A Practical Approach, Second Edition=Ronald D. Ho.pdf

DEVELOPMENTAL AND REPRODUCTIVE TOXICITY RISK ASSESSMENT 861data are not available, the database is considered to be deficient, and an additional databaseuncertainty factor may be applied. In the case of pesticides, the Food Quality Protection Act requiresthe addition of a 10-fold margin of safety to take into account the potential for pre- and postnataltoxicity and the completeness of the toxicology and exposure databases. The EPA’s Office of PesticidePrograms has published a guidance document 35 that provides direction for applying the additional 10-fold FQPA safety factor and clarifies that there is overlap between this tenfold factor and the traditionaluncertainty factors, particularly the database deficiency factor. It presumes that in most cases thetraditional uncertainty factors will be sufficient to be protective of children’s health. Nevertheless, theremay be residual uncertainties about health effects not captured in the RfD process or in the exposureassessment that provide a basis for maintaining part or all of the FQPA factor.Three types of descriptors of human risk are especially useful and important. The first of theseis related to interindividual variability, i.e., the range of variability in population response to anagent and the potential for highly sensitive or susceptible subpopulations. A default assumption ismade that the most sensitive individual in the population will be no more than 10-fold more sensitivethan the average individual; thus, a default 10-fold uncertainty factor is often applied in calculatingreference values to account for this potential difference. When data are available on highly sensitiveor susceptible subpopulations, the risk characterization can be done on them separately or by usingmore accurate factors to account for the differences. When data are not available to indicatedifferential susceptibility between developmental stages and adulthood, all stages of developmentand reproduction may be assumed to be highly sensitive or susceptible. Certain age subpopulationscan sometimes be identified as more sensitive because of critical periods for exposure; for example,pregnant or lactating women, infants, children, adolescents, adults, or the elderly. In general, notenough is understood about how to identify sensitive subpopulations without obtaining specificdata on each agent, although it is known that factors such as nutrition, personal habits (e.g., smoking,alcohol consumption, drug abuse), quality of life (e.g., socioeconomic factors), preexisting disease(e.g., diabetes), race, ethnic background or other genetic factors may predispose some individualsto be more sensitive than others to the developmental effects of various agents.The second descriptor of importance is for highly exposed individuals. These are individualswho are more highly exposed because of occupation, residential location, behavior, or other factors.For example, children are more likely than adults to be exposed to agents deposited in dust or soil,either indoors or outdoors, both because of the time spent crawling or playing on the floor or groundand the mouthing behavior of young children. The inherent sensitivity of children may also varywith age, so that both sensitivity and exposure must be considered in the risk characterization. Ifpopulation data are absent, various scenarios representing high end exposures may be assumed byuse of upper percentile or judgment based values. This approach must be used with caution, however,to avoid overestimation of exposure.The third descriptor that is sometimes used to characterize risk is the margin of exposure (MOE).The MOE is the ratio of the NOAEL (or BMDL) from the most appropriate or sensitive speciesto the estimated human exposure level from all potential sources. Considerations for the acceptabilityof the MOE are similar to those for the uncertainty factors applied to the NOAEL or BMDLto calculate the reference values. Examples of the calculation of an MOE based on developmentaltoxicity data have been described for dinoseb, 145 lithium, 123 and boric acid and borax. 124 In the caseof dinoseb, the MOEs were very small, in some cases less than 1, indicating toxicity in the animalstudies at levels to which people were being exposed. The analysis of the data on dinoseb led toan emergency suspension of this pesticide in 1986 and ultimately to its removal from the market.The risk characterization is communicated to the risk manager, who uses the results along withtechnological factors (e.g., exposure reduction measures), as well as social and economic considerations,in reaching a regulatory decision. Depending on the statute involved and other considerations,risk management decisions are usually made on a case-by-case basis. This may result indifferent, but appropriate, regulation of an agent under different statutes.© 2006 by Taylor & Francis Group, LLC