PRINCIPLES OF TOXICOLOGY - Biology East Borneo

28 GENERAL PRINCIPLES OF TOXICOLOGY1.8 EXTRAPOLATION OF ANIMAL TEST DATA TO HUMAN EXPOSURESeveral models can be used to extrapolate the human risks from chemical exposure on the basis oftoxicity tests in animals. The model chosen is primarily determined by the health hazard of mostconcern. In the past, however, two basic methods for extrapolation were used. The first type consistedof extrapolating the human risk directly from either the threshold dose or some no-observable-effectlevel(NOEL) dose. This method was applied to most toxicities or health hazards (except cancer), sincethresholds were assumed to be present for all of these health hazards. The second type of model wasgenerally used to assess the risk associated with carcinogens. Since the regulatory approach tocarcinogens has been to assume that no identifiable threshold exists for this type of toxicity, anyexposure was assumed to involve some quantifiable amount of risk. This concept dictated that themathematical models used to extrapolate to exposures far below the dosages that induce observableresponses in the test animal population involve some form of linear extrapolation at low doses. Fornoncancer-causing toxicants (those with threshold toxicity), the models for extrapolating risk arerelatively simple and similar to the methods that have been suggested or used by the National Academyof Sciences (NAS) and various governmental agencies such as the Food and Drug Administration(FDA) or the Environmental Protection Agency (USEPA). These models derive a safe dosage bydividing the threshold (or NOEL/LOEL) by uncertainty factors. The purpose of adding these uncertaintyfactors is to ensure that the allowable human dose is one that falls within the no-effect region ofthe human dose–response curve. Basically, this type of calculation assumes that humans are as sensitiveas the test species used; so, the amount of a chemical ingested by the test animal that gives no toxicresponse is considered the safe upper limit of exposure for humans (especially after inclusion ofappropriate safety factors).Calculating Safety for Threshold Toxicities: The Safe Human Dose ApproachThe calculation of a safe human dose essentially makes an extrapolation on the basis of the sizedifferential between humans and the test species. Usually this is a straightforward body-weightextrapolation, but a surface area scalar for dose could also be used. The calculation is similar to thefollowing:SHD =NOAEL = (mg / kg per day) × 70 kgUF= N mg/daywhere NOAEL = threshold dose or some other no-observable-adverse-effect-level selectedfrom the no-effect region of the dose–response curveSHD = safe human doseUF = the total uncertainty factor, which depends on the nature and reliability of theanimal data used for the extrapolationN = number of milligrams consumed per day(Note: In this example we are extrapolating for an average adult male, and so we have assumed a 70kg body weight.)Typically, the uncertainty factor used varies from 10 to 10,000 and is dependant on the confidenceplaced in the animal database as well as whether there are human data to substantiate the reliability ofthe animal no-effect levels that have been reported. Of course, the number calculated should use chronicexposure data if chronic exposures are expected. This type of model calculates one value, the expectedsafe human dosage, which regulatory agencies have referred to as either the acceptable daily intake(ADI) or the reference dose (RfD). Exposures which produce human doses that are at or below thesesafe human dosages (ADIs or RfDs) are considered safe.