Dose-response relationships thresholds

Lutz WK. 2001. Susceptibility differences in chemical carcinogenesis linearize the dose-response relationship threshold doses can be defined only for individuals. Mutat. Res. 482 71-76... 

Dose response is typically the primary thrust of basic toxicology courses. The dose-response relationship defines the potency of a chemical. It relates the amount of chemical to a specific effect. As we discussed above, there are two types of basic dose-response relationships threshold and nonthreshold. These... 

Schwartz J, Landrigan PJ, Baker EL Jr. 1990. Lead-induced anemia Dose-response relationships and evidence for a threshold. Am J Public Health 80 165-168. 

A Test of the Linear-No-Threshold Dose-Response Relationship for Radiation Carcinogenesis... 

AEGL-1 (Non-disabling) NRa NR NR NR Not recommended due to steep dose-response relationship, mechanism of toxicity, and because toxicity occurs at or below the odor threshold... 

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. 

The AEGL-2 values were derived by a three-fold reduction of the AEGL-3 values. This approach for estimating a threshold for irreversible effects was used in the absence of exposure-response data related to irreversible or other serious long-lasting effects. It is believed that a 3-fold reduction in the estimated threshold for lethality is adequate to reach the AEGL-2 threshold level because of the steep dose-response relationship. 

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. 

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). 

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. 

Heagle and associates found a reduction in yield of sweet com and soybean after exposure to ozone at 0.10 ppm for 6 h/day over much of the growing season. These exposures were carried out in field chambers set over soybean plots in the field. They suggested that a threshold for measurable effects on these crops would lie between ozone (oxidant) concentrations of 0.05 and 0.10 ppm for 6 h/day. These values are realistic in terms of growing-season averages in the eastern United States. More of these studies could help to clarify dose-response relationships for economically important crops. Table 11-5 summarizes these long-term, chronic studies. 

Differences of opinion are common among epidemiologists based on what appears to be similar, if not comparable, data. In spite of the numerous large-scale and long-term investigations, the debate eontinues over whether there is a safe (threshold) level for asbestos or other fibrous materials, or if there is a linear dose-response relationship in the induction of cancer. Conclusions and interpretations of this body of data usually reflect personal philosophy and tolerance of risk. 

There is evidence that dose-response relationships exist for both skin sensitization and respiratory hypersensitivity, although these are frequently less well defined in the case of respiratory hypersensitivity (EC 2003). The dose of a substance required to induce sensitization in a previously naive subject or animal is usually greater than that required to elicit a reaction in a previously sensitized individual therefore, the dose-response relationship for these two phases will differ. Elicitation responses depend on several factors, among which are potency of the allergen and exposure conditions. Appropriate dose-response data can provide important information on the potency of the substance under evaluation. For sensitizers it is considered prudent to assume that a threshold cannot be identified, i.e., it is not possible to identify an elicitation dose or concentration of a sensitizing substance below which adverse effects are unlikely to occur in people already sensitized to a substance (EC 2003). 

Dose-response relationship and threshold for any of the adverse toxicological effects observed in the repeated dose toxicity studies. 

For non-threshold mechanisms of genotoxic carcinogenicity, the dose-response relationship is considered to be linear. The observed dose-response curve in some cases represents a single ratedetermining step however, in many cases it may be more complex and represent a superposition of a number of dose-response curves for the various steps involved in the tumor formation (EC 2003). Because of the small number of doses tested experimentally, i.e., usually only two or three, almost all data sets fit equally well various mathematical functions, and it is generally not possible to determine valid dose-response curves on the basis of mathematical modeling. This issue is addressed in further detail in Chapter 6. 

In the hazard assessment process, described in detail in Chapter 4, all effects observed are evaluated in terms of the type and severity (adverse or non-adverse), their dose-response relationship, and the relevance for humans of the effects observed in experimental animals. For threshold effects, a No- or a Lowest-Observed-Adverse-Effect Level (N/LOAEL), or alternatively a Benchmark Dose (BMD), is derived for every single effect in all the available smdies provided that data are sufficient for such an evaluation. In the last step of the hazard assessment for threshold effects, all this information is assessed in total in order to identify the critical effect(s) and to derive a NOAEL, or LOAEL, for the critical effect(s). 

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). 

Another model, widely used in the past, is the Mantel-Bryan probit model (Mantel et al., 1975). This can be derived by assuming that the dose-response relationship for each individual has a threshold, and that the thresholds for different individuals in the population are distributed log-normally. This model gives a lower risk at low doses than does any power law and, therefore, a lower risk than the multistage or proportional models (Figure 8.5). Moreover, when backgroimd is included, Crump et al., (1976) and Pfeto (1977) have shown that it... 

---