Environmental and genetic factors affecting the response of laboratory animals to drugs

Only some of the diverse factors that can affect drug disposition and response in laboratory animals have been identified at the present time. These numerous factors contribute to large day-to-day variations that have become a major problem impeding investigation of drug disposition and response in laboratory animals. Although these variations render many experiments difficult to interpret and produce large discrepancies in the literature, few published investigations using laboratory animals provide sufficient details to permit replication of the studies under similar conditions with respect to these variables. Thus, the importance of these variables in affecting results is apparently insufficiently recognized at present. Two commonly overlooked variables affecting the activity of hepatic microsomal enzymes (HME) in rodents and hence the rate at which rodents eliminate from their bodies many foreign compounds are the bedding under the wire mesh cage and the relative cleanliness of the environment. Numerous chemicals present in relatively low concentrations in the environment of the animal room can significantly alter HME activity. Representative of these chemicals are aromatic hydrocarbons in cedarwood bedding, eucalyptol from aerosol sprays, and chlorinated hydrocarbon insecticides, each of which induces HME activity, whereas ammonia generated from feces and urine accumulated in unchanged pans under cages may inhibit HME activity. Chloroform, identified as an environmental contaminant of the water and air of certain cities, exhibits sex and strain differences with respect to toxicity (LD50) in mice. After intraperitoneal injection, twice as much chloroform accumulated in the kidneys of males from the sensitive strain (DBA/2J) as from the resistant (C57BL/6J) strain. First generation offspring were midway between parental strains both with respect to LD50 and renal accumulation of chloroform.