Dose-response data

Dose—response relationships are useful for many purposes in particular, the following if a positive dose—response relationship exists, then this is good evidence that exposure to the material under test is causally related to the response the quantitative information obtained gives an indication of the spread of sensitivity of the population at risk, and hence influences ha2ard evaluation the data may allow assessments of no effects and minimum effects doses, and hence may be valuable in assessing ha2ard and by appropriate considerations of the dose—response data, it is possible to make quantitative comparisons and contrasts between materials or between species. 

Diseased groups No extrapolations Susceptible groups Long-term, low-level effects Many covariates Minimal dose-response data Association vs. causation... 

Toxicology Animals Maximal dose-response data Realistic models of human disease ... 

Toxicity and cancer dose-response data for tire constituents of the gasoline Estimated additional cancer risk for dwelling s occupants when exposure data me combined with cancer dose-response data... 

There are statistical procedures available to determine whether the data can be fit to a model of dose-response curves that are parallel with respect to slope and all share a common maximal response (see Chapter 11). In general, dose-response data can be fit to a three-parameter logistic equation of the form... 

FIGURE 6.15 Example of application of method of Lew and Angus [10]. (a) Dose-response data, (b) Clark plot according to Equation 6.27 shown, (c) Data refit to power departure version of Equation 6.27 to detect slopes different from unity (Equation 6.28). (d) Data refit to quadratic departure version of Equation 6.27 to detect deviation from linearity (Equation 6.29). 

FIGURE 11.18 Asymmetrical dose-response curves, (a) Dose-response data fit to a symmetrical Hill equation with n = 0.65 and EC50 = 2.2 (solid line) or n= 1, EC50 = 2 (dotted line). It can be seen that neither symmetrical curve fits the data adequately, (b) Data fit to the Gompertz function with m = 0.55 and EC50= 1.9. 

Dose-response data are obtained and plotted on a semi-logarithmic axis, as shown in Figure 12.3a (data shown in Table 12.3a). 

The procedure calculates the concentrations from both curves that produce the same level of response. Where possible, one of the concentrations will be defined by real data and not the fit curve (see Figure 12.3b). The fitting parameters for both curves are shown in Table 12.3b. Some alternative fitting equations for dose-response data are shown in Figure 12.4. 

Some indication of risk of employee exposure to airborne chemicals can be gauged from an analysis of the level of exposure for comparison with known human dose/ response data such as those for carbon monoxide and hydrogen sulphide listed in... 

NOAEL (no-observed-adverse-effect level) is defined as the highest dose at which no adverse effects are observed in the most susceptible animal species. The NOAEL is used as a basis for setting human safety standards for acceptable daily intakes (ADIs), taking into account uncertainty factors for extrapolation from animals to humans and inter-individual variabilities of humans. The adequacy of any margin of safety or margin of exposure must consider the nature and quality of the available hazard identification and dose-response data and the reliability and relevance of the exposure estimations. In some cases, no adverse endpoint can be identified such as for many naturally occurring compounds that are widespread in foods. In that case, an ADI Not Specified is assigned. ... 

FIGURE 2. Dose-response data in rats and monkeys administered MDMA... 

Conversion of experimental dose/response data into a form suitable for extrapolation of human risk using least squares or, more usually, maximum likelihood curve fits. 

The following example is based on a risk assessment of di(2-ethylhexyl) phthalate (DEHP) performed by Arthur D. Little. The experimental dose-response data upon which the extrapolation is based are presented in Table II. DEHP was shown to produce a statistically significant increase in hepatocellular carcinoma when added to the diet of laboratory mice (14). Equivalent human doses were calculated using the methods described earlier, and the response was then extrapolated downward using each of the three models selected. The results of this extrapolation are shown in Table III for a range of human exposure levels from ten micrograms to one hundred milligrams per day. The risk is expressed as the number of excess lifetime cancers expected per million exposed population. 

Based on laboratory dose response data, pyrethroids are considered to be either highly toxic (an LD50 of 0.1-1.0 pg a.i./bee) or extremely toxic (an LD50 of <0.1 pg a.i./bee) to honeybees (Table 6), according to the classification proposed by the International Commission for Bee Botany [67, 68]. 

The AEGL-1 was derived from a consideration of the dose-response data, which were obtained from all of the monitoring studies and subsequently time scaled to the shorter exposure durations. Although the exposures were of chronic duration in the monitoring studies, they represent the best available human data. Symptoms observed during chronic exposures should represent the greatest potential response. An 8-h exposure duration was selected as the basis for AEGL development. 

---