Critical toxic effect, risk assessment

In summary, in studies of chemical toxicity, pathways and rates of metabolism as well as effects resulting from toxicokinetic factors and receptor affinities are critical in the choice of the animal species and experimental design. Therefore it is important that the animal species chosen as a model for humans in safety evaluations metabolize the test chemical by the same routes as humans and, furthermore, that quantitative differences are considered in the interpretation of animal toxicity data. Risk assessment methods involving the extrapolation of toxic or carcinogenic potential of a chemical from one species to another must consider the metabolic and toxicokinetic characteristics of both species. 

Similarly, the reductions in toxicity observed in laboratory toxicity tests where exposure is modified (either through the addition of sediment or by removal to clean water) are also apparent in the field. Field effect concentrations are generally observed to occur at concentrations around three to ten times above those based on standard laboratory data. Dissipation and degradation are therefore clearly the critical factors in mitigating effects of pyrethroids under field conditions. This provides reassurance that preliminary ecological risk assessments based on... 

The toxic effect occurring at the lowest dose (the most sensitive indicator of a chemical s toxicity) is selected as the critical health concern for risk assessment. 

A chemical may constitute a number of hazards of different severity. However, the primary hazard (or critical effect) will be the one used for the subsequent stages of the risk assessment process. For example, a chemical may cause reversible liver toxicity at high doses but cause tumors in the skin at lower doses. The carcinogenicity is clearly the hazard of concern. 

As risk assessment scientists continue to accumulate and develop knowledge of toxicokinetics, toxicodynamics, mechanisms of toxicity, and temporal effects of critical effects for various chemicals, evaluations become increasingly more accurate and detailed. Moreover, the science behind the use of UFs has progressed considerably. Increased understanding of... 

In the absence of human data (the most preferred data for risk assessment), the dose-response assessment for either cancer or noncancer toxicity is determined from animal toxicity studies using an animal model that is relevant to humans or using a critical study and species that show an adverse effect at the lowest administered dose. The default assumption is that humans may be as sensitive as the most sensitive experimental species. 

The characterization of ecological effects is perhaps the most critical aspect of the risk assessment process. Several levels of confidence exist in our ability to measure the relationship between dose and effect. Toxicity measured under set conditions in a laboratory can be made with a great deal of accuracy. Unfortunately, as the system becomes more realistic and includes multiple species and additional routes of exposure, even the ability to measure effects is decreased. 

The first type concerns the hazards of these chemicals their flammability, their explosivity, their radioactivity, and their toxicity. In the present context we are interested in the toxic properties of these chemicals. So, it would be necessary, under what is called the hazard evaluation step of risk assessment, to assemble all the available epidemiology and experimental toxicity data (the latter to include animal toxicity studies, ADME data, and studies of mechanisms of toxic action). The assembled data would then be critically evaluated to answer the question what forms of toxicity can be caused by the chemical of interest, and how certain can we be that human beings will be vulnerable to these toxic effects (under some conditions) ... 

The use of in vitro systems such as cell cultures, tissue slices, and cell lines has become of major importance for several reasons. First of all, the common practice of the use of experimental animal models for studying toxicity of chemicals meets serious and growing criticism for ethical and economic reasons. Toxicity studies aiming at performing a hazard or a risk assessment inevitably will include adverse effects and thus discomfort for the animals involved. Moreover, the cost of running an animal facility and performing toxicity studies is an increasingly important limitation. 

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