Functional observational battery

The protocols in this unit are divided into (1) observational assessments, and (2) manipulative tests. Each protocol is further subdivided into specific tests or endpoints (Table 5.4). These various end points may be combined into a battery of tests for neurobehavioral screening. Most or all of these protocols or end points should be used in the context of a broad neurobehavioral test battery, whereas judicious selection of specific end points may be appropriate for more focused neurological testing. Originally developed by Gad [4], Moser [7], and Moscardo [8], the functional observational battery provides excellent detailed descriptions of the method using rats, the most common species used. 

Note Generally, a sample size of five animals per sex per treatment is sufficient. It is essential that control animals be treated exactly the same as the other groups except that they are administered only vehicle or formulation (minus drug). 

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Bowen SE, Wiley JL, Balster RL The effects of abused inhalants on mouse behavior in an elevated plus-maze. Eur J Pharmacol 312 131-136, 1996a Bowen SE, Wiley JL, Evans EB, et al Functional observational battery comparing effects of ethanol, 1,1,1-trichloroethane, ether, and flurothyl. Neurotoxicol Ter-atol 18 577-583, 1996b... 

Although most Type I pyrethroids produce the T-syndrome and most Type II pyrethroids produce the CS-syndrome, there are exceptions to this classification. Fenpropathrin, a Type II pyrethroid, and permethrin, a Type I pyrethroid, produce mixed intoxication syndromes depending on the study and animal examined. Lastly, the signs of intoxication may not be independent of the routes of administration [1]. As reported recently, the results of a functional observational battery study of 12 pyrethroids in rats following acute oral exposure did not correlate well with the signs of intoxication following intravenous dosing [19]. 

Weiner ML, Nemec M, Sheets L, Sargent D, Breckenridge C (2009) Comparative functional observational battery study of twelve commercial pyrethroid insecticides in male rats following acute oral exposure. Neurotoxicology 30(Suppl 1) S 1—S16... 

Under the Food Quality Protection Act (FQPA), the U.S. EPA evaluates the potential for people to be exposed to more than one pesticide at a time from a group of chemicals with an identified common mechanism of toxicity. As part of the examinations, to clarify whether some or all of the pyrethroids share a common mechanism of toxicity, a comparative FOB (functional observational battery) studies with 12 pyrethroids were carried out under standardized conditions [15]. The FOB was evaluated at peak effect time following oral administration of non-lethal doses of pyrethroids to rats using com oil as vehicle. Four principal components were observed in the FOB data [22], Two of these components described behaviors associated with CS syndrome (lower body temperature, excessive salivation, impaired mobility) and the others described behaviors associated with the T syndrome (elevated body temperature, tremor myoclonus). From the analysis, pyrethroids can be divided into two main groups (Type I T syndrome and Type II CS syndrome) and a third group (Mixed Type) that did not induce a clear typical response. Five other pyrethroids were also classified by an FOB study conducted in the same manner [16]. The results of these classifications are shown in Table 1. The FOB results for all non-cyano pyrethroids were classified as T syndrome, and the results of four ot-cyano pyrethroids were classified as CS syndrome however, three of the ot-cyano pyrethroids, esfenvalerate, cyphenothrin, and fenpropathrin, were classified as Mixed Type. 

Tsuji R The classification of 7 pyrethroids based on the data of comparative Functional observation battery study in rats (in preparation)... 

FIGURE 4.3. Example of a control chart used to prescreen data (actually, explore and identify influential variables), from a portion of a functional observational battery. See text discussion for explanation. 

Neurotoxicology. Table 7.6 presents the FDA s current draft criteria (FDA, 1993, 2000) for endpoints to be incorporated in studies as a screen for neurotoxicity. IN practice, a functional observation battery is employed at several endpoints (usually one and three months in to the study) to fill these requirements. 

Usually a functional observational battery (FOB) is integrated into a rodent (rat) repeat dose toxicity study to meet this requirement... 

The front end of this tier approach is a screen, the functional observation battery (FOB) Gad (1982) or Irwin (1968) screen. This is the tool of choice for initial (and for most of the compounds covered by this volume, the only screen tests for) identification of potentially neurotoxic chemicals. The use of such screens, other behavioural test methods, or what are generally called clinical observations does, however, warrant one major caution or consideration. That is that short-term (within 24 hr of dosing or exposure) observations are insufficient on their own to differentiate between pharmacologic (reversible in the short term) and toxicological (irreversible) effects. 

Mattson, J.L., Spencer, RJ. and Albee, R.R. (1996). A performance standard for clinical and functional observational battery examination of rats. J. Am. Coll. Toxicol. 15 239. Megens, A. A.H.P., Awouters, EH.L. and Niemegeers, C.J.E. (1991). General pharmacology of the four gastrointestinal motility stimulants bethanechol, metoclopramide, trimehutine, and cisapride. Arzneim.-Forsch./Drug Res. 41(f)(6) 631-634. 

Nervous system 20-30 neurobehavioral endpoints Functional observational battery Rat (or mice) or dog LeBel et al. 191 Horner et al.192... 

Mattsson, J.L., Spencer, P.J., and Albee, R.R., A performance standard for clinical and functional observation battery examination of rats, /. Am. Coll Toxicol, 15, 239, 1996. 

Redfem, W.S., Strang, I., Storey, S., Heys, C., Barnard, C., Lawton, K., Hammond, T.G., and Valentin, J.P., Spectrum of effects detected in the rate functional observational battery following oral administration of non-CNS targeted compounds, /. Pharmacol. Toxicol. Methods, 52, 77-82, 2005. 

The Neurotoxicity Screening Battery test guideline (OPPTS 870.6200) consists of a functional observational battery, motor activity, and neuropathology. The test battery is not intended to provide a complete evaluation of neurotoxicity, and additional functional and morphological evaluation may be necessary to assess completely the neurotoxic potential of a chemical. 

The ICH guideline lists assessment of the effects of the test compound on motor activity, behavioural changes, co-ordination and sensory/motor reflex responses. A so-called functional observation battery or Irwin s battery will cover these parameters. Effects on body temperature should also be measured. 

Tegeris JS, Balster RL A comparison of the acute behavioral effects of alkylbenzenes using a functional observational battery in mice. Fundam Appl Toxicol 22 240-250, 1994... 

Rats exposed 5 days/week for 13 weeks to concentrations as high as 7060 ppm showed minimal effects to the nervous system as determined by functional observational battery, automated motor activity, and neuropathology. Rats exposed 6 hours/day for 90 days at 7100 ppm had increased liver and kidney weights males also had liver cell hypertrophy and increased hyaline droplets in the proximal tubules. ... 

Female Fischer 344 rats treated with a single oral dose (up to 5000 mg/kg bw) or with repeated doses (up to 1500 mg/kg bw per day for 14 days) of di(2-ethylhexyl) phthalate showed no neurobehavioural effects, as evaluated by functional observational battery and motor activity testing (Moser et al, 1995). 

Rat (Sprague- Dawley) once (GO) 2.2 132 (82% decrease in erythrocyte AChE, ataxia, alterations in functional observation battery tests 9 11 hrs post-dosing) Chow and Richter 1994... 

Table 21.10 Example of Evaluations Made in a Functional Observation Battery...

In the subchronic neurotoxicity study, end points measured are similar to those measured in the acute neurotoxicity study. However, the duration of dosing is 90 days and exposure to the test material is usually via the diet. As for the acute neurotoxicity study, these studies consist of three test groups and a control group. The functional observation battery and motor activity tests are conducted at selected intervals such as weeks 5, 9, and 13, as well as pretest. At test termination, at least 6 animals per group are perfused via the heart with fixative to ensure optimal fixation of nervous tissues for histopathology examination. Nervous tissues examined include brain, spinal cord (various segments), and selected nerves such as the optic, sciatic, tibial, and sural nerves. 

What are the neuropharmacology effects (functional observational battery, spontaneous motor activity, and motor coordination) in Sprague-Dawley rats following a single dose ... 

Mattsson JL, Spencer PJ, Albee RR (1996) A performance standard for chemical and functional observation battery examinations of rats. Journal of the American College of Toxicology 15 239-254... 

Repeated inhalation or oral exposures to moderate to high doses of -butyl acetate and -butanol are well tolerated. These aforementioned molecules are readily and rapidly metabolized to -butyric acid. The no-observed-effect level (NOEL) for repeated dose oral exposure to -butanol was 125 mg kg day. In a 90 day inhalation study in rats with -butyl acetate a NOEL of 500 ppm was reported for systemic effects, and a NOEL of 3000 ppm (highest dose tested) was reported for postexposure neurotoxicity based on functional observational battery endpoints, quantitative motor activity, neuropathy, and sched-uled-controlled operant behavior endpoints. Results of inhalation studies conducted on -butanol and -butyl acetate were negative for inducing reproductive and developmental toxicity. The NOEL for female reproductive toxicity was 6000 ppm with -butanol and 1500 ppm for -butyl acetate. In a 90 day repeated-dose inhalation toxicity study with butyl acetate the NOEL for male reproductive toxicity was 3000 ppm. For developmental toxicity, a NOEL of 3500 ppm was observed with -butanol and a NOEL of 1500 ppm (the highest exposure tested) was seen in both rats and rabbits following exposure to -butyl acetate. 

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