Evaluation of the Existing Toxicology Information

In addition to the compound being studied, search of the toxicology informational databases should consider the route and method of compound administration, type of formulation, and delivery vehicle, because these factors have the potential to modulate toxic and adverse effects. Whenever appropriate, help should be sought from information science professionals and others with specialized experience and expertise in the review of the toxicology literature and databases.

Use of Pilot Experiments

If large numbers of animals are to be administered substances with unknown toxicity profiles, pilot exposures of limited numbers of animals, or staggered starts, should be considered to minimize any potential unknown adverse outcomes. Range finding studies may be appropriate to determine dose tolerance. Low doses can be administered prior to those of high dose to minimize uncertainty.

Veterinary Medical Consultation

When adverse effects are expected or when administration procedures require more than brief physical restraint, the experiment should be reviewed with the attending veterinarian to ensure that the clinical monitoring program is appropriate for the animal model and procedure used, and that methods to minimize stress and discomfort are used in accordance with good veterinary care.

Use of Appropriate Consultants

Appropriate consultants should be used for toxicology issues that require specialized expertise. These may include industrial hygienists and health and safety professionals when there are conflicting issues between decisions of animal welfare versus laboratory safety during administration of potentially hazardous toxicants. In certain instances, the expertise of biostatisticians and toxicologists with expertise in study design may be needed to ensure that minimal numbers of animals are used to obtain the scientific objectives of the study.

Use of Experienced Personnel

Personnel must have training in laboratory animal handling and dosing methods. The experience level of personnel conducting all dosing and animal manipulative procedures should be clearly stated. This is especially important for experiments in which toxic materials are administered.

Determination of Method and Cause for Termination from Study

Prior to initiation of toxicant administration by oral, inhalation, or parenteral routes, the principal investigator should determine the criteria that would lead to humane termination of the procedure for any animal when appropriate and the method of euthanasia to be used. These criteria should be established prior to initiation of the studies and well documented. A clear chain of command for the decision-making process should be documented.

Established Procedures for Postdosing Observations

Designated personnel familiar with species-specific behaviors should observe all animals after dosing to ensure adequate recovery from compound administration procedures. Minimally, observations should be made immediately after dosing, a short time interval subsequent to dosing (30 to 60 min.), the morning after compound exposure, and appropriate subsequent intervals (at least once daily). Schedules and methods for observations should be determined by the experience with the toxicant being studied, as well as the type of expected biological outcomes.

Clinical Monitoring of Animals on Study

Provisions for clinical monitoring of study animals, including periodic body weight evaluation and food and water consumption, should be used in studies with compounds of unknown toxicity. The attending veterinarian should be consulted whenever there are questions of palatability in dosed feed or water studies, or when there is evidence of significant body weight depression (i.e., 10% below controls) or dehydration.

Determination of Factors Responsible for Adverse Outcome

Whenever compound administration procedures lead to unexpected adverse effects or to unscheduled termination of animals, attempts should be made by the attending veterinarian to elucidate the responsible factors. A summary of these findings should be forwarded to the IACUC for review.

Schedule and Method of Substance Administration

Proper volumes and administration schedules must be used for the method, exposure route, and the species. When parenteral administration is used, one should consider sterility, irritation, and pyrogenicity issues and attempt to use materials that are close to isotonicity and are blood biocompatible. Efforts should be made to administer substances free from extremes in Ph. Irritant and corrosive effects of administered materials should be evaluated by in vitro prescreening whenever possible.

Physical Restraint

Physical restraint should be as brief as necessary for conduct of the compound administration procedures. Animals should be acclimated to the equipment and procedures prior to initiation of dosing. Acclimation procedures should be used for metabolism cages whenever possible. Alternatives to prolonged physical restraint should always be evaluated and discussed with the attending veterinarian.

Equipment

Equipment and methods used in toxicant exposure should allow ready animal access for intervention and clear visualization of tests subjects when unknown compounds are tested or for which there is the potential for adverse effects.

Standard Operating Procedures (SOPs)

For each commonly used repetitive compound administration regimen, SOPs should be established and documented. These should be formulated with respect to the type of compound to be studied and the laboratory animal species used. These SOPs should be reviewed by the IACUC and the attending veterinarian at periodic intervals.

IACUC members at the Chemical Industry Institute of Toxicology and Participants at the National Welfare Education Workshop, Current Issues in IACUC Protocol Review, held in Raleigh, NC, in February 1994.