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Department of Nutrition, University of California, Davis, Davis, CA 95616
1To whom correspondence should be addressed. E-mail: rbrucker{at}ucdavis.edu.
See related article: J. Nutr. 132: 3142–3145, 2002.
In the paper by Prohaska and Brokate (1
), "Timing of Perinatal Copper Deficiency in Mice Influences Offspring Survival," a key observation is made that copper deficiency can have an important and negative effect on the survival of offspring. Further, several approaches are used to extrapolate from data derived from mice to potential application in humans. In this commentary, we wish to address the appropriateness of approaches that are often used for extrapolation. We suggest that when making interspecies comparisons from a nutrition perspective, the strongest case is made when a measure of metabolic body size or food intake, rather than body weight, is used to extrapolate the dosages required for a given response.
Although it is a common practice to use body weight as a reference in comparative toxicology studies (2
), this can lead to inappropriate conclusions when small animals are used to estimate the amounts of a given nutrient required to produce a deficiency or toxicity in a large animal. This point is illustrated by using values that are recommended to meet essential mineral requirements [see Table 1
, Fig. 1
, and Refs. (3
–7
)]. In homeothermic animals, mineral requirements are similar across species if expressed per unit of energy intake or as the concentration in dry food (assuming an energy density equivalent to 3.9–4.2 kcal/g or 
16 kJ/g). Direct extrapolation to an adult human on the basis of dosages administered to a mouse or rat may be in error by a factor of 10 or more. As an example, most would agree that a daily dose of Zn equivalent to 0.25 mg/kg body weight is sufficient for most humans (i.e., a daily intake of 15 mg of Zn/d for a person weighing 70 kg). For a 30-g mouse, however, an extrapolation based on the data and weight for a human would suggest that only 6–7 µg Zn/d is required. Yet, the actual requirement for the mouse is closer to 60 µg Zn/d, assuming that the mouse consumes daily 60–75 kJ or 3–4 g of dry food. As a "rule of thumb," extrapolation from a large animal to a small animal often leads to an underestimate in dosage, whereas extrapolations from a small animal to a large animal lead to an overestimates for the large animal. This point is developed in Table 1
, where requirements for selected minerals and a range of species are expressed as a concentration (amount per unit of diet) vs. per kilogram of body weight. Log plots (daily intake vs. body weight) are also given in Figure 1
. It is noteworthy that the regression equations that describe the relationships are similar. The characteristics of such equations follow those described by Kleiber, Baldwin and others for energy relationships (8
–10
).
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–14
). Mordenti (11
) examined the literature for 14 antineoplastic agents and concluded that power equations were required to describe adequately the relationship between a toxic dose and animal weight. Lathrop et al. (12
) came to a similar conclusion, using the retention time to reach a given concentration in blood as a correction. It was observed that the retention of technetium 99 (Tc99), injected as pertechnetate, reached 10% of the initial dose in mice in 1 d, whereas 7 d were required in humans. This observation is consistent with the use of power equations that describe the metabolic transfer rate. That is, if the clearance of a substance is related to the metabolic transfer rate, then turnover (the daily transfer into and out of the body pool) should be function of kpwt/kawt3/4, where weight is expressed in kg, kp is the empirically derived animal-specific constant related to the total body pool, and ka is the empirically derived animal-specific constant related to the daily transfer rate (8
). The ratio of wt1/4 for humans (60–80 kg) to wt1/4 for mice (20–30 g) is also 7–8. Our point is that the use of metabolic size has utility well beyond interspecies energy comparisons (8
–10
).
As a final example, the experiment by West et al. (14
), in which a male Asiatic elephant named Tusco, was given lysergic acid diethylamide (LSD) provides an important lesson. LSD was used to modulate the phenomenon of going "on musth," in which aggressive behavior is a characteristic. The dose of LSD for Tusco was based on amounts tolerated by humans and the observation that proportionally larger doses per kilogram body weight were required for psychotomimetic effects in small animals. A dose of 300 mg or 0.1 mg/kg killed Tusco. Consideration of metabolic size or a similar power function would have kept Tusco possibly much happier and among the living. Using several approaches to estimate risk or potential need, as was done by Prohaska and Brokate (1
), forces one to broaden their perspective because it relates to predicting a response, which at the very least makes the discussion of the data used to define the response much more comprehensive and lively.
Manuscript received 22 July 2002. Revision accepted 26 July 2002.
LITERATURE CITED
1. Prohaska, J. R. & Brokate, B. (2002) Timing of perinatal copper deficiency in mice influences offspring survival. J. Nutr. 132:3142-3145.
2. Hardman, J. Limbird, L. E. eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics 9th ed. 1996 McGraw-Hill Health Professional Division New York, NY. .
3. Subcommittee on Swine Nutrition, Committee in Animal Nutrition, National Research Council (1998) Nutrient Requirements of Swine 10th rev. ed. 1998 National Academy Press Washington, DC. .
4. Subcommittee on Laboratory Animal Nutrition, Committee on Animal Nutrition (1995) Nutrient Requirements of Laboratory Animals, Nutrient Requirements of Poultry 4th rev. ed. 1995 National Academy Press Washington, DC. .
5. Subcommittee on Poultry, Committee on Animal Nutrition (1994) Nutrient Requirements of Poultry 9th ed. 1994 National Academy Press Washington, DC. .
6. Subcommittee on Dogs, Committee on Animal Nutrition (1985) Nutrient Requirements of Dogs 1985 National Academy Press Washington, DC. .
7. Panel on Micronutrients, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and Standing Committee on the Scientific Evaluation of Dietary Reference Intakes (2002) Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc 2002 Food and Nutrition Board, NAS Washington, DC. .
8. Kleiber, M. (1975) The Fire of Life: An Introduction to Animal Energetics 1975 R. E. Krieger Publishing Huntington, NY. .
9. Baldwin, R. L. (1995) Modeling Ruminant Digestion and Metabolism 1995 Chapman & Hall Publishers New York, NY. .
10. Rucker, R. B. & Steinberg, F. M. (2002) Vitamin requirements: relationship to basal metabolic need and functions. J. Biochem. Mol. Biol. Educ. 30:86-89.
11. Mordenti, J. (1986) Dosage regimen design for pharmaceutical studies conducted in animals. J. Pharm. Sci. 75:852-857.[Medline]
12. Lathrop, K. A., Tsui, B. M., Chen, C. T. & Harper, P. V. (1989) Multiparameter extrapolation of biodistribution data between species. Health Phys 57(Suppl.):121-126.
13. Patel, B. A., Boudinot, F. D., Schinazi, R. F., Gallo, J. M. & Chu, C. K. (1990) Comparative pharmacokinetic and interspecies scaling of 3'-azido-3'-deoxythymidine (AZT) in several mammalian species. J. Pharmacobio-Dyn. 13:206-211.[Medline]
14. West, L. J., Pierce, C. M. & Thomas, W. D. (1962) Lysergic acid diethylamide: its effects on a male Asiatic elephant. Science (Wash., DC) 138:1100-1104.
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