Dose—response relationships at low doses

Although several figures in Table IV are significant, the estimates are probably accurate to the first digit at best. However, they do suggest that widespread but low-level exposures from automobiles and service stations provide the majority of benzene molecules that enter human bodies. Whether these are the most biologically significant emissions depends on the behavior of dose-response relationships at low dose levels. 

FIGURE 6.1 Various types of dose-response relationships at low doses. 

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). 

A weight of evidence approach to assessing reproductive toxicity requires rigorous evaluation of all available data. However, often only limited information is available, and default assumptions must be made because of uncertainties in understanding mechanisms, dose-response relationships at low dose levels and human exposure patterns. Several of these assumptions are basic to the extrapolation of toxicity data from animals to humans, while others are specific to reproductive toxicity. The general default assumptions for reproductive toxicity stated in the IPCS (1995) report are summarized as follows ... 

By using UCL and assuming that the model accurately reflects the dose-response relationship at low doses, there is only a five percent chance that the true response is higher than the response predicted by the model. 

Meijerink J., Carlsson M. A. and Hansson B. S. (2003) Spatial representation of odorant structure in the moth antennal lobe a study of structure response relationships at low doses. J. Comp. Neurol, (in press). 

Anderson ME, Barton HA. 1998. The use of biochemical and molecular parameters to estimate dose-response relationships at low levels of exposure. Environ Hlth Perspect 106 Suppl. 1 349-356. 

The epidemiological studies that establish the basic validity of dose—toxic response relationships at low exposures also establish the validity of general causality of various adverse effects by lead. Equally important, such studies also establish the validity of a physician choosing to include lead-related effects when articulating a diagnosis of specific causality of some effect in a given patient. 

The doses of hazardous substances at which responses can be observed in humans or animals are higher (sometimes by large factors) than doses relevant to waste disposal and other routine exposure situations. Therefore, most dose-response relationships at the low doses of interest in protection of human health are calculated rather than measured they are based not only on scientific data but also on various assumptions and extrapolation models which, while scientifically plausible, cannot yet be subjected to empirical study... 

Potency estimates derived from such animal studies help to characterize the dose-response relationship at the low-exposure levels to which humans are likely to be exposed and to predict the quantitative estimate of the risks that humans are likely to encounter at ambient exposures. Experimental evidence for various shapes of the dose-response curve for carcinogens showed that reliable high-dose data from human studies contain examples of superlinearity, linearity, and sublinearity. These are also seen in animal studies. But there are no data to indicate the shape of the dose-response relationship corresponding to lifetime risk of one in a million, the insignificant risk level generally used by the regulatory agencies. 

Dibenz[a,h]anthracene. Dibenz[a,h]anthracene has also demonstrated tumor-initiating activity using a standard initiation/promotion protocol (Slaga et al. 1980a). Dibenz[a.h]anthracene has been reported to initiate skin development in a dose-response relationship at doses as low as 0.028 pg followed by promotion with TPA (for 25 weeks) (Buening et al. 1979a). 

Abramsson-Zetterberg, L. 2003. The dose-response relationship at very low doses of acrylamide is linear in the flow cytometer-based mouse micronucleus assay, Mutat. Res. 535 215-222. 

Experimental exposure studies have attempted to associate various neurological effects in humans with specific trichloroethylene exposure levels. Voluntary exposures of 1 hours resulted in complaints of drowsiness at 27 ppm and headache at 81 ppm (Nomiyama and Nomiyama 1977). These are very low exposure levels, but the results are questionable because of the use of only three test subjects per dose, lack of statistical analysis, sporadic occurrence of the effects, lack of clear dose-response relationships, and discrepancies between the text and summary table in the report. Therefore, this study is not presented in Table 2-1. No effects on visual perception, two-point discrimination, blood pressure, pulse rate, or respiration rate were observed at any vapor concentration in this study. Other neurobehavioral tests were not performed, and the subjects were not evaluated following exposure. 

---