Dose-response relationship, toxic chemicals

The task for ecotoxicity assessment is to provide qualitative and quantitative indicators of the potential environmental impacts of chemicals, such as changes in the abundance of individual species or the diversity of the species community, taking into account the concentration and the time of exposure (dose-response relationships). Toxic action at the level of the organism may be classified according to Ariens (1984) ... 

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. 

With some possible exceptions (to be discussed in Chapter 9), dose-response relations identical or similar to those shown in Figure 3.1 are observed for all expressions of chemical toxicity. Indeed, the absence of such a dose-response relationship is often used as evidence that a chemical has not caused a particular response. Criteria for causation in... 

It seems that large numbers of chemicals, in equally large numbers of test systems, from mammals to insects, vertebrates to invertebrates, microorganisms to plants, exhibit hormetic dose-response relationships. The relationship is not the same as that described earlier for nutrients, in two ways. First, in the case of hormesis the biological response - the toxicity endpoint - is the same in the protective region and in the region of toxicity (i.e., liver cancer incidence is reduced relative to control incidence over a range of low doses, and then as the NOAEL is exceeded, liver cancer incidence increases above that of controls). This is true hormesis. 

W. K. Lutz, S. Vamvakas, A. Kopp-Schneider, J. Schlatter and H. Stopper, Deviation from additivity in mixture toxicity relevance of nonlinear dose-response relationships and cell line differences in genotoxicity assays with combinations of chemical mutagens and g-radiation. Environmental Health Perspectives Supplements, 2002,110(6), 915-918. 

SSDs are being routinely used for the display and interpretation of effects data (Parkhurst et al. 1996 Posthuma et al. 2002). An SSD for atrazine (shown in Figure 7.3) displays the typical S-shaped curve associated with many chemical dose-response relationships. Each point on the curve represents an LC50 for a particular species exposed to atrazine under standard toxicity test protocols. The SSD approach uses only a single statistically derived endpoint from each available toxicity test (e.g., the LC50 or EC50). In contrast, all data collected during any specific toxicity test can be used in a hierarchical model. The ability to use all available data to make inferential decisions is a marked improvement over the standard SSD effects distribution. 

It is natural to consider one or another of these trans-species dose prescriptions for scaling dose-response relationships in carcinogenesis. But in any chronic effect, such as carcinogenesis, another parameter enters namely, time. Whereas the LDjo describes the acutely toxic properties of a chemical, the relevant dose for carcinogenesis is usually accumulated over a long time. One must consider, therefore, the relationship between daily dose, total lifetime dose, and body weight. The difference in life spans between man and mouse—70 years versus 2 years—amounts to a factor 35. Most analyses, however, consider that it is the daily dose that is more relevant, and that the shorter lifetime of the mouse represents the effects of its higher metabolic rate. The difference between these various interspecies dose conversion schemes is illustrated in Thble 8.1. 

Exposure to toxic chemicals and the effect or response need to be quantitated to define the dose response relationship. These use what are called biomarkers, and new technology is constantly expanding the range of possible measurements. Susceptibility, important in risk assessment, can also be quantitated with biomarkers. 

Group VI biomarkers have the same fundamental properties as those in group IV, so they also share basic uses. But group VI has another important attribute toxicity information is available. It could be the dose-response relationship with the parent chemical in animals or in humans or the rela-... 

EPA bases its procedures for estimating RfD on several assumptions, the most basic of which is that a threshold exists in the dose-response relationship for the critical response. If the dose is above the threshold (not the same as RfD) and is of sufficient duration, EPA considers that the chemical will cause the response in some segment of the exposed population. The U.S. Food and Drug Administration uses a similar approach to identify safe levels of exposure to food additives and certain residues. Studies on many substances have shown that before toxicity occurs, the chemical must deplete a physiological reserve or overcome the various repair capacities in the human body (Klaassen et al., 1996). 

Dose-response data based largely on animal studies. It is noteworthy that rodent studies now used to predict the dose-response relationship in humans were never intended for that purpose (Barr, 1988). These studies were designed for purposes of hazard identification (see Section 3.1.4.1.2) and were not intended to be the basis for estimating human responses at low doses (Paustenbach, 1995). For example, there usually are significant differences between animals and humans with respect to the rate at which chemicals are metabolized, distributed, and excreted, and these are not taken into account when animal tests are designed. Also, animal tissues will frequently respond differently to toxicants than human tissue. 

Some information about cyanide toxicity in humans is available from research on accidental exposures—for example in industrial accidents—although the usefulness of these data is limited because exposure durations and concentrations are often not known or not reported, because small numbers of individuals were exposed, and because other details, such as possible exposure to other chemicals, also are often not reported. Scrutiny of blood cyanide concentrations in victims of cyanide poisoning could be misleading for the purposes of characterizing dose-response relationships, depending on the length of the delay before performing the assay (Chaturvedi et al. 1995). 

The RACB studies were designed by NTP to test chemicals for potential reproductive toxicity in males and females. In addition, this two-generation study design can be used to characterize the toxicity and to define the dose-response relationship for each chemical. 

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