of the polynomial, qi, is used to carry out low-dose extrapolation. The linear response at low doses is considered to be conservative with regard to risk, as the dose-response relationship at low doses may well be sublinear. Although supralinearity at low doses cannot be excluded, it is usually considered to be unlikely. 

The 95% confidence limits of the estimate of the linear component of the LMS model, /, can also be calculated. The 95% upper confidence limit is termed qi and is central to the US-EPA s use of the LMS model in quantitative risk assessment, as qi represents an upper bound or worst-case estimate of the dose-response relationship at low doses. It is considered a plausible upper bound, because it is unlikely that the tme dose-response relationship will have a slope higher than qi, and it is probably considerably lower and may even be zero (as would be the case if there was a threshold). Lfse of the qj as the default, therefore, may have considerable conservatism incorporated into it. The values of qi have been considered as estimates of carcinogenic potency and have been called the unit carcinogenic risk or the Carcinogen Potency Factor (CPF). 

Immunotoxicity. There are currently no data on the effects of 2-hexanone on the human immune system via any route of exposure. Animal data included an inhalation study in which there was a 40% decrease in peripheral white blood cells in rats exposed to 2-hexanone (Katz et al. 1980). In addition, 2,5-hexanedione, a metabolite of 2-hexanone, was shown to adversely affect lymphoid organs of the immune system in rats and to cause impairment of immunity in mice (Upreti and Shanker 1987). Immunological assessments, including analysis of peripheral blood components and effects on lymphoid tissue, conducted as part of intermediate-or chronic-duration studies and skin sensitization tests would be useful in developing a dose-response relationship and assessing the potential risk to chronically exposed persons in the vicinity of hazardous waste sites or to exposed workers. 

For experimental studies of mixtmes, consideration is given to the possibility of changes in the physicochemical properties of the test substance during collection, storage, extraction, concentration and delivery. Chemical and toxicological interactions of the components of mixtmes may result in nonlinear dose-response relationships. 

The evaluation of dose-response relationships is a critical component of hazard characterization (OECD, 1989 ECETOC, 1992 US , 1997a IPCS, 1999). Evidence for a dose-response relationship is an important criterion in establishing a toxic reproductive effect. It includes the evaluation of data from both human and laboratory animal studies. Because quantitative data on human dose-response relationships are infrequently available, the dose-response evaluation is usually based on the assessment of data from tests performed using laboratory animals. However, if data are available in humans with a sufficient range of doses, dose-response relationships in humans can also be evaluated. 

Risk assessment An empirically based paradigm that estimates the risk of adverse effects) from exposure of an individual or population to a chemical, physical or biological agent. It includes the components of hazard identification, assessment of dose-response relationships, exposure assessment and risk characterization. 

It is important to note that the T1 screening program will not determine dose-response relationships, mechanism of action, or the adversity of a chemical s effect, if any. Rather, it is designed to demonstrate interaction with components of the endocrine system. 

Identifying dose-response relationships is an important component of any risk assessment. This process establishes the exposure levels that produce effects, as well as those that produce no effects. As noted in Box 2, it is important to characterize what data were used, what model was employed to develop the dose-response curve(s), and whether chemical-specific information is available to support the observed dose-response relationship. While the risk assessment paradigm shown in Figure 21 separates hazard... 

Whole mixture approach for common mixtures. This is an option if dealing with a common, and often complex, mixture with more or less constant concentration ratios between the mixture components, for example, coke oven emissions. A reference value (e.g., PNEC) or dose-response relationship can be established for the mixture as if it were 1 (complex) compound, and a safe level can be determined like for single compounds based on toxicity data on the mixture itself or a sufficiently similar mixture. The effect data can subsequently be used in future assessments of mixtures that are identical (e.g., originating from the same source) or sufficiently similar. 

The 2 boxes in the upper right corner of Figure 5.11 reflect a situation in which the mixture of concern is well characterized, for example, because a lot of information is available about its composition, its origin, and its dose-response relationship. A well-characterized mixture can be thought of as a commonly occurring mixture with a stable chemical composition, which is more or less known, for example, coke oven emissions. It is often infeasible to determine the exact chemical composition of the mixture at hand because the mixture contains hundreds or thousands of different components. This is also unnecessary because dose-response data on the mixture of concern are available from previous studies, for example, epidemiological data on coke oven emissions. A mixture is also considered well characterized if it can be... 

The establishment of a safe dose or concentration level for mixtures is useful only for common mixtures with more or less constant concentration ratios between the mixture components and for mixtures of which the effect is strongly associated with one of the components. For mixtures of unknown or unique composition, determination of a safe concentration level (or a dose-response relationship) is inefficient, as the effect data cannot be reused to assess the risks of other mixtures. One alternative is to test the toxicity of the mixture of concern in the laboratory or the field to determine the adverse effects and subsequently determine the acceptability of these effects. Another option is to analyze the mixture composition and apply an algorithm that relates the concentrations of the individual mixture components to a mixture... 

Since acute radiation toxicity responses become apparent shortly after exposme, history is an important criterion in determining whether the radiation is related to the cause of a particular complication or adverse effect. As with any attempt to specify a dose-response relationship, the dose is an important component. In contrast, late radiation toxicity in organs such as the kidneys, fiver, or central nervous system (CNS) will not be seen until months or perhaps even years after radiation exposure (Center for Drug Evaluation, 2005). The integrated response is often to the radiation response and attempts to heal any radiation damage that has been caused. 

Interactive toxicity is defined as effects of mixtures deviating from the additive toxic response expected based on the dose-response relationships obtained from individual components. 

Interaction Effect of a mixture that is different from additivity based on the dose-response relationships of the individual components. 

TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxin, and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin, all of which were shown to be effective blockers of ovulation in this assay (Gao et al. 1999, 2000). The mixture was administered at TCDD-TFQ doses ranging from 0.0038 to 0.0303 mg/kg. Parallel dose-response relationships for inhibition of ovulation were found for the individual agents and for the equipotent mixture. This finding is consistent with the hypothesis that the agents in the tested mixture are likely to block ovulation by additive joint action in a similar mechanism and supports the use of the TEF approach for this type of endocrine disruption. Another PCB congener, 2,2, 4,4 -tetraCB (which has no detectable Ah receptor agonist activity), was inactive at the dose examined in this assay (41.9 mg/kg). The effect of its presence in a mixture with effective components, however, was not studied (Gao et al. 2000). 

As described in a highly referenced document (NRC, 1983), important components of this process include hazard identification, assessment of exposure and dose-response relationships, and characterization of the risk. Uncertainty factors are built into the risk assessment process to account for variations in individual susceptibility, extrapolation of data from studies in laboratory animals to humans (i.e. interspecies variation in toxicokinetics), and extrapolation from high-dose to low-dose exposures. In the case of the association between exposure to chemicals and drugs and autoimmunity or autoimmune diseases, much of the information needed to evaluate risk in the context of the traditional United States National Research Council paradigm is not available. The following represents a discussion of issues in chemical-induced autoimmunity relevant to the use of existing data and data needs in risk assessment. 

The hormetic dose-response can occur as an overcompensation to a disruption in homeostasis or as a direct stimulation. The incorporation of a repeated measures analysis component into the study design would be an essential element in both identifying and understanding dose-response relationships. Dose-time-effects relating to hormesis have typically been associated with the concept of a rebound /overcompensation effect with a robust supportive literature. 

Pharmacology, the study of agents and their actions, can be divided into two branches. Pharmacodynamics is concerned with the effects of a drug on the body and, therefore, encompasses dose-response relationships as well as the molecular mechanisms of drug activity. Pharmacokinetics, on the other hand, is concerned with the effect of the body on the drug. Drug metabolism, transport, absorption, and elimination are components of pharmacokinetic analysis. 

Chloramphenicol causes two distinct forms of toxicity in humans. The most serious form is an irreversible aplastic anaemia. This rare idiosyncratic response (the incidence is 25,000-60,000) may have an immunological component however, the meehanism of chloramphenicol-induced aplastic anemia remains unknown. Neither a dose-response relationship nor a threshold dose for the induction of aplastic anaemia has been established. Aplastic anemia is associated with reduced numbers of erythrocytes, leukocytes, and platelets (pancytopaenia), with resultant bleeding disorders and secondary infections. The condition tends to be irreversible and fatal. By comparison, leukemia may be a sequel of hypoplastic anemia. Because thiamphenicol and florfenicol lack the p-nitro moiety, they do not induce irreversible aplastic anemia in humans. 

Results from this extensive effects testing demonstrates that PDMS has a relatively low toxicity to freshwater, marine and terrestrial organisms. As a result, in most cases no dose/response relationships or toxicity differences between species exist. The toxicity test methods that most realistically simulate PDMS exposure in the environment produce the most reliable measure of potential PDMS environmental effects. For example, sediment-bound PDMS will be the primary route of exposure in the aquatic environment, because PDMS has not been measured in overlying water (due to its negligible water solubility and potential for sorption onto sediments). Therefore, studies in which PDMS was dosed as a component of sediment are the most realistic exposure... 

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