Animal toxicity data

The AEGL-2 value is supported by animal toxicity data, which produce a higher value. The threshold for narcosis for several animal species is approximately 200,000 ppm (Collins 1984 Silber and Kennedy 1979a). Adjustment by interspecies and intraspecies UFs of 3 each (for a total of 10) results in an AEGL-2 value of 20,000 ppm. 

The in vivo data sets can be classified as compound details, adverse drug reaction data (ADR), pharmacokinetic data and animal toxicity data. 

BioPrint also includes a small animal toxicity data set. Blood chemistry and organ toxicity data have been gathered for more than 200 compounds. 

No studies were located in humans regarding the inhalation absorption of 1,2-dibromoethane. The available animal toxicity data (see Section 2.2.1) indicate that absorption of 1,2-dibromoethane occurs in rats, mice, rabbits, guinea pigs, and monkeys exposed via inhalation for acute, intermediate, and chronic durations (Rowe et al. 1952 Stott and McKenna 1984). Based on the findings in animal studies, 1,2-dibromoethane is expected to be absorbed in humans exposed via the inhalation route. 

Animal toxicity data collected by the same route of exposure as that experienced by humans are preferred for risk assessment, but if the toxic effect is a systemic one, then data from other routes can be used, with appropriate adjustments. 

The interindividual variability reflects differences in toxicokinetics as well as in toxicodynamics. With respect to toxicokinetic factors, interindividual differences in the metabolism of chemicals are generally considered as the most significant explanatory factor. Hardly any knowledge is available with respect to the factors that influence toxicodynamics. Thus, it is necessary to take such variation into account when extrapolating animal toxicity data to the human simation. 

Vocci, F. and T. Farber. 1988. Extrapolation of animal toxicity data to man. Regul. Toxicol. Pharmacol. 8 389-398. 

It may also be possible for time and money to be saved by eliminating requirements for animal toxicity data that are found to be no longer necessary. Excessive use of toxicity data has been criticised by some, reminiscent of the days when LD50 values in laboratory animals were routinely performed even when the precision sought in such studies was unnecessary for product development. 

Animal toxicity data generated in other countries may be accepted in India, and may not need to be repeated in India, depending upon the quality of data and the accreditations of the laboratories where the data were generated. 

The regulatory guidelines adopted for nonclinical safety assessment during drug development are primarily those of the ICH (1). The Indian regulatory system accepts any animal toxicity data generated in other countries as well. 

The 1980 Registry of Toxic Effects of Chemical Substances listed the following animal-toxicity data ... 

As provided in the Botanical Guidance, clinical studies have been permitted for many botanical preparations prior to a complete set of conventional animal toxicity testing. The decisions were not difficult for submissions with substantial and well-documented history of past human use. But some other applicants had not presented an adequate summary of the past human experiences and had failed even to document well-known toxicity of the herbal ingredients. Between these two extremes, how to adjust the requirements of animal toxicity data and substitute that with large quantity but poor quality of human experiences is another big challenge to the regulatory agency in the review of botanical applications. 

Zhou et al. 2001, 2002). The available data indicate that the thyroid is a particularly sensitive target of acute oral exposure and justify using thyroid effects as the basis for an acute oral MRL, but acute effects of PBDEs on the liver are not as well characterized as thyroid effects. Other studies indicate that immunosuppression and neurobehavior are important and potentially critical health end points for acute exposure to PBDEs that need to be further investigated (see discussions of data needs for Immunotoxicity and Neurotoxicity). Studies in other species would help to clearly establish the most sensitive target and species for acute exposure, as well as which animal toxicity data are the most relevant to humans and useful for assessing acute health risks. 

Therefore in practice, normally, animal toxicity data is required (see above). Of course, the differences between humans and other species must always be recognized and taken into account (see below). It may be possible to use in vitro data both from human cells and tissues as well as those from other animals to supplement the epidemiological and animal in vivo toxicity data. However, at present such data cannot replace experimental animal or human epidemiological data. The predictive use of structure-activity relationships is also possible, and it is an approach, which is becoming increasingly important. 

Various proposals for a logical classification of toxicities have been made in the past, both verbal or quantified. One of the most cited is the classification by Spector published in 1956.15 This classification even attempted to show a relationship between acute animal toxicity data and the expected lethal dose for human beings, which was meant to give a practical orientation (Table 2). 

EXTENSIONS AND COMMENTARY With an entirely new hetero atom in the molecule (the selenium), and with clear indications that large dosages would be needed (100 milligrams, or more), some discretion was felt desirable. There was certainly an odd taste and an odd smell. I remember some early biochemical work where selenium replaced sulfur in some amino acid chemistry, and things got pretty toxic. It might be appropriate to get some general animal toxicity data before... 

This method of calculation is based on the use of animal toxicity data to determine limits. As mentioned earlier, this method is particularly suited for determining limits for materials that are not used medically. This method is based upon the concepts of acceptable daily intake (ADI) and no observed effect level (NOEL) developed by scientists in the Environmental Protection Agency [7], the U.S. Army Medical Bioengineering Research and Development Laboratory [8], and the toxicology department at Abbott Laboratories [9], This method has also been recently used to calculate the limits of organic solvent residues allowed in APIs [10]. 

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. 

The preclinical stage of drug development focuses on activities necessary for filing an IND/CTA. The completed IND/CTA contains information that details the drug s composition and the synthetic processes used for its production. The IND/CTA also contains animal toxicity data, protocols for early phase clinical trials, and an outline of specific details and plans for evaluation. Process research, formulation, metabolism, and toxicity are the major areas of responsibility in this development stage. Analysis activities that feature LC/MS primarily focus on the identification of impurities, de-gradants, and metabolites. 

Seed J, Carney EW, Corley RA, Crofton KM, DeSesso JM, Foster PMD, Kavlock R, Kimmel G, Klaunig J, Meek ME, Preston RJ, Slikker W Jr, Tabacova S, Williams GM, Wiltse J, Zoeller RT, Fenner-Crisp P, Patton DE (2005) Overview Using mode of action and life stage information to evaluate the human relevance of animal toxicity data. Crit Rev Toxicol, 35(8-9) 664-672. 

TABLE 2 8 Experimental Animal Toxicity Data, Exposure to Ammonia... 

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