Dose-frequency relationship

Abrahamson, S., and Friedman, L. D. (1964), X-ray induced mutations in spermat-ogonial cells of Drosophila and their dose-frequency relationship. Genetics 49, 357-361. 

In the first group, treatment with both kinds of mercuric compounds increased the incidence of wild type with increasing doses, but in the II B group of Table 3, treatment with saline only yielded a very high frequency. Further experiments on the dose-frequency relationship showed that the frequency did not necessarily increase with increase of the administered dose. Genetic analysis of the wild-type individuals indicated that these exceptional were mainly triploids (Table 4). 

The criterion employed for a positive response in this assay is a reproducible statistically significant increase in mutation frequency (weighted mean for duplicate treated cultures) over the concurrent vehicle control value (weighted mean for four independent control cultures). Ideally, the response should show evidence of a dose-response relationship. When a small isolated significant increase in mutation frequency is observed in only one of the two duplicate experiments, then a third test should be carried out. If the third test shows no significant effects, the initial increase is likely to be a chance result. In cases where an apparent treatment-related increase is thought to be a result of unusually low variability or a low control frequency, comparison with the laboratory historical control frequency may be justified. 

Fox et al., proceed, however, to describe a dose-effect relationship, in spite of the fact that the dust levels available to these authors were not prospective. They use levels of dustiness measured at the time of the survey. It should be stressed that the effect related by this curve does not Include chronic or irreversible disorder, since the plot is based exclusively on reversible effects. Furthermore, the suggestion of a cumulative effect, which would appear supported by a frequency somehow proportioned to duration of employment (i.e., seniority), may not be justified. 

An exposure assessment is the quantitative or qualitative evaluation of the amount of a substance that humans come into contact with and includes consideration of the intensity, frequency and duration of contact, the route of exposure (e.g., dermal, oral, or respiratory), rates (chemical intake or uptake rates), the resulting amount that actually crosses the boundary (a dose), and the amount absorbed (internal dose). Depending on the purpose of an exposure assessment, the numerical output may be an estimate of the intensity, rate, duration, and frequency of contact exposure or dose (the resulting amount that actually crosses the boundary). For risk assessments of chemical substances based on dose-response relationships, the output usually includes an estimate of dose (WHO/IPCS 1999). 

If the hazard assessment indicates that the compound is potentially hazardous, the next step is to evaluate the various possibilities for exposure. What is the most likely route of exposure oral, inhalation or skin How much absorption is expected from the different routes of exposure Information is also needed on amount, duration, and frequency of exposure. Is exposure occurring in the home, workplace, school, or other areas This information helps to define the population of concern. Exposure information may also be important for designing appropriate studies on hazard assessment and certainly for the next step of establishing dose-response relationships. 

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

There may be no clear dose-response relationship for immune responses, as the magnitude of the response is dependent on the type of reaction of the endogenous immune system, not on the concentration of the foreign compound. However, there may be a relationship between likelihood of a response occurring and size of response with size of exposure and frequency of... 

Two types of responses from exposure to hazardous substances, called stochastic or deterministic,5 are of concern in risk assessment. The two types of responses are distinguished by the characteristic features of the dose-response relationship, i.e., the relationship between the dose of a hazardous substance and the probability (or frequency) of a response. 

The Japanese atomic-bomb survivors also are a potentially important source of data on the dose-response relationship for severe hereditary responses. However, no evidence for inherited genetic effects has been observed in spite of nearly 50 y of study. In the absence of data in humans, estimates of the frequency of radiation-induced hereditary responses have been based primarily on data from studies in mice. 

The conclusion about the uncertainty in the dose-response relationship for radiation stated above takes into account the uncertainty in extrapolating the data at high doses and dose rates in the Japanese atomic-bomb survivors to the lower doses and dose rates of concern in routine exposures of the public. The issue of extrapolation to low doses and dose rates is a matter of considerable controversy and is an important source of uncertainty (NCRP, 1997 2001). Forpurposes of radiation protection, the frequency of responses at low doses and dose rates generally has been assumed to be a factor of two less than MLE of the frequency of responses in the Japanese atomic-bomb... 

In particular, high-dose data usually cannot identify a threshold. A threshold is a dose or exposure below which there is no effect. It is often assumed that there is no threshold for an end point, like a gene mutation, that may involve one molecule of the toxicant and one target molecule in such a case, the dose-response relationship would be linear at low doses. If the observed relationship is linear over the dose range studied and if the fitted line is extrapolated to no effect (or the background frequency of effects) at zero dose, linear kinetics with no threshold are likely. But data are usually not clear. Even such a large carcinogenesis study as the EDqi study conducted by... 

Dose Levels and Frequency of Exposure In chronic toxicity studies, it is desirable to have a dose-response relationship as well as a no-observed-toxic-effect level (NOEL). Therefore, at least three dose levels should be used in addition to the concurrent control group. The highest-dose level should elicit some signs of toxicity without causing excessive lethality. The low dose should produce signs of toxicity. For a diet mixture, the highest concentration should not exceed 5% with the exception of nutrients. 

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. 

The prime objective in epidemiologic studies is to associate particular exposures with potential health effects and thus to define cause-effect relationships. Since this process is an indirect assessment, it is highly dependent on the accuracy and specificity of observations recorded both for exposure and outcome. It is a more powerful study if dose-response relationships can be shown, that is, if increasing levels of exposure are associated with increasing frequency of the health effects in individuals. 

The proportion of female Sprague-Dawley rats developing mammary tumors decreases very rapidly as the dose decreases (American Biogenics Corporation, 1986 McCormick, 1988 Thakur, 1991, 1992). The observed dose-response relationship is sublinear. Furthermore, the biological mechanism by which atrazine and simazine cause this response is most likely a threshold mechanism thus, the sublinear dose-response relationship contains a range of positive doses for which the frequency of the response is not increased above the background frequency at zero dose (Andersen et al., 1998 Connor et al., 1998 Eldridge et al 1998 Simpkins et al, 1998). 

Dose-response relationship a quantitative relationship between the extent of exposure to the factor and the frequency or severity of the disease must be demonstrated. 

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