Factors Modifying the Activity of Toxicants

Even as the route of exposure and the molecular interactions that cause the toxic effects are delineated, that is not the entire story. Chapter 6, Factors Modifying the Activity of Toxicants, describes the myriad physiological and environmental factors that can alter the exposure of the organism to the toxicant and also the response to the compound. Nutritional status, complexing elements in the environment, as well as the organism and reproductive status can all drastically affect the response of an organism to environmental exposure. 

Another situation occurs in an API facility when actives are often made without the knowledge of what the ultimate route of administration to the patient might be. For example, it might be that an active made first in the equipment would be intended for oral administration only, but the next scheduled synthesis is for the active for a product to be administered intravenously. The amount of material that can give a medical or toxic effect intravenously may be much less than that given orally, and the limits would need to be appropriately modified. This information should be factored into the limits calculation. 

ChE) activity in rats. The lowest-observed-adverse-effect level (LOAEL) of GB was 0.075 mg/kg per day in a subchronic toxicity stndy (Bucci and Parker 1992). In that study, male and female rats were administered GB by gavage for 5 days per week for 13 weeks. Becanse of the discontinuons exposnre regimen, ORNL adjusted the LOAEL (LOAEL for continuous exposures by multiplying 0.075 mg/kg per day by a factor of 5/7 (i.e., 5 days/7 days) to yield a LOAELadj of 0.054 mg/kg per day. The RfD for GB was calculated to be 2 x 10 mg/kg per day by dividing the LOAELadj by 2,700, the product of the uncertainty factors and the modifying factor selected by ORNL. 

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