Document g2QYMd9aKGg81wLQKvk21jRZq

March 9, 1981 W D Davis, Manager Chemical Material Safety Subject: Risk Assessment of VCM Ingestion in Sprague-Dawley Rats Summary Data from two feeding studies by Maltoni with regard to the effect of VCM on Sprague-Dawley rats was combined to approximate the risk that might occur due to the presence of VCM in PVC film. A linear extrapolation model was employed to determine risk at very low doses. This was then applied to some hypothetical human diets in order to estimate the risk of cancer due to residual VCM in the film in which food is wrapped. Discussion Maltoni conducted two experiments (BT-11 and BT-27) in which male and female Sprague-Dawley rats were fed VCM in their daily diets, 4-5 days per week. In BT-11 the rats began this regimen at 13 weeks of age and continued for 52 weeks. Correspondingly, in BT-27, rats were started at 10 weeks of age and fed for 59 weeks on diets containing VCM. Both experiments were terminated at 136 weeks. Table 1 gives the combined data from BT-11 and BT-27 with respect to two responses, all malignant tumors and liver angiosarcomas. GTR 448 Page 2 Table! Combined Data for BT -11 and BT-27 Dose MG/KG PPM* Animals Tested Malignant Tumors 0 0.03 0.3 1.0 3.33 16.65 50.0 0 0.6 6.0 20.0 66.6 333.3 1000 0 230 150 150 150 80 80 80 35 27 20 38 8 24 31 Liver Angiosarcomas 0 0 1 3 0 10 17 *In rats 1 MG/KG/Day == 20 PPM in diet. This data was then fitted by a multi-stage model with low dose estimation being done by linear extrapolation. In order to apply the results of this modeling to the risk of cancer in man certain assumptions had to be made concerning the total diet and the VCM in the film: (1) The total diet consists of 1500 gm of food/day. (2) It takes 1 sq. in. of film to wrap 10 gm of food. (3) The film weighs 0.0159 gm per sq. in. (4) All the residual VCM in the film migrates to the food. It can be shown, from these assumptions that; VCM in Diet (PPM) = (1.59 X 10"3)vP (1) Where, v = VCM (PPM) in film P = Proportion of diet wrapped in film Notation: Let ar = increased risk, and D * dose in PPM Two responses were then considered: (1) All malignant tumors (2) Liver angiosarcomas GTR 449 Page 3 (1) All Malignant Tumors From the data in Table 1, 1 Ar = (3.2494 x 10 ) D = D = (3.0775) R / (5.1665 x 10 ) vP (2) (3) In Table 2 the increased risk of malignant tumors is compared for the multi-stage and linear extrapolation models. Table 2 Increased Risk of Malignant Tumors aI5 10 10 -6 10 -7 Multi - Stage 95% D(PFM) 2 LCL _2 UCL n 3.59 x 10 ,, 3.59 x 10"-? 3.59 x 10'4 2.36 x 10 o 2.36 x 10 , 2.36 x 10-4 5.46 x 10 ,, 5.46 x 10", 5.46 x 10~4 Linear Extrapolation D 3.08 x 10"5 3.08 x 10 3.08 x 10"7 In Table 3 the increased risk of malignant tumors is given as a function of the VCM in film (v) and the proportion of diet wrapped in film (P). Table 3 Increased Risk of Malignant: Tumors V PPM .001 .005 .010 .050 .100 .500 1.000 PPB 1 5 10 50 100 500 1000 .25 1.29x10 6.46x10"' 1.29x10" 6.46x10"!? 1.29xl0-"> 6.46x10*5 1.29xl0"4 P 5 _7 2.58x10 ' 1.29x10" 2.58x10" 1.29x10*5 2.58x10"5 1.29xl0"4 2.58xl0"4 .75 , 3.87x10 t 1.94x10^ 3.87x10" 1.94xl0"5 3.87x10"5 1.94xl0"4 3.87xl0"4 1 -7 5.17x10 2.58x10"^ 5.17x10" 2.58x10"; 5.17xl0"5 2.58xl0"4 5.17xl0"4 For example, in a diet consisting of 50% of the food wrapped in film which contains 5(KPPrD residual VCM, the increased risk of malignant tumors would oe 11.29x10"-* or a little greater than 1 in 1 hundred thousand, y GTR 450 Page 4 In Table 4 various combinations of v and p which result in a 1 in a million increased risk are given. Table 4 -6 Increased Risk of Malignant Tumors = 10 as a Function of v and P v p PPM PPB .25 .008 8 .50 .004 4 .75 .003 3 1 .002 2 (2) Liver Angiosarcomas Similarly, from the data in Table 1, Ar - (8.523 x 10"3) D = (1.3552 x 10-5) v P D = (1.1733 x 10"2)Ar (4) (5) Tables 5, 6 and 7 give the corresponding results for liver angiosarcomas. Table 5 Increased Risk of Liver Angiosarcomas Ar 10"2 10I^ 10-7 Multi - Stage 95% D (PPM) ,, LCL ,, UCL o 3.56x10"^ 3.56x10"^ 3.56xl0-4 2.59x10"^ 2.59x10';; 2.59xl0"4 4.87x10 _ 4.87x10 , 4.87xl0-4 Linear Extrapolation D 1.17xlO"2 1.17x10"* 1.17x10 GTR 451 U i CTv ON Page 5 Table 6 Increased Risk of Liver Angiosarcomas ooo oo m oo ih oo ro-(ion roo- i ioon v PPM PPB 1 5 10 50 100 500 1000 ^15 _9 3.39x10 I 1.69x10" 3.39x10" 1.69xlO"Z 3.39x10'^ 1.69x10" 3.39x10" P -il _9 6.78x10 I 3.39x10" 6.78x10" i iQvin"' .75 1.02x10" 5.08x10" 1.02x10"' 5.08x10"' 1.02x10" 5.08x10" 1.02xl0`5 1.36x10 6.78x10" 1.36x10 6.78x10" 1.36x10" 6.78x10" 1.36x10 Table 7 Increased Risk of Liver Angiosarcomas = 10 As a Function of v and P_________ p PPM PPB .25 .295 295 .50 .148 148 .75 .098 98 1 .074 74 S J Ganocy Biostatistician crb GTR 452