Dose and effect

The target biomolecule (B) at the concentration CB reacts with the toxicant (T) at the concentration CT to give the destroyed biomolecule (BT) at the concentration CBT. The reaction may be reversible, as indicated by the double arrow. C is the total concentration of the biomolecule and K is the equilibrium constant. If the onset speed of the symptoms is proportional with the disappearance rate of the biomolecules (-dCB/dt), we get this simple mathematical expression telling us that the higher the concentration of the toxicant is, the faster CB will decrease and the symptoms appear  

These simple formulae illustrate that higher concentrations of a toxicant give a lower amount of the biomolecule and thus stronger symptoms. The onset of symptoms may start when CB is under a certain threshold or CBT is above a threshold. 

The real situation is more complicated. The toxicant may react with many different types of biomolecules. It may be detoxified or need to be transformed to other molecules before reacting with the target biomolecule. 

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The chemical agents should contact the parasite by prevention, or diffusion through the cells and tissues of the host at suitable doses and effective concentrations. 

Several aspects of the problem of herbicides being contaminated with nitrosamines, and the resulting inadvertent introduction of nitrosamines into the environment, will be discussed in other papers in this symposium. Unrecognized until less than five years ago, the situation has inspired intense debate and prompted several of the environmental chemistry studies mentioned in this paper. Like the presumed threat from the in vivo nitros-ation of pesticide residues, discussions sometimes lack the type of anticipated dose and effect calculations just mentioned. Unlike the active ingredients, whose benefits can justify residue tolerances and acceptable daily intakes, nitrosamine contaminents afford no known benefits, and the desirability of minimizing their levels is undisputed. 

Acute-Duration Exposure. Acute oral LD50 data are available for mice and rats (Hart 1976) and for ducks (Aulerich et al. 1979). Acute oral toxicity studies, including histopathological observations, are available for ducks, mice, rats, dogs, and mink (Aulerich et al. 1979 Hardisty et al. 1977 Hart 1976, 1980). Limited acute dermal toxicity are available for rats (Hart 1976). These data suggest a relatively low toxicity. However, a clear relationship between dose and effect has not been elucidated. Inhalation data of any kind were not identified, and dermal data were very limited. 

Due to the various sources of uncertainties associated with both groups of input data (dose and effect) needed for risk assessment, at present it is only possible to give an upper limit for the pure Rn-d related cancer risk. 

Following the discovery and clinical use of chloroform in 1847, The Royal Medical and Chirurgical Society (later to become The Royal Society of Medicine) had already set up in 1864 a committee to enquire into the uses and the physiological, therapeutical and toxicological effects of chloroform. There had been 109 fatalities following administration of chloroform. A critical relationship had been demonstrated between the dose and effect of this anaesthetic. The committee commented on the need for animal experiments to compare chloroform with ether and also on the relative cardiac safety of ether. 

Bolus The onset of action is generally 0.5 to 1 hour after an intrathecal bolus dose. Peak spasmolytic effect is seen at about 4 hours after dosing and effects may last 4 to 8 hours. Onset, peak response, and duration of action may vary with individual patients depending on the dose and severity of symptoms. 

In order to compare the safety and efficacy of drugs and their formulations, the therapeutic index, an estimate of therapeutic effects in relation to side effects, is often used (Figure 5.9B).The dose or concentration of a drug needed to ehcit a therapeutic effect in 50% of the population (median effective dose) is called the ED50. Typically a median lethal dose or LD50 is characterized for each drug in relevant experimental animals. The relationship of median lethal dose and effective dose comparison is the therapeutic index ... 

The relation between dose of a drug and the clinically observed response may be complex. In carefully controlled in vitro systems, however, the relation between concentration of a drug and its effect is often simple and can be described with mathematical precision. This idealized relation underlies the more complex relations between dose and effect that occur when drugs are given to patients. 

The relationship between dose and effect can be separated into pharmacokinetic (dose-concentration) and pharmacodynamic (concentration-effect) components. Concentration provides the link between pharmacokinetics and pharmacodynamics and is the focus of the target concentration approach to rational dosing. The three primary processes of pharmacokinetics are absorption, distribution, and elimination. 

All air quality-related legislation is based on the presumption of a direct line connecting emissions, ambient air quality, exposure, uptake, dose and effect. Pursuing this idea, regulation starts at the point of emission. Whilst the emissions... 

Checkmark in lower portion of table means that biomarkers in group can inform about stated elements of dose and effect. 

The threshold for a toxic effect, it is determined from the graph of the relationship between dose and effect, oestrogen... 

The characterization of ecological effects is perhaps the most critical aspect of the risk assessment process. Several levels of confidence exist in our ability to measure the relationship between dose and effect. Toxicity measured under set conditions in a laboratory can be made with a great deal of accuracy. Unfortunately, as the system becomes more realistic and includes multiple species and additional routes of exposure, even the ability to measure effects is decreased. 

Species Order Slruin/Life stage Dose and effect Reference... 

Integrated biomarker models can provide a mechanistic link between the dose and effect, thus becoming part of the scientific rationale for drug use and approval. 

We conclude this chapter with two examples from the literature of highly complex behavior between dose and effect that are modeled with direct PD models. The first example involves the chronopharmacokinetics of the anticancer drug 5-fluorouracil (5-FU). The second example covers nicotine and morphine drug tolerance. 

V5. Van den Brenk, H. A. S., Elliot, K., and Hutchings, H., Further observations on radiocurability of a solid Ehrlich tumour and tissue reactions in the mouse with fractionated radiation doses and effects of oxygen. Brit. J. Cancer 17, 281-288... 

One Interesting consequence of using a linear model for relating dose and effect Is that the total number of cancers caused is independent of how the dose is spread out in the population, provided the risk to each individual remains small (less than about 10% lifetime risk, or 0.0014 annual risk). Thus we can use the same simplified formula ... 

Hazard evaluation is used here to mean examination and evaluation of the hazards (adverse effects) observed in toxicity studies, including reproductive, teratogenic, and general toxicity studies plus other pertinent data. Because of the complexities of the reproductive system as well as embryogenesis and maturation of the conceptus, hazard evaluations must go beyond the mere determination of statistical effects, no observed effect levels (NOELS), relationships between dose and response, dose and effects, and the determination of margins of safety. Most... 

One of several kinds of mathematical relationships can be used to relate dose and effect in order to translate these data to risk estimates at low doses, e.g., linear, quadratic, logit, Weibull, one-hit, multi-hit. Each model is based on certain biochemical and physiological assumptions and has advantages and disadvantages. No one method has been shown to be better than the others. Often they all show a good fit to the experimental data available for different chemicals at higher doses. 

Since nonstochastic effects have a threshold, all that is needed to satisfy requirement 2 is to set the exposure limits below that threshold. For nonstochastic effects, the maximum allowed dose is set at 0.5 Sv (50 rem) for any tissue, except for the lens of the eye, for which the limit is set at 0.15 Sv (15 rem). For stochastic effects the limits are set at an acceptable level of risk. Ideally, the limit should be zero, since any exposure is supposed to increase the probability for stochastic effects to occur. Obviously, a zero limit is not practical. For stochastic effects the 10CFR20 sets the limiting exposure on the basis that the risk should be equal regardless of whether the whole body is irradiated uniformly or different tissues receive different doses. Recognizing the fact that different tissues have different sensitivities and, therefore, the proportionality constant between dose and effect is not the same for all tissues, the limit is expressed in terms of the effective dose equivalent (Ffg), defined as... 

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