Document rpYVXOgEyYR78krOwV0qybG0E

t 8 9 0 H l0 0 0 ffNA January 23, 1991 DRAFT DO NOT CITE OR QUOTE REVIEW AND COMPARISON OF DETERMINING ACCEPTABLE AMBIENT AIR CONCENTRATIONS FOR VINYL CHLORIDE BASED ON CARCINOGENICITY IN TWO EPA REPORTS There are two recent EPA documents in which estimates were derived for ql* values for vinyl chloride. In the first document (Health Effects Assessment for Vinyl Chloride, EPA, 1984, Office of Health and Environmental Assessment, EPA/540/1-86-036) the animal ql* was given as 4.23xl0-3 (mg/kg/day) and the human ql* was given as 2.5xl0-2 (mg/kg/day)-1 (see Appendix 1 for determination of animal ql* value using GLOBAL86). Inhalation studies in rats were used and total tumors were used as the toxicological end point. This ql* value can be converted to units of ppm-1 or (ug/m3)-1 as follows by employing the same conversion factors used by EPA in converting animal exposures in ppm to human equivalent exposures in mg/kg/day: 1. Correction for surface area between humans and rats [(1/(70-kg human/.35 kg rat))1/3] * 2.5xl0-2 = 4.27xl0-3 (mg/kg/day)-1 2. Adjustment for body weight of rat 4.27xl0-3/.35 kg rat = 1.22X10-2 (mg/day)-1 3. Adjustment for breathing rates of rats .233 m3/d * 1.22X10-2 = 2,72xlO"3 (mg/m3)-1 or 2.72X10-6 (ug/m3)-1 or n\ 2.56X103 (ug/m3*ppm)*2.72xl0-6 (ug/m3)-1 = 6.96X10-3 ppm-1 (EPA84 calculation was 6.80xl0-3 ppm-1) 4. It was assumed that all the vinyl chloride inhaled was absorbed into systemic circulation. This is a conservative estimate. In a more recent update (Health and Environmental Effects Profile for chloroethene, EPA, 1985, Environmental Criteria and Assessment Office ECAO-Cinn-P155) the rat ql* was determined to be 5.04X10-2 (mg/kg/day) (see Appendix 2 for determination of the rat ql* value using GLOBAL86) and the human ql* was determined to be 2.95xl0-1 (mg/kg/day)-1. Animal studies from the same 1 VRD 0002040685 A investigator were used as in the EPA 1984 report; instead of using total tumor incidence, however, angiosarcomas of the liver were used as the only toxicological end point. Corrections to the dose were made since the observation period was extended after exposure stopped and an assumption was made that only 50% of the inhaled vinyl chloride was being absorbed. By using the same conversion factors above and correcting for % uptake the following inhalation ql* was determined. 1. Correction for surface area between humans and rats [(1/(70/.35))1^3]*2.95xl0_1 (mg/kg/d)"1 = 5.05xl0"2 (mg/kg/d)"1 2. Adjustment for body weight and breathing rate of rats [5.05xl0-2 (mg/kg/d)"1/.35kg]*.223 m3/d = 3.22xl0"2 (mg/m3)"1 or 3.22x10" (ug/m3)"1 3. In this assessment EPA assumed that only 50% of the vinyl chloride was absorbed through the lungs. To correct for this the gl* value has to be multiplied by .5. (.5)*3.22xl0~5 (ug/m3)'1 = l.SlxlO-5 (ug/m3)*"1 or 4.12X10"2 ppm"1 The state of Mississippi is recommending a gl* value of 4.2X10"5 (ug/m3)"1. This value is derived from the more recent EPA report just described from the ql* value of 2.95xl0_1 (mg/kg/d)"1. This number is 2.6-fold greater than the number calculated above (1.61 xo"5) . Mississippi derived their number as follows. 12.95xl0-1 (mg/kg/d)-1]*(.5)*(20 m3/d) *(l0-3mg/ug)/70 kg = 4.21X10"5 (ug/m3)"1 This calculation is incorrect, since the same conversion factors used by EPA to convert experimental levels (ppm) to human exposure equivalents (mg/kg/day) were not used by the state of Mississippi to back-calculate from (mg/kg/day) to ppm or ug/m3. Analysis of the data used bv EPA in determininq_a human ql* of 2.95xio~1(mq/kg/dav)~^rin theii^l985 report Figure 1 illustrates the relationship between liver angiosarcoma and vinyl chloride exposure in rats. No dose-response relationship is obvious. Furthermore, EPA did not use all the data in determining the ql* value. It only selected data points 0, .172, .344 and .86 mg/kg/day. There was no rationale provided why other data points were omitted. In addition, the data points 2 9090*01000 Sa are not even taken from the same experiment. For example, data points .344 and .86 were from Maltoni et al. experiment BT15 and data point 1.719 was taken from Maltoni et al. experiment BT1. Therefore, the manner in which the ql* value was calculated is scientifically incorrect and meaningless. In the 1985 report the length of the experiment was reported to be up to 1029 days, whereas the exposure period to vinyl chloride was for 365 days. In the transformation of experimental doses to human equivalent doses an adjustment factor of 365/1029 was used. From a biological sense this dose-averaging approach may not be appropriate. The actual time to tumor data needs to be obtained in order to make the appropriate adjustments to dose. The first ql* value established by EPA in 1984 was based on total tumors rather than liver angiosarcomas. Although in some instances total tumors may not provide the most sensitive assessment of cancer risk, the data as shown in figure 2 do show a linear dose response relationship up to 239.1 mg/kg/day. Therefore, these data provide a much better data base to determine a human ql* value, than the data base given in the EPA 1985 report. Discussions with EPA1s Cancer Assessment Group EPA's Office of Health and Environmental Assessment often has contractors provide health profiles and reports on various chemicals. These documents are used primarily as guidance to provide available information on the toxicity of various environmental agents and to provide the agency scientists and regulators with initial data to determine what chemicals potentially should take greater priority in being regulated. Although these documents have undergone some peer review within EPA they have not undergone the extensive scientific peer review that is usually necessary to support program office regulations. The more recent 1985 EPA report entitled "Health and Environmental Effects Profile for Chloroethene," which is being used by the State of Mississippi, is a first draft report and has the disclaimer that it is "for review purposes only and does not constitute Agency policy." Discussions with EPA scientists in the Cancer Assessment Group revealed that they are aware of the deficiencies in the approach taken in the 1985 EPA report for calculating a ql* value for vinyl chloride and that additional evaluations of the data base are necessary to derive a more scientifically sound quantitative risk assessment. Discussion The state of Mississippi elected to use a unit risk factor of 2.95x10"* (mg/kg/day) taken from an EPA report "Health and 3 1890*01000 S' Environmental Effects Profile for Chloroethene" September 1985. From this value they converted the units to obtain a ql* value of 4.21x10-5 ug/m3. This value is not appropriate to use to set acceptable ambient exposure levels to vinyl chloride for the following reasons: 1. The conversion from mg/kg/day to ug/m3 was done incorrectly (see above). The correct conversion would reduce the unit risk by a 'factor of 2.6. 2. The calculation was performed using a ql* value that EPA has not endorsed. This is stated in the disclaimer in the 1985 document. 3. The data used in calculating the ql* value in the 1985 EPA report are not of sufficient quality to determine a ql* value. a. There is no dose-response relationship. b. Results from different experiments were pooled in order to get a dose response relationship without any scientific rationale provided. c. Only certain data points were selected for determining the unit risk without any scientific rationale provided. d. Two of the data points available in the original Haltoni et al. paper were not included in the 1985 EPA report. No scientific rationale was provided. 4. Vinyl chloride is known to require metabolic activation to the proximate carcinogen. These pharmacokinetic considerations were not incorporated into the dose-response data used in determining the unit risk determination in the 1985 EPA report. 5. Many other studies are available than Maltoni et al. to estimate the carcinogenic risk of vinyl chloride. These other studies should be assessed, and pharmacokinetic/biologically based models should be considered to estimate more accurately the human carcinogenic risk of exposure to vinyl chloride gas. Conclusions The use of the unit risk presented in the 1985 EPA report entitled "Health and Environmental Effects Profile for Chloroethene" to establish acceptable ambient levels of vinyl chloride in the air is not scientifically justifiable because of 4 VRD 0002040688 the misuse of the data, lack of critical peer review of the methods employed in the report, and insufficient use of critical data pertinent in considering the carcinogenic risk of vinyl chloride. Until a more scientifically sound risk assessment is performed the former ql* value of 2.72X10"6 (ug/m3)-1 from the 1984 EPA report entitled "Health Effects Assessment for Vinyl Chloride" should be used to estimate cancer risk for vinyl chloride in the air. Although there are also deficiencies in the data on which this ql* value is based, a solid dose-response relationship for total tumors (figure 2) was used to estimate risk. 5 6890t0Z000 APPENDIX 1 GLOBAL 86 (MAY 1986) BY RICHARD B. HOWE AND CYNTHIA VAN LANDINGHAM CLEMENT ASSOCIATES, 1201 GAINES STREET RUSTON, LA 71270 (318) 255-4800 INC vinyl chloride: data taken from EPA 1984 report (total tumors) POLYNOMIAL DEGREE SELECTED BY PROGRAM, (POLY-DEGREE0) CHI-SQUARE TEST USED IN SELECTION GROUP DOSE ^RESPONSES OBSERVED/#ANIMALS #RESPONSES PREDICTED 1 .000000 2 4.90000 3 23.9000 4 47.8000 5 239.100 6/ 10/ 16/ 22/ 32/ 58 59 59 59 59 9.81 10.69 13.35 16.50 34.98 CHI-SQUARE GOODNESS OF FIT STATISTIC IS 5.6876 P-VALUE FOR THE CHI-SQ TEST WITH 3 DEGREES OF FREEDOM IS .1278379359 FORM OF PROBABILITY FUNCTION: P(DOSE) - 1 - exp( -Q0 - Q1 * D - Q2 * DA2 ) MAXIMUM LIKELIHOOD ESTIMATES OF DOSE COEFFICIENTS Q( 0) = Q( 1) Q( 2) = .185324445807 2.983355597998E--03 .000000000000 MAXIMUM VALUE OF THE LOG-LIKELIHOOD IS -163.144925015 CALCULATIONS ARE BASED UPON EXTRA RISK G**LO**B*A*L*8*6**U*P*P*E*R**C**O*N*F*ID*E*N*C**E**L*IM**IT*S***O*N**R*IS*K***F*O*R**F*IX*E**D**D*O*S*E* DOSE MLE RISK UPPER BOUND ON RISK CONFIDENCE COEFFICIENTS FOR LIMIT SIZE CONFIDENCE LIMIT 1.0000 2.97891E-03 4.22255E-03 NORMAL COMPLETION! 95.0% Q( 0) = Q( 1) * Q( 2) = .15535 4.23149E-03 .00000 APPENDIX 2 GLOBAL 86 (MAY 1986) BY RICHARD B. HOWE AND CYNTHIA VAN LANDINGHAM CLEMENT ASSOCIATES, 1201 GAINES STREET RUSTON, LA 71270 (318) 255-4800 INC . 0690m m 33 C3 A vinyl chloride: data taken from EPA 1985 report (liver angiosarcomas) POLYNOMIAL DEGREE SELECTED BY PROGRAM, (POLY-DEGREE-O) CHI-SQUARE TEST USED IN SELECTION GROUP DOSE ^RESPONSES OBSERVED/# ANIMALS #RESPONSES PREDICTED 1 .000000 2 .344000 3 .860000 4 1.71900 0/363 1/119 5/120 1/ 60 .00 1.17 2.92 2.89 CHI-SQUARE GOODNESS OF FIT STATISTIC IS 2.8312 P-VALUE FOR THE CHI-SQ TEST WITH 2 DEGREES OF FREEDOM IS .2427793524 FORM OF PROBABILITY FUNCTION: P(DOSE) 1 - exp( -Q0 - Q1 * D - Q2 * DA2 ) MAXIMUM LIKELIHOOD ESTIMATES OF DOSE COEFFICIENTS Q( 0) = Q( 1) = Q( 2) = .000000000000 2.867931930907E-02 .000000000000 MAXIMUM VALUE OF THE LOG-LIKELIHOOD IS -33.1407703774 CALCULATIONS ARE BASED UPON EXTRA RISK G**LO**B*A*L*8*6**U*P*P*E*R**C**O*N*F*ID*E*N*C*E**L*I*M**IT*S**O**N*R**IS*K***FO**R**F*IX*E*D***D*O*S*E* DOSE MLE RISK UPPER BOUND ON RISK CONFIDENCE LIMIT SIZE COEFFICIENTS FOR CONFIDENCE LIMIT 1.0000 2.82720E-02 4.91334E-02 95.0% Q ( 0) = Q( 1) Q( 2) * .00000 5.03816E-02 .00000 NORMAL COMPLETION! VRD 0002040691 Figure 1 EPA85 (liver angiosarcomas) tumor incidence tumor incidence Figure 2 EPA84 (total tumors) 0.6 0082040692 50