Final Program - Society for Risk Analysis

W3-G.1 Walderhaug MO, Mitkus R, Hess M, King D; mark.walderhaug@fda.hhs.govFDA CBERUPDATED SAFETY ASSESSMENT OF ALUMINUM EXPOSURESFROM VACCINATION IN INFANTS USING PHARMACOKINETICMODELINGAluminum salts (hydroxide or phosphate) are important adjuvants for specificvaccines. These specific, adjuvanted vaccines are more effective in eliciting an immuneresponse when the antigens are complexed with aluminum particles, whichactivate specific cellular responses in antigen presenting cells. During the first yearof life, infants receive vaccinations according to a set schedule recommended by theAdvisory Committee on Immunization Practices (ACIP). Despite the therapeuticbenefit of aluminum in specific vaccines, some of the public remain concerned aboutthe safety of aluminum. We evaluated the relative contribution to aluminum levelsin infants from vaccines and from diet, by updating both the pharmacokinetic modeland the parameters used by the Agency for Toxic Substances and Disease Registry,which evaluated the safety of aluminum in 2002. We revised the analysis by using a2010 vaccination schedule, a more recent aluminum retention function from humanvolunteers, an adjustment for the kinetics of aluminum efflux from the site of injection,the latest minimal risk levels (MRLs), baseline aluminum levels at birth, and themost recent infant body weight data available for children from the National Healthand Nutrition Examination Survey (NHANES). The results show that despite morestringent exposure standards, infant aluminum exposure levels from vaccinations anddiet remain safe.P.54 Walker JT, Walker TD, Walker OA; walker.teneille@epa.govUS Environmental Protection AgencyAN ANALYSIS OF THE GROWTH CURVES OF CONTROL SPRAGUE-DAWLEY RATS FED AD-LIBITUM FROM WEANING TO 90 DAYS OFAGESprague-Dawley (SD) rats have been extensively used in 90-day toxicity studiesfor the purpose of understanding the effects of drugs, environmental chemicals,and other agents on growth. Currently, however, no suitable mathematical modelsexist that can describe the growth of these animals. In an attempt to solve this problem,we fitted the growth data of these animals, utilizing a Diphasic-Logistic Growth(DPLG) model. The model assumes that the total body weight, during the periodfrom weaning to 90 days of age, is due primarily to the combined effects of a pubertaland post-pubertal growth process. The model’s biological parameters were estimatedby applying a Levenberg-Marquardt nonlinear least squares fitting technique. Ourresults demonstrated that the DPLG model was very effective and efficient in describingthe growth of these animals. The fits resulted in high R2 and adjusted R2188values, large F values, low residual means, Durbin-Watson statistics that were veryclose to 2, and small standard error estimates for the model parameters. Furthermore,the graphs of the residuals essentially showed no model bias. Male Sprague-Dawleyrats were found to have large pubertal and post-pubertal growth rates compared tofemales. The timing of the pubertal and post-pubertal growth spurts in males wasalso found to be larger. We conclude that the model is an excellent tool for describingthe growth of Sprague-Dawley rats in a 90-day study period and can be used forstudying the growth of other rodents. We also discuss how the model can be appliedin risk assessment. Disclaimer: The views expressed in this presentation are those ofthe author and do not necessarily reflect the views or policies of the U.S. EnvironmentalProtection AgencyP.55 Walker JT, Walker TD, Walker OA; walker.james-doctor@epa.govUS Environmental Protection AgencyA MATHEMATICAL DESCRIPTION OF NATIONAL TOXICOLOGYPROGRAM (NTP) 2-YEAR GROWTH CURVES OF MALE AND FE-MALE F344/N RATSIt is well known that the NTP routinely presents rodent growth data and curvesin 2-year bioassay studies. These serve as useful and comprehensive sources of growthdata that can be used for age-specific PBPK modeling and other risk assessment efforts.Currently, however, suitable mathematical models are not available to the riskassessment community that can properly describe these curves. In this study, we usedthe Triphasic-Logistic Growth (TPLG) Model to describe NTP growth curves ofcontrol male and female F344/N rats taken from 2-year bioassay studies. The modelwas fitted to average weight growth data of F344/N rats obtained from five NTPbioassay studies, utilizing a Levenberg-Marquardt nonlinear least squares fitting techniqueto estimate the model parameters. Our results demonstrated that the TPLGmodel was very effective and efficient in describing the growth of these animals.The fits from each of the five studies resulted in high R2 and adjusted R2 values,large F values, low residual means, Durbin-Watson statistics that were very close to2, and small standard error estimates for the model parameters. In addition to an agingcomponent, we identified three major growth components or processes in bothmale and female growth curves according to the period when they reached their peakweight velocity: pubertal, young adult, and adult. The model parameters were used tocharacterize the growth of these animals from weaning to old age. Our results are significant,because the new model is able to accurately describe the age specific weight,weight velocities, and specific growth rates of NTP male and female F344/N rats forthe entire period from weaning to 2 years of age. The impact of these results on riskassessment will be discussed. Disclaimer: The views expressed in this presentationare those of the author and do not necessarily reflect the views or policies of the U.S.Environmental Protection Agency