Toxicity factor, dose-response relationship

In addition to the effect of biological variabihty in group response for a given exposure dose, the magnitude of the dose for any given individual also determines the severity of the toxic injury. In general, the considerations for dose—response relationship with respect to both the proportion of a population responding and the severity of the response are similar for local and systemic effects. However, if metabohc activation is a factor in toxicity, then a saturation level may be reached. 

Uncertainty Factors/Rationale Total uncertainty factor 30 Interspecies 10—The 10-min LC50 value for the monkey was about 60% of the rat value and one-third the rabbit value. The mouse data were used to calculate the AEGL levels, because the data exhibited a good exposure-response relationship and the endpoint of decreased hematocrit levels can be considered a sensitive indicator of arsine toxicity. In addition, arsine has an extremely steep dose-response relationship, allowing little margin in exposure between no effects and lethality. 

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. 

An additional assessment factor, of up to 10, has been apphed in some cases where the NOAEL has been derived for a critical effect, which is considered as a severe and irreversible effect, such as teratogenicity or non-genotoxic carcinogenicity, especially if associated with a shallow dose-response relationship. The principal rationale for an additional factor for nature of toxicity has been to provide a greater margin between the exposure of any particularly susceptible humans and the dose-response curve for such toxicity in experimental animals. 

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. 

Dose levels should be chosen in a manner that a dose-response relationship can be established including a toxic dose and a no observed adverse effect level (NOAEL). The selection of dose levels should be justified by using pharmacological/physiological effects. Availability of suitable test material can be also an important and accepted factor for the limitation of the dose regimen especially with regard to the determination of the high dose level. 

Because the literature describes several limitations in the use of NOAELs (Gaylor 1983 Crump 1984 Kimmel and Gaylor 1988), the evaluative process considers other methods for expressing quantitative dose-response evaluations. In particular, the BMD approach originally proposed by Crump (1984) is used to model data in the observed range. That approach was recently endorsed for use in quantitative risk assessment for developmental toxicity and other noncancer health effects (Barnes et al. 1995). The BMD can be useful for interpreting dose-response relationships because it accounts for all the data and, unlike the determination of the NOAEL or LOAEL, is not limited to the doses used in the experiment. The BMD approach is especially helpful when a NOAEL is not available because it makes the use of a default uncertainty factor for LOAEL to NOAEL extrapolation unnecessary. 

Organophosphates illustrate several points. First, repeated exposure can be a problem not only because of accumulation of the substance (as can occur with other substances such as aspirin) but also because of accumulation of the effect, if it is irreversible. Therefore the dose-time relationship is important as weU as the dose-response relationship. Secondly, understanding the mechanism allows effective detection and treatment thirdly, other factors such as decomposition and exposure to other chemicals can have a large impact on toxicity and finally the dose is crucial, and it would seem, at least from the information available at present, that OPs can be used safely if they are used sparingly and carefully. 

See also Acceptable Daily Intake (ADI) Dose-Response Relationship Reference Dose (RfD) Toxicity, Acute Toxicity, Chronic Uncertainty Factors. 

Toxicity assessment includes characterization of the toxicity of a chemical, development of a dose-response relationship, and ultimately the development of exposure criteria. Toxicity values express a dose that is associated with either a given risk of cancer occurring over a lifetime of exposure (e.g., slope factors and unit risks) or a dose that is not expected to cause harm (e.g., RfDs). Some toxicity values are used as the basis for developing exposure criteria (RfDs) and some can be used as exposure criteria (e.g., RfCs). US EPA has developed toxicity values for many chemicals commonly associated with environmental contamination. Verified US EPA criteria are available in the Integrated Risk Information System (IRIS). 

By determination of factors including the dose-response relationship, potency, species variation in susceptibility mechanism of toxicity. 

The effect of a chemical on the environment (open ocean, coastal waters, estuary, aquatic fauna, aquatic flora, etc.) depends on the toxicity of the chemical and on the amount of the chemical the environment is exposed to (for example, the amount of chemical discharged, the administered dose, the concentration of chemical, and the length of exposure). Accordingly, to determine the effects, two factors have to be investigated toxicity and exposure. Identification of hazards requires studies of toxicity, whereas exposure data are needed for the estimation of risk. Risk is the probability that the exposure conditions are such that the hazards may materialize and result in an effect. Toxicity data consist of dose-response relationships and, in the aquatic environment, dose is usually given by the concentration and the length of exposure. 

Effects data applicable for QSAR analyses are reported in terms of a constant equivalent response - that is, isoeffective concentrations that correspond to the number of moles of the compounds evoking the same effect. Activity measures such as toxicity parameters should be based on a dose-response curve, not only on a single point determination. Various factors act as determinants in dose-response relationships, such as route of exposure, duration of exposure and species sensitivity (Figure 2.8). 

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