Animal data, human risk assessment

It is of note that this considerable reliance on laboratory animal data for risk assessment purposes for enviromnental chemicals is in sharp contrast to the situation with ionizing radiation. The cancer risk estimates for ionizing radiation (X rays and y rays) are based to a very great extent on human tumor data obtained from the Life Stage Study (LSS) of the atomic bomb survivors in Hiroshima and Nagasaki, Japan... 

In the absence of information to demonstrate that such a selection is incorrect, data from the animal species, strain, and sex showing the greatest sensitivity to a chemical s toxic properties will be selected as the basis for human risk assessment. 

Establish and develop better (molecular) markers of effects on reproduction and development. Those that may have a human and animal congruence would be particularly useful and would aid in the evaluation and use of animal data in human risk assessment. 

ECETOC (1988) Methylene Chloride (Dichloromethane) Human Risk Assessment using Experimental Animal Data (Technical Report No. 32), European Centre for Ecotoxicology and Toxicology of Chemicals... 

In section 2.3 of this chapter the present approach to characterisation of dose-response relationships was described. In most cases it is necessary to extrapolate from animal species that are used in testing to humans. It may also be necessary to extrapolate from experimental conditions to real human exposures. At the present time default assumptions (which are assumed to be conservative) are applied to convert experimental data into predictive human risk assessments. However, the rates at which a particular substance is adsorbed, distributed, metabolised and excreted can vary considerably between animal species and this can introduce considerable uncertainties into the risk assessment process. The aim of PB-PK models is to quantify these differences as far as possible and so to be able to make more reliable extrapolations. 

Provide guidance on the evaluation of human and animal data on developmental toxicity. Guidelines describe the procedures EPA follows in evaluating potential developmental toxicity by analyzing and organizing data for risk assessments. 

Because human pharmacokinetic data are often minimal, absorption data from studies of experimental animals-by any relevant route of exposure-might assist those who must apply animal toxicity data to risk assessment. Results of a dermal developmental toxicity study that shows no adverse developmental effects are potentially misleading if uptake through the skin is not documented. Such a study would be insufficient for risk assessment, especially if it were interpreted as a negative study (one that showed no adverse effect). In studies where developmental toxicity is detected, regardless of the route of exposure, skin absorption data can be used to establish the internal dose in the pregnant animal for risk extrapolation to human dermal exposure. For a discussion pertinent both to the development and to the application of pharmacokinetic data, risk assessors can consult the conclusions of the Workshop on the Acceptability and Interpretation of Dermal Developmental Toxicity Studies (Kimmel and Francis 1990). 

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 initial process in the application of toxicity (dose-response) data in risk assessment is the extrapolation of findings to establish acceptable levels (AL) of human exposure. These levels may be reference values (inhalation reference concentrations, RfC or oral reference doses, RfD), minimal risk levels (MRL) values, occupational exposure limits, and so on. When the toxicity data are derived from animals, the lowest dose representing the NOAEL (preferably) or the LOAEL defines the point of departure (POD). In setting human RfD, RfC, or MRL values, the POD requires several extrapolations (see [13] and revisions). Extrapolations are often made for interspecies differences, intraspecies variability, duration of exposure, and effect level. Each area is generally addressed by applying a respective uncertainty factor having a default value of 10 their multiplicative value is called the composite uncertainty factor (UF). The UF is mathematically combined with the dose at the POD to determine the reference value ... 

Basic problems of animal-to-human extrapolation are in the OTA s report (op. cit.) and comprehensively treated in Edward Calabrese, Principles of Animal Extrapolation (John Wiley and Sons New York, 1983). The particular problem of extrapolation of teratology data from animals to humans is concisely discussed by V. Frankos in his paper FDA perspectives in the use of teratology data for human risk assessment (Fundamental and Applied Toxicology, Vol. 5, 1985, pp 615-25). 

Turesky, R.J. (2005) Interspecies metabolism of heterocyclic aromatic amines and the uncertainties in extrapolation of animal toxicity data for human risk assessment. Mol. Nutr. 

Human Risk Assessment from Animal Data... 

McClain, R. M. Mechanistic consideration for the relevance of animal data on thyroid neoplasia in human risk assessment. Mutation Res., 1995, 333, 131-142. 

In risk characterization, step four, the human exposure situation is compared to the toxicity data from animal studies, and often a safety -margin approach is utilized. The safety margin is based on a knowledge of uncertainties and individual variation in sensitivity of animals and humans to the effects of chemical compounds. Usually one assumes that humans are more sensitive than experimental animals to the effects of chemicals. For this reason, a safety margin is often used. This margin contains two factors, differences in biotransformation within a species (human), usually 10, and differences in the sensitivity between species (e.g., rat vs. human), usually also 10. The safety factor which takes into consideration interindividual differences within the human population predominately indicates differences in biotransformation, but sensitivity to effects of chemicals is also taken into consideration (e.g., safety faaor of 4 for biotransformation and 2.5 for sensitivity 4 x 2.5 = 10). For example, if the lowest dose that does not cause any toxicity to rodents, rats, or mice, i.e., the no-ob-servable-adverse-effect level (NOAEL) is 100 mg/kg, this dose is divided by the safety factor of 100. The safe dose level for humans would be then 1 mg/kg. Occasionally, a NOAEL is not found, and one has to use the lowest-observable-adverse-effect level (LOAEL) in safety assessment. In this situation, often an additional un-... 

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