Toxicity factor, dose-response

There are of course many mathematically complex ways to perform a risk assessment, but first key questions about the biological data must be resolved. The most sensitive endpoint must be defined along with relevant toxicity and dose-response data. A standard risk assessment approach that is often used is the so-called divide by 10 rule . Dividing the dose by 10 applies a safety factor to ensure that even the most sensitive individuals are protected. Animal studies are typically used to establish a dose-response curve and the most sensitive endpoint. From the dose-response curve a NOAEL dose or no observed adverse effect level is derived. This is the dose at which there appears to be no adverse effects in the animal studies at a particular endpoint, which could be cancer, liver damage, or a neuro-behavioral effect. This dose is then divided by 10 if the animal data are in any way thought to be inadequate. For example, there may be a great deal of variability, or there were adverse effects at the lowest dose, or there were only tests of short-term exposure to the chemical. An additional factor of 10 is used when extrapolating from animals to humans. Last, a factor of 10 is used to account for variability in the human population or to account for sensitive individuals such as children or the elderly. The final number is the reference dose (RfD) or acceptable daily intake (ADI). This process is summarized below. 

Exposure assessment is a necessary component in understanding the hazard involved by exposure to naturally (i.e., radon) or non-naturally existing toxicants (i.e., chemicals emitting from construction materials) [12]. However, the other two (toxicity and dose-response assessments) are the next two important factors to know. 

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. 

Commercial PCBs Toxic and Biochemical Effects. PCBs and related halogenated aromatic hydrocarbons ehcit a diverse spectmm of toxic and biochemical responses in laboratory animals dependent on a number of factors including age, sex, species, and strain of the test animal and the dosing regimen (single or multiple) (27—32). In Bobwhite and Japanese quad, the LC q dose for several different commercial PCB preparations ranged from 600 to 30,000 ppm in the diet the LC q values for mink that were fed Aroclors 1242 and 1254 were 8.6 and 6.7 ppm in the diet, respectively (8,28,33). The... 

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). 

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. 

Renwick considered that in relation to carcinogenicity for non-genotoxic chemicals and teratogenicity, the application of an extra factor for nature of toxicity is difficult to justify scientifically. He concluded that if a safety factor for nature of toxicity is to be used then logically it should be apphed to the NOAEL for the toxicity, which resulted in its use. For example, in relation to teratogenicity, a factor for nature of toxicity should be applied to the NOAEL for teratogenicity and not for maternal toxicity or some other endpoint. For carcinogenicity, the extra factor should be applied only to the NOAEL for the detection of tumors in those studies where this effect was the rationale for the use of an extra factor. In relation to a steep dose-response, it was concluded that this, in reality, concerns the precision of the NOAEL and therefore relates to the adequacy of the database rather than nature of toxicity. 

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. 

The NOEL is the "no observed effect level" and it is determined from the dose-response curve when the toxic effect being measured is plotted against the dose. It is the highest dose where no toxicity is observed. The ADI is the "acceptable daily intake" and is usually determined as NOEL/100. The arbitrary factor of 100 is applied to account for individual differences between humans (factor of 10) and for species differences (factor of 10) as the NOEL is derived from animal toxicity studies. The ADI is the amount of a food additive that is felt to be safe to be ingested on a daily basis. 

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