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Humane endpoints in animal experiments for biomedical research Remote monitoring of experimental endpoints in animalsusing radiotelemetry and bioimpedance technologies L. B. Kinter1 & D. K. Johnson21 Astra Merck and 2 Nycomed Amersham Inc., Wayne, Pennslyvania, USA Advances in radiotelemetry and bioimpedance technology are providing improved and morehumane approaches for monitoring physiological functions in experimental animals.
Telemetry systems consist of miniaturized sensors and transmitters which detect andtransmit pressures, ¯ows, temperatures, pH, and electrical potentials to remote receivers.
Three general types of systems are currently available: (1) fully implantable systems; (2)partially implanted systems (in which animals carry non-implanted components inbackpacks); and (3) capsule systems which traverse the gastrointestinal tract. Currently, thetechnology can be applied in all commonly used laboratory species from mice to monkeys.
Non-invasive bioimpedance technologies can also be used to monitor several physiologicallyimportant parameters including cardiac output and total body electrical conductivity(TOBEC, an index of lean body mass). The feasibility, validity, and utility of TOBEC tomonitor changes in body composition is demonstrated in Sprague-Dawley rats. Telemetry andbioimpedance technologies are replacements for traditional non-survival procedures that cansubstantially improve animal welfare and reduce animal use in laboratory research.
Comprehensive evaluations of physiological chronic monitoring of physiological para- traditionally required invasive techniques. In the last 50 years, acute (non-survival) tech- modern animal researchers to the principles of reduction and re®nement of animal use sophisticated, surgically prepared chronic animal models. In these models, catheters, cannulae, electrodes, and electronic probes models was the vulnerability of the trans- are implanted and connectors exteriorized so that the animals can be readily connected= accidental damage. The presence of externa- (see Gellai & Valtin 1979). Because these requires that these animals be single-housed prolonged measurements in individual ani- and closely monitored for the duration of their experimental utility. These factors potentially allow the re-use of animals in limited their utility in pharmaceutical safety multiple studies, they have resulted in sub- stantial reductions in animal use which have pathology, co-administration of antibiotics, offset, in part, the additional costs associated issues and added signi®cantly to overall also afforded quantal improvements in the quality and quantity of experimental data collected. Collectively, the development of been leveraged through re®nements, which Radiotelemetry and bioimpedance technologies and experimental endpoints left cannulae and connectors in sterile sub- located within or near the animal's cage or experimental set-up. Following their recov- vascular access port was successfully adapted ery from surgery to implant the electronics, for subcutaneous arterial, venous, and biliary telemeterized animals can be maintained and access, and has also been used for the in¯a- even studied while in their `home' laboratory tion of vascular cuffs (Mann et al. 1987, environment. The range of laboratory species 1991). For more sophisticated technologies, (Schnell & Wood 1993, Brackee et al. 1995, can be accessed for experimental measure- Kinter et al. 1997, Brockway et al. 1998).
ments through a small incision (under local anaesthetic) in a miniaturized sterile ®eld itored using telemetry include blood pres- (Kinter et al. 1994). Transcutaneous con- sure, heart rate, ventricular pressures, ECG, nectors (or studs) are reported to minimize EMG and body temperature. Respiratory rate and animal activity can be monitored indir- placed, are not damaged by the animal. The osmotic infusion pump was the ®rst fully (1998) have reported the telemeterization of implantable infusion technology widely used respiratory pressures using a novel variant of in both rodent and non-rodent species (see the oesophageal balloon procedure. The use- ful lifetime of these systems ranges from animal damage to external equipment, ani- several months to over a year depending upon mals are generally group-housed, reducing the electrical power requirements and power the concerns of some welfarists that reduc- tions in animal use were being achieved at the expense of reductions in animal welfare.
However, these models still required sub- these systems, sensors are implanted surgi- procedures to collect physiological data, with encumbant stress factors, model limitations, externally in a jacket worn by the subject.
These systems permit the use of electronic greater transmission ranges, and unlimited `wireless' reporting technologies, including battery life, than can be accommodated by currently available fully implantable sys- tions. Several of these technologies and their tems. However, they are susceptible to many potential impact on animal study designs and of the weaknesses of the previous hard-wire animal welfare are brie¯y discussed in this Fully implantable miniaturized telemetrysystems are the state of the art in radio- Variants of the implantable radiotelemetry telemetry (Brockway & Hassler 1993). These systems include capsule telemetry systems systems consist of one or more sensors (¯uid- ®lled cannulae, catheters, electrodes) con- tems include a miniaturized sensor, a trans- nected to hermetically-sealed transducer- radiotransmitters and power supplies. The enterically compatible capsule. After the transmitter broadcasts the signal from the capsule is activated and swallowed, it tra- transducer to a remote antenna, generally verses the gastrointestinal tract. Systems Humane endpoints in animal experiments for biomedical research that detect pH can be used to monitor gastric que currently requires the temporary place- pH, gastric emptying time, intestinal pH and ment of surface electrodes (similar to ECG intestinal transit time. Similar systems have electrodes), but potentially replaces the more been used to monitor core body temperatures invasive aortic ¯ow probe preparations, and in thermally unstable individuals, and in invasive thermal and dye-dilution techni- remote situations (e.g. Astronaut J. Glenn in 1998). The primary drawback of these sys- future be combined with telemetry technol- tems today is the low transmission distance ogy for completely wireless monitoring.
such that the subject may need to wear or lieupon the antenna. While the applications for limited, compared with implantable systems,their robust and non-invasive nature and the Total body electrical conductivity provides a fact that their use requires no surgery, offer non-invasive and non-destructive means for advantages in preclinical safety assessment.
the estimation of lean body mass (Walsberg1988). Mechanically restrained or lightlyanaesthetized animals are temporarily inser- ted into a low energy electromagnetic ®eld;the magnitude of the current ¯ow induced by ture systems powered intermittently using body is related to its lean mass. By measuring external inductance technologies. While this the change in the inductance of the current approach has the theoretical advantage of ¯ow in the applied magnetic ®eld, caused by inde®nite use following implantation, trans- the induced current ¯ow in the animal, the ponders are restricted to very short trans- electrical conductivity of the animal's body mission ranges, usually requiring some type of animal=human interaction (e.g. to wand estimated. The technique potentially repla- the transponder). The most common of these ces current technologies that are labour- systems are currently used for individual intensive, require expensive and specialized animal identi®cation (animal number trans- equipment, lack sensitivity, and are not suit- ponders) and for the monitoring of biopoten- tials (e.g. body temperature, heart rate).
composition of live laboratory animals.
nology has been demonstrated in laboratory (Sprague-Dawley) rats (Kinter et al. 1993,Dowling et al. 1994). In these studies, TOBEC was determined using a small animal biological current ¯ows through endogenous body composition analyser (Model SA-2, EM- or exogenous magnetic ®elds. For example, SCAN, Spring®eld, Illinois, USA). Rats were [40=5 mg=kg, i.p.] or methohexital [50 mg=kg, across the thorax; changes in thoracic impe- i.p.]), weighed and measured (nasal±anal dance are related in part to changes in the volume and velocity of aortic blood ¯ow. The rats in a supine position, using the `Fixed' impedance changes during the cardiac cycle mode of instrument operation, according to the manufacturer's instructions. Five to 10 from which cardiac output can be calculated.
succession on each object or animal at each observation point and the average value used for subsequent calculations. After recovering both clinical and animal research purposes from anaesthesia, the rats were returned to (see DePasquale & Fossa 1996). The techni- their cages. All numerical data are expressed Radiotelemetry and bioimpedance technologies and experimental endpoints lysed for lean body mass and body lipid con- (SEM). Body weights and body compositions tent by carcass extraction and the results lowed by Dunnett's multiple comparisons.
measurement (Kinter et al. 1993). The cor- relation coef®cients for lean and non-lean methodologies were performed using linear regression and Pearson correlation coef®- reference method were > 0.99 and > 0.90, respectively. The slopes of the relationships close to the origin. Overall, the correlations selected male and female rats fed a certi®ed rodent chow either ad libitum or approxi- DO rats were highly signi®cant (P < 0:001) mately 70% of ad libitum (diet optimized, over a physiological range of body sizes and DO) (7±8=sex per group, see Fig 1) were ana- that increases body weight and proteindeposition and decreases the rate of fatdeposition in rats (Carter et al. 1991). MaleSprague-Dawley rats (10=group) were lightlyanaesthetized and TOBEC was measured ontwo occasions prior to treatment and fouradditional occasions during and followingtreatment (2.0 mg=kg per 24 h clenbuterol or0.5 ml=h sterile water, i.p., for 14 days usingan osmotic minimump; Dowling et al. 1994).
The effects of clenbuterol on body composi-tion is shown in Fig 2. All the rats gainedbody weight and lean body mass over thecourse of the study; however, clenbuterol-treated rats gained approximately 65 g( $ 13%) more body weight=lean mass thandid the control rats after 2 weeks of treat-ment (P < 0:05). Mean body weight in theclenbuterol-treated rats remained increased,although no longer statistically signi®cantly,2 weeks following the cessation of drugtreatment. The protein-sparing effect ofclenbuterol appears to be due to a reductionin protein catabolism resulting from theinhibition of loss of speci®c mRNAs (Babij & Fig 1 The relationships between lean mass, non- Booth 1988, Rogers & Fagan 1991).
lean mass and % body fat estimated by TOBEC (vertical axes), and lean mass, lipid mass and % lipidestimated by the reference method (horizontal axes) ments are that they are sensitive to the size, in 23-week old ad libitum (open circles) and DO geometry, and positioning of the subject. The (closed circles) male and female Sprague-Dawley rats present studies show that these variables are after 14 weeks on either regimen. The correlation controlled when lightly anaesthetized rats coef®cients are 0.993, 0.903, and 0.702, respectively.
are positioned consistently in the instru- Regression analyses show a high degree of correlation ment. Anaesthesia can be avoided if the rats for both lean and non-lean mass values estimatedusing these two methods (P < 0.0001). Data from are mechanically restrained in a simple dis- posable plastic cone (Decapi Cone, Braintree Humane endpoints in animal experiments for biomedical research body fat content. Lean body mass is also arelatively large mass, and tissue=lean bodymass ratios are less susceptible to errorsassociated with ratios with very smalldenominators (e.g. tissue=brain weightratios).
Modern telemetry and bioimpedance tech-nologies offer opportunities substantially toreduce and re®ne animal use and to reduceresearch costs. Consider the savings whentelemetry or bioimpedance technologies areused to replace destructive techniques (e.g.
carcass analysis), or are used in conjunctionwith traditional study endpoints (e.g. a singledose, dose-ranging, or repeat-dose toxicologystudy). The study illustrated in Fig 2 repre-sents more than an 80% reduction in animaluse using TOBEC, compared with the samestudy design using traditional carcass analy-sis. When physiological and toxicologicaldata are gained from one set of animals, thedata complement one another, and the need Fig 2 Effects of 2-week clenbuterol treatment onbody composition of male Sprague-Dawley rats.
for separate studies (e.g. safety pharmacology TOBEC measured on two occasions prior to dosing studies) is eliminated. A decrease in blood (pre-treatment; weeks BASE and 0). Rats were then pressure, increase in heart rate, electro- given clenbuterol (2.0 mg=kg per day; broken line) or cardiogram change, or other physiological vehicle (sterile water; 0.5 ml=h; open symbols=single response may provide direct evidence of a line) for 2 weeks (weeks 1 and 2). An additional 2 dose-limiting effect (Morgan et al. 1994, weeks of recovery (weeks 3 and 4) was allowed. Body Kinter et al. 1997), eliminating the need to weight, body length, TOBEC (conductivity indexunits), lean mass, non-lean mass, and % body fat were evaluate higher doses for toxicity, which determined weekly. Values are means; closed symbols saves animals, time, and other resources.
represent statistically signi®cant differences from the vehicle control (P < 0.05; n ˆ 8=group). The results technologies permit continuous or periodic show that TOBEC analysis is able to detect the data collection over prolonged periods of pharmacological effect of clenbuterol to selectively time, they are compatible with the use of increase lean body mass in Sprague-Dawley rats. Data randomized block study designs in place of conventional completely randomized studydesigns. Blocking works to ®lter out the Scienti®c, Braintree, Massachusetts, USA) to inter-animal variation, reducing the number preserve a constant orientation and geometry of animals needed to obtain the same level of (unpublished ®ndings). Finally, lean body statistical power for evaluating dose=treat- ment responses (Snedecor & Corcoran 1980, Festing 1994). In a conventional completely weight) for the normalization of the organ weight data without the potential confound- groups of animals, with each animal in each ing factors of differences in body fat content.
group receiving one treatment. In a rando- Lean body mass re¯ects a more homogeneous mized block design, there is one group of weight and is not susceptible to differences in Radiotelemetry and bioimpedance technologies and experimental endpoints mized block designs are that a suf®cient health and welfare of the test animal and the washout period can be incorporated between proper function of the telemetry or bioimpe- dance system. Item 4 requires the investi- gator to review all experimental records to design is one in which all animals receive all ensure that critical physiological systems treatments, but in an ascending order (e.g.
were not inadvertently compromised in pre- vehicle, then low, mid, and high dose). This ceding studies. This is particularly important when telemeterized preparations are to be power as the randomized block design, but reused in safety studies. Items 3 and 4 may be may require an additional time control to facilitated through the periodic evaluation of separate treatment effects from time effects.
pharmacological responses to standard agents For comparable levels of power and error, the (Table 1). Item 5 is to permit suf®cient time use of the randomized block design provides for the recovery from previous procedures for up to a 75% reduction in the numbers of and the clearance of previously administered drugs. As a general rule, individual tele- Because of the prolonged lifetime of tele- meterized animals should be left to recover metry and bioimpedance systems, investiga- for at least 7 days between studies.
tors may consider reusing study animals to In conclusion, telemetry and bioimpedance study additional doses, different treatments, technologies are replacements for traditional or alternate routes of administration, or to verify individual response differences. The principle in the reuse of animal preparations itoring of laboratory animals maintained (for is to de®ne objective criteria with which to the most part) in their home environments.
re-qualify and schedule animals for addi- In addition to improvements in animal wel- tional studies in a proactive fashion. Re- fare, the overall reductions in animal use that quali®cation criteria should include the fol- may be achieved using telemetry and bioim- pedance technologies are as follows. Reduc-tions achieved by eliminating an extra study or study group are at least 50%. Reductions (2) Haematology, serum biochemistry, uri- designs in place of completely randomized designs are 75%, depending upon the inher- ent pure error variation (s) and the power (4) Clinical history from prior studies.
required. Further reductions achieved by re- (5) Suf®cient time for the washout of pre- viously administered test substances.
animals in additional studies are a factor of Table 1 Standard agents and doses for assessments of stability of pharmacological responses ininstrumented dogs Values are unreported data from our laboratories, and those of Dr S. Pettinger. The doses are used to establishresponses in individual animals, to monitor those responses for changes over time and exposure to multiplestudies Humane endpoints in animal experiments for biomedical research two per additional study. In our laboratories, Festing MFW (1994) Reduction of animal use: experi- we have achieved total reductions through mental design and quality of experiments. Labora- eliminating extra studies and study groups, Gellai M, Valtin H (1979) Chronic vascular constric- tions and measurements of renal function in animals in multiple studies in excess of 90%, conscious rats. Kidney International 15, 419±26 Kinter LB, Choi J, Keller W, et al. (1993) Effect of diet optimization on body fat content in Sprague-Dawley rats. Toxicologist 13, 236 (Abstract 876) Kinter LB, Murphy DJ, Mann WA, et al. (1997) Major Acknowledgments The authors acknowledge the organ systems toxicology: an integrated approach technical assistance of Keith Dowling, William A.
to pharmacodynamic safety assessment in animals.
Mann, W. Keller, A. Silver, and J. Ventre (SmithKline In: Toxicological Testing and Evaluation (Williams Beecham Pharmaceuticals), Dr R. Martin (University P, Hottendorf GH, eds), Vol. 2 of Comprehensive of Georgia), C. Metz (EM-SCAN Inc., 3420 Constitu- Toxicology (Sipes IG, McQueen CA, Gandol® AJ, tion Drive, Spring®eld, Illinois, USA) and support eds). Amsterdam: Elsevier Science, pp 155±68 from Drs T. Leonard, D. J. Meyer, W. D. Kerns, and Kinter LB, Mann WA, Weinstock J, Ruffolo RR, Jr D. G. Morgan. Clenbuterol was prepared by Smith- (1994) Effects of catechol ring ¯uorination on Kline Beecham chemists. We thank B. Clemmer for cardiovascular and renal activities of fenoldopam technical assistance in preparing the manuscript.
Mann WA, Landi MS, Horner E, Woodward P, Camp- bell S, Kinter LB (1987) A simple procedure fordirect blood pressure measurements in consciousdogs. Laboratory Animal Science 37, 105±8 Mann WA, Welzel GE, Goldstein RS, et al. (1991) Characterization of the renal effects and renal Anon (1990) The temperature pill: space research elimination of sulotroban in the dog. Journal of spawns a medical breakthrough. NASA Technical Pharmacology and Experimental Therapeutics Babij P, Booth FW (1988) Clenbuterol prevents or Mojaverian P (1996) Evaluation of gastrointestinal pH inhibits loss of speci®c mRNAs in atrophying rat and gastric residence time via the Heidelberg skeletal muscle. American Journal Physiology 254, radiotelemetry capsule: pharmaceutical applica- tion. Drug Development Research 38, 73±85 Brackee G, Young E, Coffey T, Perry R, Banknieder R Morgan DG, Kelvin AS, Kinter LB, et al. (1994) The (1995) Technique for telemetric determination of application of toxicokinetic data to dosage selec- blood pressure and heart rate in the conscious, tion in toxicology studies. Toxicologic Pathology pregnant rabbit. Contemporary Topics 34, 59±61 Brockway BP, Hassler CR (1993) Application of Murphy DJ, Renninger JP, Gossett KA (1998) A novel radiotelemetry to cardiovascular measurements in method for chronic measurement of pleural pres- pharmacology and toxicology. In: New Technolo- sure in conscious rats. Journal of Pharmacological gies and Concepts for Reducing Drug Toxicity, Chapter 9 (Salem H, Baskin SI, eds). Boco Raton: Rogers KL, Fagan JM (1991) Effect of b-agonists on protein turnover in adipose tissue. Life Sciences 48, Brockway BP, Mills P, Kramer K (1998) Fully implanted radio-telemetry for monitoring labora- Russell WMS, Burch RL (I959) The Principles of Carter WJ, Dang AQ, Faas FH, Lynch M.E (1991) Methuen (reprinted by Universities Federation for Effects of clenbuterol on skeletal muscle mass, body composition, and recovery from surgical Schnell CR, Wood JM (1993) Measurement of blood stress in senescent rats. Metabolism 40, 855±60 pressure and heart rate by telemetry in conscious, DePasquale M.J, Fossa AA (1996) Use of bioimpe- unrestrained marmosets. American Journal of dance for measuring cardiac output in the con- scious dog. Drug Development Research 38, Snedecor GW, Corchran WG (1980) Statistical Meth- ods, 7th edn. Ames: Iowa State University Press, Dowling K, Keller W, Mann WA, Metz C, Kinter LB (1994) Total body electrical conductivity estimates Walsberg GE (1988) Evaluation of a nondestructive of lean body mass in Sprague-Dawley rats: effects of method for determining fat stores in small a b-adrenergic agonist, clenbuterol. Toxicologist 14, birds and mammals. Physiology and Zoology 61, Radiotelemetry and bioimpedance technologies and experimental endpoints Webb RL, Navarrete AE, Davis S (1998a) Effects of Webb RL, Navarrete AE, Davis S, de Gasparo M valsartan and hydrochlorothiazide alone and in (1998b) Synergistic effects of combined converting combination on blood pressure and heart rate in enzyme inhibition and angiotensin II antagonism conscious-telemetered spontaneously hypertensive on blood pressure in conscious telemetered spon- rats (SHR). American Journal of Hypertension 11, taneously hypertensive rats. Journal of Hyperten-

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