Toxicants dose-response curves

However, one caveat should be mentioned at this point. If you examine Figure 7.3 closely, you will observe that the lines for lethality and efficacy do not exactly follow the same slope. In cases where the mortality/toxicity dose-response curves follow a shallower slope, the TI will necessarily be lower in the lower dosage range. This is... 

Determining anticipated route and magnitude of exposure is an important component in the overall assessment of safety and must be done on a nanomaterial-by-nanomaterial basis, with secondary exposures taken into consideration when necessary. The estimated exposure levels for a nanomaterial may then be compared with the calculated safe dose derived from the hazard identification evaluation. The procedures and factors considered in the exposure assessment process are not expected to be any different for nanomaterials than for larger particles or chemicals. The degree of hazard associated with exposure to any chemical or substance, regardless of its physicochemical characteristics, depends on several factors, including its toxicity, dose-response curve, concentration, route of exposure, duration and/or frequency of exposure. However, depending on the route of anticipated exposure (dermal, inhalation, oral) and types of associated toxicities (local or systemic), a chemical may not pose any risk of adverse effects if there is no... 

Fig. 5. Toxic chemical dose—response curves (a) no effect (b) linear effect (c) no effect at low dose and (d) beneficial at low dose.

However, there are multiple routes of entry to the body for some materials. When a toxic chemical acts on the body or system, the nature and extent of the injurious response depends upon the dose received, that is, the amount of the chemical actually entering the body or system. This relationship of dose and response is shown in Figure 3. The dose-response curve varies with the type of material and the response. 

Hazard characterization, or dose-response characterization, by using experimental animals to reveal target organs and toxic doses, and the shape of the dose-response curve... 

FIGURE 5.56 The threshold region for chronic dose-response curves. [Reprinted with permission from Tardiff, R.G., and Rodricks, J.V. (1987). (Eds.), Toxic Substances and Human Risks Principles of Data Interpretation. New York Plenum Press.]... 

If the exposure level (E) exceeds tliis tlireshold (i.e., E/RfD exceeds unity), tliere may be concern for potential noncancer effects. As a rule, tlie greater tlie value of E/RfD above unity, tlie greater tlie level of concern. However, one should not interpret ratios of E/RfD as statistical probabilities a ratio of 0.001 does not mean tliat tliere is a one in one tliousand cliance of the effect occurring. Furtlier, it is important to empliasize tliat tlie level of concern does not increase linearly as tlie RfD is approached or exceeded because RfDs do not have equal accuracy or precision and are not based on tlie same severity of toxic effects. Thus, tlie slopes of the dose-response curv e in excess of the RfD can range widely depending on tlie substance. 

Figure 4-114. Determination of lethal toxicity from the dose-response curve [32A]. (Courtesy SPE.)...

Toxic equivalency factors (TEFs) are estimated relative to 2,3,7,8-TCDD, which is assigned a value of 1. They are measures of the toxicity of individual compounds relative to that of 2,3,7,8-TCDD. A variety of toxic indices, measured in vivo or in vitro, have been used to estimate TEFs, including reproductive effects (e.g., embryo toxicity in birds), immunotoxicity, and effects on organ weights. The degree of induction of P450 lAl is another measure from which estimations of TEF values have been made. The usual approach is to compare a dose-response curve for a test compound with that of the reference compound, 2,3,7,8-TCDD, and thereby establish the concentrations (or doses) that are required to elicit a standard response. The ratio of concentration of 2,3,7,8-TCDD to concentration of test chemical when both compounds produce the same degree of response is the TEF. Once determined, a TEF can be used to convert a concentration of a dioxin-like chemical found in an environmental sample to a toxic equivalent (TEQ). 

Fig. 11.1 A hypothetical dose-response curve for a toxic chemical.

The results of the studies reviewed here show that the neurotoxic effects of MDMA generalize to the primate. Further, they indicate that monkeys are considerably more sensitive than rats to the serotonin-depleting effects of MDMA, and that the dose-response curve of MDMA in the monkey is much steeper than in the rat. Perhaps as a consequence of this, the toxic effects of MDMA in the monkey involve serotonergic nerve fibers as well as cell bodies, whereas in the rat, only nerve fibers are affected. The present studies also show that the toxic dose of MDMA in the monkey... 

Endpoint/Concentration/Rationale 5 ppm for 1 h considered as a no-observed-effect level (NOEL) for decreased hematocrit levels. A NOEL was used because of an extremely steep dose-response curve and the fact that the ultimate toxic effect, renal failure, is delayed for several days. 

Third as with most toxicological effects, toxic effects to the immune system are dependent upon dose to the target site. The dose-response curve can be used to determine no-effect and low-effect levels for immunotoxicity. These levels can then be compared to the therapeutic levels to assess whether there is an adequate margin of safety for humans. 

Reproductive Toxicity. No information was located regarding reproductive effects in humans. Intermediate-duration inhalation studies in animals (Eustis et al. 1988 Kato et al. 1986) indicate that the testes may undergo degeneration and atrophy at high exposure levels, but the dose- response curve is not well defined. Further studies in animals to identify the threshold for this end point would... 

For all toxic effects other than carcinogenicity, a threshold in the dose-response curve is assumed. The lowest NOAEL from all available studies is assumed to be the approximate threshold for the groups of subjects (humans or animals) in which toxicity data were collected. Alternatively, a benchmark dose (BMD) may be estimated from the observed dose-response curve, and used as the point-of-departure for risk assessment (see below and Box). 

As intake increases above the range of adequacy a region will be reached at which the adverse effects of excessive intake will begin to manifest themselves. Figure 9.1 depicts these interesting dose-response curves, and the curve at the right side of the figure represents a typical dose-response relationship for toxicity, in this case caused by excessive intakes of substances we cannot live without at lower doses. 

The more classical approach to assess the presence of marine biotoxins in seafood is the in vivo mouse bioassay. It is based on the administration of suspicious extracted shellfish samples to mice, the evaluation of the lethal dose and the toxicity calculation according to reference dose response curves, established with reference material. It provides an indication about the overall toxicity of the sample, as it is not able to differentiate among individual toxins. This is a laborious and time-consuming procedure the accuracy is poor, it is nonspecific and generally not acceptably robust. Moreover, the mouse bioassay suffers from ethical implications and it is in conflict with the EU Directive 86/609 on the Protection of Laboratory Animals. Despite the drawbacks, this bioassay is still the method of reference for almost all types of marine toxins, and is the official method for PSP toxins. 

Causes of adverse effects over-dosage (A). The drug is administered in a higher dose than is required for the principal effect this directly or indirectly affects other body functions. For instances, morphine (p. 210), given in the appropriate dose, affords excellent pain relief by influencing nociceptive pathways in the CNS. In excessive doses, it inhibits the respiratory center and makes apnea imminent The dose dependence of both effects can be graphed in the form of dose-response curves (DRC). The distance between both DRCs indicates the difference between the therapeutic and toxic doses. This margin of safety indicates the risk of toxicity when standard doses are exceeded. 

For most of the toxic effects that might be exerted by a chemical substance, the dose-response curve is S-shaped as illustrated in Figure 4.1. This means that no response occurs at the lower dose levels, but as the dose level increases the response will become more and more pronounced until a plateau is reached. 

Other dose-response relationships may also be seen for certain compounds such as, e.g., essential metals, where symptoms of dehciency may occur if the intake is too low, whereas toxic symptoms may occur if the intake is too high. For such compounds, the dose-response curve is generally U-shaped as illustrated in Figure 4.2. It should be noted that the right part of the U-shaped curve representing the toxic effects in reality is the typical S-shape observed for toxic effects in general. 

As mentioned above, a NOAEL is usually not derived in acute toxicity smdies. It is more usual that the only numerical value derived is the LD50 or LC50 value. The LD50 or LC50 values (or the discriminating dose if the Fixed Dose Procedure was used or the result of the Acute Toxic Class Method) give an indication of the relative lethal potency of a substance. The slope of the dose-response curve is a particularly useful parameter as it indicates the extent to which reduction of exposure will reduce the lethality the steeper the slope, the greater the reduction in response for a particular finite reduction in exposure. 

---