Toxicology data, animal

Preclinical and clinical process laboratories serve a critical function in the development and organization of toxicology data, animal testing results, and ultimately of human test results. Again, the GLPs provide guidance and assure both minimization of misinterpretation and control of both the potential risks to human subjects and the suffering of test animals. 

New toxicological data on some of the synthetic antioxidants cautioned against their use. In the recent past, natural antioxidants attracted the attention of many food manufacturers as a result of the necessity to produce healthy foods. Numerous antioxidative efficacious compounds that are found in animal or plant tissues and that are also available as synthetic molecules are used in several food applications. Herbs and spices occupy a special position in foods as traditional food ingredients and hence are appropriately used directly for their antioxidant characteristics. If they are applied to foods, they do not need to be declared as antioxidants. 

There are many circumstances in which the only information we can develop on toxic hazards and dose-response relationships derives from experiments on laboratory animals. The example of the food additive, presented in the opening pages, is just one of many circumstances in which condition A involves animal toxicology data, and condition B involves a human population, almost always exposed at small fractions of the dose used in animals, and sometimes exposed for much larger fractions of their lifetime than the animals, and even by different routes. Extrapolations under these circumstances should cause individuals trained in the rigors of the scientific method to seek some form of psychological counsel, or, better yet, to return to the laboratory. 

On the basis of the foregoing discussion, it appears that, if traditional criteria for hazard evaluation are applied to the toxicologic data on experimental animals, there is little room for complacency r arding current ambient concentrations of ozone. Functional, biochemical, and structural effects in both pulmonary and extrapulmonary sterns have been reported by numerous investigators at or near concentrations that are at least occasionally achieved in some polluted urban centers. Unfortunately, there are no adequate methods for extrapolating data to obtain reliable quantitative estimates of population risk at environmental concentrations near the standard, and there is no assurance that the risk is zero. 

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). 

The anlmal-toxlclty data in this section, taken from several sources,1 ,20,35,36,40,44 show that the compounds most studied in animals and humans were DMHP and DMHP acetate (more light- and air-stable than DMHP). Although eight optical isomers of the acetate were tested in humans, no specific toxicology data were found. 

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... 

From the literature, statistically relevant toxicological data for acute toxicity testing (e. g., LCS(), LD50, dermal) are based on the exposition of 6 animals (minimum) with a control group of 6. Normally, several doses are used, one at a time, starting from close to the no-effect level (e. g., via the respiratory tract for a defined time). After exposure the animals are observed... 

In addressing consumer safety the VPC achieves this by consideration of the toxicological data and the no effect level (NEL = No observed Effect Level) for that substance in experimental animals. This, together with an additional safety factor to allow for any inter-species and intra-species variability, is used to calculate the acceptable daily intake (ADI). For an adult human the ADI is calculated from the NEL by using the following formula for a 60 kg person ... 

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. 

This maximum legal exposure, often referred to as the Theoretical Maximum Residue Contribution, or TMRC, is compared with established toxicological criteria such as the reference dose (RfD) or Acceptable Daily Intake (ADI) which represent, after analysis of animal toxicology data and extrapolations to humans, the daily exposure that is not considered to present any appreciable level of risk. When it is determined that the TMRC exposure is below the RfD or ADI, the EPA usually considers the risks from the pesticide in question to be negligible and approves the manufacturer s petition to establish a tolerance at or slightly greater than the maximum levels identified from the manufacturer s controlled field trials (Winter, 1992a). 

Nonclinical research provides very useful information and plays a considerable role in the successful development of a new drug. It is also required by current regulatory statutes. Nonetheless, no matter how meticulously, rigorously, and comprehensively nonclinical testing is conducted, no animal model is a perfect model of the drug s actions and effects in humans. Therefore, in addition to an appreciation of the usefulness of nonclinical data, it is valuable to have an appreciation of their limitations and of statistical considerations of particular pertinence to toxicological data. 

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