Toxicology data, animal assessment

The MOE approach is often used to determine the acceptability of acute risks for single chemicals and MOEs of >100 or >10 are usually considered acceptable when derived from toxicological data from animal and human studies, respectively. The US-EPA favors this concept for performing aggregate and cumulative risk assessments (Whalan and Pettigrew 1997). 

An important outcome of the JECFA evaluation is the establishment of an ADI for a food additive. The ADI is based on the available toxicological data and the no adverse effect level in the relevant species. JECFA defines the ADI as an estimate of the amount of a food additive, expressed on a body weight basis, that can be ingested daily over a lifetime without appreciable health risk (8). JECFA utilizes animal data to determine the ADI based on the highest no-observed-adverse-effect level (NOAEL), and a safety factor is applied to the NOAEL to provide a margin of safety when extrapolating animal data to humans. JECFA typically uses safety factors of 50, 100, or 200 in the determination of an ADI. The NOAEL is divided by the safety factor to calculate the ADI. The food additive is considered safe for its intended use if the human exposure does not exceed the ADI on a chronic basis. This type of information may potentially be used to help assess the safety of a pharmaceutical excipient that is also used as a food additive, based on a comparison of the ADI to the estimated daily intake of the excipient. 

For example, the Threshold of Toxicological Concern concept has been proposed, which reduces the amount of toxicological data necessary and therefore reduces the number of animals used in the assessment of hazard. This uses a tiered approach and excludes certain kinds of chemicals such as dioxins and organophosphates. It also makes use of structural alerts and chemical classes to select out chemicals, which are likely to be of little toxicological concern (13). 

A good example of the difficulties involved in accessing toxicological data of organo-fluorine compounds can be seen by examining the work of Hodge, Smith and Chen,5 published in 1963. This included results many of which were mainly preliminary toxicity data, reported in the literature until 1961. Much data that was not comparable in depth of focus, meaningfulness, mode of application, animal material, doses, and quality of research was summarized in this article. Information contained within such an article is difficult for experimental chemists to assess. Further data on the toxicity of fluoroalkanes, fluoroalkenes and fluoropolymers has been published.6... 

After assessing patterns of use in farm animals, the metabolism and pharmacokinetics, toxicological data, residue depletion (under field conditions) and analytical criteria for each compound, JECFA recommends acceptable daily intakes (ADIs) for them. 

Although this risk assessment does include some qualitative discussion of the uncertainties associated with the quantitative characterization of the risk, it does not include important qualitative discussions of the available toxicological data, the assumption that adverse health effects observed in animals will necessarily be observed in humans, the absence of observed adverse health effects in humans, etc. 

Combes R, Barratt M, and Balls M (2003) An overall strategy for the testing of chemicals for human hazard and risk assessment under the EU REACH system. Alternatives to Laboratory Animals ATLA 31 7-19. Hanway RH and Evans PE (2000) Read-across of toxicological data in the notification of new chemicals. Toxicology Letters 116(Suppl. 1) 61. 

The extrapolation of animal toxicology data and combination with human exposure data aiay be used to estimate risk for those situations where exposure is likely. Methods for integrating these data as well as the assumptions for extrapolation from the animal studies are dependent upon the safety data. Risk assessment includes consideration of the type of toxicity involved and its potency, species comparisons, time considerations, dose response, kinetics of homeostatic mechanisms, and mechanisms of toxicity. When the essential components for extrapolations are well understood, more precise estimates can be made. In the absence of such understanding, more conservative approaches are appropriate. 

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