Hazard assessment data from experimental animals

The risk assessment comprises an effect assessment (hazard identification and hazard characterization) and an exposure assessment. The principles for the effect assessment of the active substances are in principle similar to those for existing and new chemicals and are addressed in detail in Chapter 4. Based on the outcome of the effect assessment, an Acceptable Daily Intake (ADI) and an Acceptable Operator Exposure Level (AOEL) are derived, usually from the NOAEL by applying an overall assessment factor addressing differences between experimental effect assessment data (usually from animal studies) and the real human exposure situation, taking into account variability and uncertainty for further details the reader is referred to Chapter 5. As a part of the effect assessment, classification and labeling of the active substance according to the criteria laid down in Directive 67/548/EEC (EEC 1967) is also addressed (Section 2.4.1.8). 

Finally, the use of different types of information (human data, data from studies in experimental animals, in vitro test data, and other data such as, e.g., data on physico-chemical properties and (Q)SAR) in the hazard assessment for a specific endpoint is addressed in more detail. 

As mentioned previously, the assessment of hazard and risk to humans from exposure to chemical substances is generally based on the extrapolation from data obtained in smdies with experimental animals. In the absence of comparative data in humans, a basic assumption for toxicological risk assessment is that effects observed in laboratory animals are relevant for humans, i.e., would also be expressed in humans. In assessing the risk to humans, an assessment factor is applied to take account of uncertainties in the differences in sensitivity to the test substance between the species, i.e., to account for interspecies variability (Section 5.3). If data are available from more than one species or strain, the hazard and risk assessment is generally based on the most susceptible of these except where data strongly indicate that a particular species is more similar to man than the others with respect to toxicokinetics and/or toxicodynamics. Two main aspects of toxicity, toxicokinetics and toxicodynamics, account for the namre and extent of differences between species in their sensitivity to xenobiotics this is addressed in detail in Chapter 5. 

As mentioned previously, there are no test guideline methods for respiratory irritation. Good data, often clearly related to exposure levels, can be obtained on respiratory and mucous membrane irritation, from well-designed and well-reported inhalation studies in animals. Also the Alarie test (Alarie 1973, 1981), an experimental animal test assessing the concentration that results in a 50% reduction of the breathing frequency, may provide useful information on sensory irritation of the upper respiratory tract and the results may be used for hazard identification. 

Data from studies in experimental animals are the typical starting points for hazard and risk assessments of chemical substances and thus differences in sensitivity between experimental animals and humans need to be addressed, with the default assumption that humans are more sensitive than experimental animals. The rationale for extrapolation of toxicity data across species is founded in the commonality of anatomic characteristics and the universality of physiological functions and biochemical reactions, despite the great diversity of sizes, shapes, and forms of mammalian species. 

The most relevant study to base a hazard assessment and derivation of a tolerable intake upon is a study that reflects the human exposure situation as well as possible. Eor numerous substances, data are only available from acute (single exposure), subacute (14—28 days), or subchronic (90 days) animal studies. In order to derive, e.g., a TDl or RfD for such a substance, it may be necessary to base the assessment on data from a shorter duration study. An assessment factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that, in general, the experimental NOAEL will decrease with increasing exposure duration as well as other and more serious adverse effects may appear with increasing exposure duration. 

Modeling health effects from various hazard levels is a difficult task. Risk assessments are typically based on the risk of death or serious injury. Obviously there are no experimental data available on the dose-response relationship of material concentration and exposure duration, thermal radiation intensity or blast overpressures on humans. What little there is has been inferred from actual accidents. Models that predict the impact of exposure to hazardous materials are heavily influenced by animal experiments. Typically, they have large safety factors built in. It is believed that models based primarily on exposure of experimental animals are conservative when applied to humans, especially when, on a body weight difference, the animals are much smaller than humans. In fact, many will argue that they are too conservative. These estimates are difficult to make, and unfortunately little can be done to improve the degree of uncertainty. 

It is a requirement of any food law that food offered for sale and consumption by the public should be wholesome. Hence any ingredient of food and also any technological additive used in food should be safe when ingested by man. Evidence for the harmlessness of food additives rests essentially on the demonstration that, in the doses in which they are ingested by man, no adverse toxic effects will arise . Since direct experimentation in man is clearly impossible, reliance has to be placed on experiments with laboratory animals. From the observed results, predictions by extrapolation are made of the reactions likely to occur in man, and the eventual hazards from ingestion by man are assessed. Obviously hazard evaluation can be meaningful only on the basis of adequate data. These, in turn, require that the appropriate animal experiments are carried out and conducted in an adequate manner. 

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