Toxic dose curve

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... 

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... 

Figure 2-8 The various types of response vs. log dose curves. ED, effective dose TD, toxic dose LD, lethal dose. For gases, LC (lethal concentration) is used.

Finally, if the response to the agent is toxic (an undesirable response that is not lethal but is irreversible, such as liver or lung damage), the response-log dose curve is called the toxic dose, or TD curve. 

Most often, response-dose curves are developed using acute toxicity data. Chronic toxicity data are usually considerably different. Furthermore, the data are complicated by differences in group age, sex, and method of delivery. If several chemicals are involved, the toxicants might interact additively (the combined effect is the sum of the individual effects), synergisti-cally (the combined effect is more than the individual effects), potentiately (presence of one increases the effect of the other), or antagonistically (both counteract each other). 

Toxicants are compared for relative toxicity based on the LD, ED, or TD curves. If the response-dose curve for chemical A is to the right of the response-dose curve for chemical B, then chemical A is more toxic. Care must be taken when comparing two response-dose curves when partial data are available. If the slopes of the curves differ substantially, the situation shown in Figure 2-13 might occur. If only a single data point is available in the upper part of the curves, it might appear that chemical A is always more toxic than chemical B. The complete data show that chemical B is more toxic at lower doses. 

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. 

FIGURE 1-4 Cumulative dose-response curve. The median effective dose CED5tl) is 10 mg, and the median toxic dose (TD50] is 320 mg. The therapeutic index (Tf) for this drug is 32. 

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... 

Multiple exposures to the same chemical may have an effect similar to a single exposure. This is the case when each dose is too low to cause any adverse effects, and it is excreted by the body before the next dose is administered (see the short arrows and the dotted curve in Figure 9.25). But if the exposure period is shortened and the excretion is not complete, the chemical concentration in blood increases from day to day, and finally reaches that of a toxic dose (see the long arrows and the solid curve in Figure 9.25). Therefore it is not only the total exposure that is critical, but also the exposure frequency. 

The same conflicts exist for the escalation scheme. Once the current dose level has been demonstrated to be safe, the move to next higher level is clouded by uncertainty about the steepness of the dose-toxic response curve. Recently, there has been an appreciation of the linkage between choices for starting dose and escalation rate. In particular, the combination of a cautious starting dose with a very conservative escalation rate can lead to trials that are so lengthy that they serve the interests of no one. 

The drug exposure (area under the curve AUC) ratio at approximately equitoxic doses has much less variability, indicating that pharmacokinetic differences account for almost all of the differences observed for toxic doses of this set of drugs between humans and mice. 

As shown in Figure 1-2-5, these D-R curves can also be used to show the relationship between dose and toxic effects of a drug. The median toxic dose of a drug (TD50) is the dose that causes toxicity in 50% of a population. 

The form of Eq. (4) and the shape of the curves in Fig. 16.2 show that there is not a single toxic dose. In other words, the product C x f is not constant. Higher concentrations of chlorine are more dangerous than the assumption of a toxic dose would indicate. This seems to be a widespread if not a general phenomenon. When the independent variable in the probit equation is expressed as C"t, the exponent normally is greater than 1.0. Lees [83] gives an approximate value of 2.75 for both ammonia and chlorine. 

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... 

Effective dose (ED) The dosage at which the effects of a toxic material are noticeable but minor and reversible. The specific values are often plotted as dose-response curves or given as EDio or EDso- The latter is the effective dose at which symptoms are noticeable in 50% of flie reported subjects. The values of the ED are always less than tire toxic dose (TD). See lethal dose and toxic dose. 

Toxic dose The dosage at which the effects of a material are noticeable and irreversible. Data are often plotted on response vs. dosage curves or listed as, for example, TDio or TD50. TD50 is the dose at which symptoms are toxic for 50% of the reported subjects. Also see effective dose and lethal dose. 

The quantal dose-effect curve provides a guide to toxic effect frequencies relative to exposure under the conditions of the laboratory toxicity test. Doses corresponding to other toxic effect frequencies may be extrapolated from cumulative dose-effect curves. For example, the 10% toxic dose, or TD,q, represents a dose corresponding to a cumulative-effect incidence of 10% of the test population it is determined by finding the dose that corresponds to a 10% cumulative-effect frequency (in the sigmoidal curve) or 3.7 probit units (in the probit plot). The 75% toxic dose, or TD75, is the dose corresponding to 75% cumulative-effect incideuce or 5.8 probits. 

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.

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