Case Study - Alliance for Risk Assessment

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41Development of the 24-hr ReV (refer to Table 3-1)Dose MetricFor the reproductive/developmental key study (Hackett et al. 1987b), the most appropriate dose metricfor a 24-hr exposure is likely area under blood concentration curve of DEB or DEB concentration intarget tissue; however, this data was not available. Therefore, data on the exposure concentration of theparent chemical was used as the default dose metric.Dose-Response Modeling and Points of Departure (PODs)The TCEQ (2008) performed benchmark concentration (BMC) modeling for numerous endpoints fromHackett et al. (1987b). The endpoint with the lowest relevant BMCL was decrease in maternalextragestational weight gain (BMCL 1 SD = 51.3 ppm with a BMC 1 SD of 723 ppm), followed by decreasein fetal body weight (BMCL 05 = 54.7 ppm BMC 05 of 65.8 ppm).Duration and Default Dosimetry AdjustmentsTable C-1 provides information on duration adjustments from a 6-hr exposure to a 24-hr exposure usingHaber’s Rule as modified by ten Berge (1986) with “n” = 1. Default dosimetry adjustments fromanimal-to-human exposure were based on methods for Category 3 gases producing systemic effects(USEPA 1994; TCEQ 2012). For BD, the (H b/g ) A / (H b/g ) H , > 1 (TCEQ 2008). When (H b/g ) A / (H b/g ) H , >1, a default value of 1 is used for the regional gas dose ratio (RGDR) (USEPA 1994). Table 1 comparesthe derivation of the 24-hr ReV to the derivation of the 6-hr ReV and a 24-hr ReV value based on a ratstudy (ACC 2003).Uncertainty FactorsA full UF H of 10 was used to account for intraspecies variability. There is experimental evidence thatindicates BD-sensitive human subpopulations may exist due to metabolic genetic polymorphisms(USEPA 2002), although recent studies indicate that variability due to genetic polymorphisms is lessthan 10 based on metabolism of BD in humans with different genotypes. (Albertini et al. 2001, 2003).A UF A of 3 was used for extrapolation from animals to humans because default dosimetric adjustmentsfrom animal-to-human exposure were conducted, which account for toxicokinetic differences but nottoxicodynamic differences. This approach is likely conservative, since existing studies indicate that miceare relatively sensitive laboratory animals in regards to the reproductive effects of BD.A database UF D of 1 was used because the overall acute toxicological database for BD includes acuteinhalation studies in humans; two inhalation bioassays in different species investigating a wide range ofendpoints; and several prenatal developmental toxicity studies in different species (USEPA 2002; TCEQ2008). Both the quality of the studies and the confidence in the acute database is high..41
42Table 3-1: Derivation of the 1-Hr and 24-Hr ReV based on a Mouse study (Hackett et al.1987b)Alternate 24-Hr ReV based on a Rat study (ACC2003)StudyStudypopulationHackett et al. 1987b ACC 2003CD-1 mice (18-21 pregnant mice per dose group) Crl:CD® (Sprague-Dawley) IGS BR rats (12 male and 12female rats per dose group)Study quality High HighExposureMethods0, 40, 200, and 1,000 ppm BD on gestation days (GD) 6-15 for 6 h/day 0, 300, 1,500, and 6,000 ppm BD (14 days prior tobreeding, during gestation, and lactation) for 6 h/dayCritical Effects Reduction in extragestational weight gain and fetal body weight; developmentaltoxicityPersistent reductions in body weight parameters in F 0 andF 1 males and females6- hr Acute ReVmice24 hr Acute ReVmice24 hr Acute ReVratPOD 51.3 ppm (BMCL 1 SD ) 51.3 ppm (BMCL 1 SD ) 300 ppm (NOAEL)Duration 6 h 6 h 6 hExtrapolation toother durationsNo adjustment to 1 hr because thecritical effect was a maternal/developmental endpointExtrapolation to 24 hr51.3 ppm (BMCL 1 SD ) x 6/24Extrapolation to 24 hr300 ppm (NOAEL) x 6/24POD animal 6 hr POD mice =51.3 ppm (BMCL 1 SD )24 hr POD mice =12.8 ppm (BMCL 1 SD )24 hr POD rat75 ppm (NOAEL)POD HEC 6-hr POD HEC51.3 ppm (gas with systemic effects,based on default RGDR = 1.0)24-hr POD HEC12.8 ppm (gas with systemic effects, basedon default RGDR = 1.0)24-hr POD HEC75 ppm (gas with systemic effects, based on defaultRGDR = 1.0)Total UFs 30 30 30Interspecies UF 3 3 3Intraspecies UF 10 10 10LOAEL UF Not applicable Not applicable Not applicableDatabase UFDatabase111Qualityacute ReV3,700 µg/m 3 (1,700 ppb)[6 hr] miceHigh950 µg/m 3 (430 ppb)[24 hr] miceHigh5,500 µg/m 3 (2,500 ppb)[24 hr] ratHigh42
Page 4: 1INTERPRETATION OF 24-HOUR SAMPLING
Page 7 and 8: 1,3-Butadiene concentration parts p
Page 9 and 10: 24-Hour Benzene Concentrations (ppb
Page 11 and 12: 8mortalityresponse relationship of
Page 13: 10Section 4 Twenty-Four Hour Refere
Page 17 and 18: 14Haber’s rule is dependent on th
Page 19 and 20: 161, which is considered to be cons
Page 21 and 22: 18Viluksela, M, Stahl, BU, Birnbaum
Page 23 and 24: 20Example 1: Development of a 24-Ho
Page 25 and 26: Log Concentration (µg/m 3 )22Total
Page 27 and 28: 24References1. Agency for Toxic Sub
Page 29 and 30: 26The TCEQ has historically develop
Page 31 and 32: 28Three subacute mouse studies iden
Page 33 and 34: 30higher than the multiple-day LOAE
Page 35 and 36: Log Concentration (µg/m 3 )32A UF
Page 37 and 38: 34This value is sufficiently conser
Page 39 and 40: 36Example 3: Development of a 24-Ho
Page 41 and 42: difficulty focusing; Human; (E)DecB
Page 43: 40Figure 3-2 Schematic of BD Metabo
Page 47 and 48: 1,3-Butadiene concentration parts p

Case Study - Alliance for Risk Assessment

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