The dose-response relationship

In order for any substance to cause injury to an individual, it must first be taken up by the body. Knowing the way in which substances are taken up is critical in order to understand and prevent toxicity. The body may be exposed to toxic substances through any one or a combination of four routes  

Occupationally, inhalation is the most common route of entry by toxic substances. It is fairly common for substances to have more than one route of entry, and some may cause injury through all four routes. 

When an individual receives a relatively large dose over a single (or brief) time period, we refer to this type of exposure as acute. An 

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After the critical study and toxic effect have been selected, the USEPA identifies the experimental exposure level representing the highest level tested at which no adverse effects (including the critical toxic effect) were demonstrated. This highest "no-obserx cd-adversc-effcct-lever (NOAEL) is the key datum obtained from the study of the dose-response relationship. A NOAEL obserx ed in an animal study in which the exposure was intermittent (such as five days per week) is adjusted to reflect continuous exposure. 

A potential pitfall with stop-time experiments comes with temporal instability of responses. When a steady-state sustained response is observed with time, then a linear portion of the production of reporter can be found (see Figure 5.15b). However, if there is desensitization or any other process that makes the temporal responsiveness of the system change the area under the curve will not assume the linear character seen with sustained equilibrium reactions. For example, Figure 5.16 shows a case where the production of cyclic AMP with time is transient. Under these circumstances, the area under the curve does not assume linearity. Moreover, if the desensitization is linked to the strength of signal (i.e., becomes more prominent at higher stimulations) the dose-response relationship may be lost. Figure 5.16 shows a stop-time reaction dose-response curve to a temporally stable system and a temporally unstable system where the desensitization is linked to the... 

Environmental benefits of Emission Controls. Information in Figure 5 illustrate that the emission of sulphur in eastern North America has declined over the past decade. This decline allows for a possible verification of the dose-response relationships on which the environmental concerns for emissions have been based. A decline in sulphate deposition in Nova Scotia has apparently resulted in a decrease in acidity of eleven rivers over the period 1971-73 to 1981-82 (47), In the Sudbury, Ontario area where emissions have dechned by over 50% between 1974-76 and 1981-83, a resurvey of 209 lakes shows that most lakes have now become less acidic. Twenty-one lakes that had a pH < 5.5 in 1974-76 showed an average decline in acidity of 0.3 pH units over the period (48), Surveys of 54 lakes in the Algoma region of Ontario have shown a rapid response to a decline in sulphate deposition. Two lakes without fish in 1979 have recovered populations as pH of the water moved above 5.5 (49). Evidence is accumulating to support the hypothesis of benefits that were projected as a consequence of emission controls. This provides increased confidence in the projections. 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a specified magnitude of changes in a specified adverse response. For example, a BMDio would be the dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 10%. The BMD is determined by modeling the dose response curve in the region of the dose response relationship where biologically observable data are feasible. 

Stages in hazard characterization according to the European Commission s Scientific Steering Committee are (1) establishment of the dose-response relationship for each critical effect (2) identification of the most sensitive species and strain (3) characterization of the mode of action and mechanisms of critical effects (including the possible roles of active metabolites) (4) high to low dose (exposure) extrapolation and interspecies extrapolation and (5) evaluation of factors that can influence severity and duration of adverse health effects. 

We have not explored all of the dose-response relationships. And with respect to the nature of the cue, we have studies underway now with a variety of serotonin agonists and antagonists, for example, fluoxetine. And have looked at MDMA. We eannot bloek the cue with fluoxetine. We are also looking at 8-hydroxy-DPAT, buspirone. PCPA pretreatment is on the way. So there are a variety of manipulations that we have in process. 

No data were located regarding PBPK/PD modeling to explain the biological basis for the dose-response relationship in humans or animals after exposure to diisopropyl methylphosphonate. 

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. 

Endpoint/Concentration/Rationale 15 ppm for 1 h induced a significant decrease in hematocrit levels that may be approaching a degree of hemolysis that can lead to renal failure. Given the steepness of the dose-response relationship this is justified as an estimate of the lethality threshold. An exposure of 26 ppm for 1 h resulted in 100% lethality. 

Studies using the inhalation route might be useful to determine the potential human health risk in populations that may be occupationally exposed to hexachloroethane vapors for long periods. Additional chronic oral studies may be useful to help further clarify the dose-response relationships and better characterize thresholds. Studies by the dermal route would not be useful until the rate and extent of absorption have been better characterized. 

Decision Analysis. An alternative to making assumptions that select single estimates and suppress uncertainties is to use decision analysis methods, which make the uncertainties explicit in risk assessment and risk evaluation. Judgmental probabilities can be used to characterize uncertainties in the dose response relationship, the extent of human exposure, and the economic costs associated with control policies. Decision analysis provides a conceptual framework to separate the questions of information, what will happen as a consequence of control policy choice, from value judgments on how much conservatism is appropriate in decisions involving human health. 

Our assignment for EPA was to apply quantitative risk analysis methods to the determination of risk for a particular chemical. The health risks for perchloroethylene turned out to be highly uncertain, but by using decision analysis concepts we were able to display this uncertainty in terms of alternative assumptions about the dose response relationship. Similar methods might be used to characterize uncertainties about human exposure to a chemical agent or about the costs to producers and consumers of a restriction on chemical use. 

Generally, in vivo nonclinical studies should be designed to include a sufficient number of animals per group to permit a valid estimation of a drug s toxicologic and pharmacologic effects in terms of incidence, severity and the dose-response relationships involved (Thomas and Myers, 1998). The latter point requires, as... 

Note that the testing for trend is seen as a more sensitive way of picking up a possible treatment effect than simple pairwise comparisons of treated and control groups. Attempting to estimate the magnitude of effects at low doses, typically below the lowest positive dose tested in the study, is a much more complex procedure, and is heavily dependent on the assumed functional form of the dose-response relationship. 

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... 

Note (a) Recti linearity of the dose-response relationship, transformed or untransformed, is often obtained only over a very limited range. It is this range that must be used in calculating the activity and it must include at least three consecutive doses in order to permit rectilinearity to be verified,... 

We have seen that many different factors can contribute to chemical hazard in the workplace. The degree of hazard, however, is fundamentally determined by two factors the basic toxicity of the agent concerned, that is, its intrinsic capacity to damage or affect biological tissue and the severity of the exposure, or what is sometimes called the dose-response relationship. The duration of the exposure, of course, must also be considered. 

No information is available on the effects of intermediate-duration oral exposure in humans, but two animal studies (Boorman et al. 1986 Danse et al. 1984) provide sufficient data to identify the main target tissue (the stomach epithelium) and to define the dose-response relationship for this effect. These studies are suitable for derivation of an intermediate oral MRL, but further studies would still be helpful to search more specifically for possible subclinical neurological effects. This is important since neurological effects appear to be the most sensitive effect by the inhalation route, and people may be exposed to low levels of bromomethane in drinking water drawn from contaminated groundwater sources. No information is available on intermediate- duration dermal exposure to bromomethane. However, humans are not likely to experience significant dermal exposures to bromomethane near waste sites, so research in this area does not appear to be essential. 

Bryant CA, Farmer A, Tiplady B, Keating J, Sherwood R, Swift CG, Jackson SH. (1998). Psychomotor performance investigating the dose-response relationship for caffeine and theophylline in elderly volunteers. EurJ Clin Pharmacol. 54(4) 309-13. 

Models for determining the dose-response relationship vary based upon the type of toxicological hazard. In the dose-response for chemical carcinogens, it is frequently assumed that no threshold level of exposure (an exposure below which no effects would occur) exists, and, therefore, any level of exposure leads to some finite level of risk. As a practical matter, cancer risks of below one excess cancer per million members of the population exposed (1 x 10 ), when calculated using conservative (risk exaggerating) methods, are considered to represent a reasonable certainty of no harm (Winter and Francis, 1997). 

Figure 3.3 teaches some additional and important features of dose-response relationships. Such relationships are depicted for two different compounds (A and B), and responses in two different species, rats and guinea pigs, are shown for compound A. Because the dose-response relationship for compound B is to the right of that shown for A, we can conclude that B is less toxic than A, at least for the particular response plotted here (according to our principles, such a pattern could he reversed for some other manifestation of the toxicity of A and B). As seen in the figure, toxic responses to B consistently occur only at higher doses than they do for A, so B is less toxic. 

As has been emphasized so many times in the preceding chapters, these various manifestations of toxicity all display dose-response characteristics, where by response we refer to the incidence or severity of specific adverse health effects. As we demonstrated in earlier chapters, toxic responses increase in incidence, in severity, and sometimes in both, as dose increases. Moreover, just below the range of doses over which adverse effects can be observed, there is usually evidence for a threshold dose, what we have called the no-observed adverse effect level (NOAEL). The threshold dose must be exceeded before adverse effects become observable (Chapter 3). Deriving from the literature on toxic hazards, descriptions of the dose-response relationships for those hazards comprise the dose-response assessment step of the four-step process. 

Pharmacokinetics has played a crucial and somewhat unusual role in the assessment of health risks from methylmercury. Some of the epidemiology studies of this fish contaminant involved the measurement of mercury levels in the hair of pregnant women, and subsequent measurements of health outcomes in their offspring (Chapter 4). Various sets of pharmacokinetic data allowed estimation of the level of methylmercury intake through fish consumption (its only source) that gave rise to the measured levels in hair. In this way it was possible to identify the dose-response relationship in terms of intake, not hair level. Once the dose-response relationship was established in this way, the EPA was able to follow its usual procedure for establishing an RfD (which is 0.1 ag/(kg b.w. day)). 

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