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Methodology A summary of the calculated low-dose risk assessments from a number of animal and human studies is shown in Table 4. The epidemiological data were analyzed using a linear nonthreshold model to estimate risk. The animal data were analyzed by fitting a linearized multistage procedure to doseresponse data from the animal cancer bioassays. The results of the U.S. EPA’s Carcinogen Assessment Group (CAG) epidemiologic-based assessments are also included in the table for comparative purposes (U.S. EPA, 1979). CDHS (1984) recommended that cancer potency values in the range of 24 to 170 × 10 -6 per ppb (i.e., 0.024 to 0.17/ppm) be used in estimating risks from low level exposure to benzene. Slightly higher upper bound values were obtained when shortened survival times in the studies analyzed were taken into account. Assuming that humans breathe 20 m 3 per day and weigh 70 kg and that an air concentration of 1 ppm benzene is equivalent to 3.25 mg/m 3 , the CDHS range of potency values is equivalent to 0.03 to 0.2 (mg/kg-day) -1 . In 1988, CDHS (under Proposition 65) recommended that the potency value of 0.1 (mg/kg-day) -1 [unit risk = 2.9 × 10 -5 (µg/m 3 ) -1 ] be used to estimate risk specific intake levels from exposure to benzene. This value falls within the range of estimates derived by CDHS (1984) and the U.S. EPA (1979, 1985), and is the upper 95% confidence bound estimate from the analysis of human data considered most credible by the U.S. EPA. 87
Table 4: Summary of benzene low-dose risk assessments. Study Route of Exposure Lifetime a TWA Dosage NTP (1983) Gavage 17.9 mg/kgday b NTP (1983) Gavage 17.9 mg/kgday b NTP (1983) Gavage 17.9 mg/kgday b NTP (1983) Gavage 17.9 mg/kgday b Maltoni et al. (1983) Maltoni et al. (1983) Infante et al. (1977) Rinsky et al. (1981) Askoy et al. (1974, 1976,1977) Ott et al. (1978) CAG (US EPA, 1979) Gavage 13.9 mg/kgday c Inhalation d 16.45 mg/kg-day e Inhalation Inhalation Inhalation Inhalation 2.81 ppm f (2.99 mg/kgday) 2.81 ppm f (2.99 mg/kgday) 4.22 ppm f (4.49 mg/kgday) 0.171 ppm f (0.182 mg/kg-day) Tumor Type Species Sex Type of Zymbal gland carcinomas Preputial gland carcinomas Lymphoma or Leukemia Mammary carcinomas Zymbal gland carcinomas Zymbal gland carcinomas Leukemia (Myelocytic or Monocytic) Leukemia (Myelocytic or Monocytic) Analysis Mouse M Crude Attack Rate Lifetable Adj. Rate Mouse M Crude Attack Rate Lifetable Adj. Rate Mouse M Crude Attack Rate Lifetable Adj. Rate Mouse F Crude Attack Rate Lifetable Adj. Rate Rat F Crude Attack Rate Rat M, F Crude Attack Rate Human M Fatal Tumor Life Table Human M Fatal Tumor Life Table Multi-Stage Model for Human Equivalent Cancer Risk/ppb Benzene MLE: 7.4 × 10 -6 95% UCL: 34 × 10 -6 MLE: 6.9 × 10 -6 95% UCL: 47 × 10 -6 MLE: 78 × 10 -6 95% UCL: 170 × 10 -6 MLE: 140 × 10 -6 95% UCL: 340 × 10 -6 MLE: 49 × 10 -6 95% UCL: 81 × 10 -6 MLE: 170 × 10 -6 95% UCL: 230 × 10 -6 MLE: 32 × 10 -6 95% UCL: 57 × 10 -6 MLE: 61 × 10 -6 95% UCL: 92 × 10 -6 MLE: 26 × 10 -6 95% UCL: 42 × 10 -6 MLE: 6.4 × 10 -6 95% UCL: 12 × 10 -6 15 × 10 -6 48 × 10 -6 Leukemia Human M Fatal Tumor 20 × 10 -6 Leukemia Human M Fatal Tumor 46 × 10 -6 Inhalation Leukemia Human M Fatal Tumor 24 × 10 -6 Assumptions: 60 kg person, human inhalation at 20 m 3 /day. MLE = Maximum likelihood estimate. 95% UCL = 95% upper confidence limit on risk for provided dose. a Dosages provided without scaling factors. b Lowest dose used in three dose risk assessment, Cochran-Armitage linear trend test for these tumors: preputial gland, p < 0.001; Zymbal gland, p < 0.001; lymphoma or leukemia, p = 0.035; mammary carcinoma, p < 0.001. c Lowest dose used in two point risk assessment, Cochran-Armitage linear trend test for these tumors, p < 0.001. 88
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Air Toxics Hot Spots Program Risk A
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Prepared by: John D. Budroe, Ph.D.
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This document is one of five docume
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TABLE OF CONTENTS PREFACE i INTRODU
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N-Nitrosodimethylamine 401 N-Nitros
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Hot Spots Unit Risk and Cancer Pote
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Additional ATES and PETS documents
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data. If several data sets (dose an
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US EPA Calculation of Carcinogenic
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exposure to a concentration of 1 µ
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incidences for each of the dose lev
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computes the surface area of a sphe
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Comparison of Hot Spots Cancer Unit
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Gold, L., de Veciana, M., Backman,
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Animal Studies Rats Woutersen et al
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ased on sufficient evidence of carc
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ACETAMIDE CAS No: 60-35-5 I. PHYSIC
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Methodology Expedited Proposition 6
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cancer mortality. However, US EPA (
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Table 2. Lung adenoma incidence in
Page 45 and 46: Table 3 (continued). Acrylamide-ind
Page 47 and 48: Robinson M, Bull RJ, Knutsen GL, Sh
Page 49 and 50: Also, a trend was observed correlat
Page 51 and 52: eported. Cause-specific expected de
Page 53 and 54: Bio/Dynamics Inc. conducted a study
Page 55 and 56: examination. Interim sacrifices wer
Page 57 and 58: Table 8. Tumor incidence in male an
Page 59 and 60: Gaffey WR and Strauss ME. 1981. A m
Page 61 and 62: (technical grade; 98% pure) by gava
Page 63 and 64: International Agency for Research o
Page 65 and 66: still alive in the low-dose control
Page 67 and 68: ANILINE CAS No: 62-53-3 I. PHYSICAL
Page 69 and 70: fibrosarcomas, stromal sarcomas, ca
Page 71 and 72: ARSENIC (INORGANIC) CAS No: 7440-38
Page 73 and 74: elationship between arsenic exposur
Page 75 and 76: al. (1988) did not induce lung tumo
Page 77 and 78: A risk assessment was also conducte
Page 79 and 80: Chen C, Chuang Y, You S, Lin T and
Page 81 and 82: Schrauzer G, White D, McGinness J,
Page 83 and 84: Table 1: Summary of epidemiologic s
Page 85 and 86: had at least one animal demonstrati
Page 87 and 88: mesothelioma, recommended lifetime
Page 89 and 90: National Institute for Occupational
Page 91 and 92: BENZENE CAS No: 71-43-2 I. PHYSICAL
Page 93 and 94: Animal Studies Available experiment
Page 95: Table 3: Summary of NTP bioassay re
Page 99 and 100: Maltoni C, Conti B and Cotti G. 198
Page 101 and 102: a benign tumor of the kidney. No ba
Page 103 and 104: al. (1968) found no tumors in lifet
Page 105 and 106: following relationship, where C(t 1
Page 107 and 108: Miakawa M. and Yoshida O. 1975. Pro
Page 109 and 110: human population and that BPDE-DNA
Page 111 and 112: demonstrated the tumor initiating a
Page 113 and 114: Table 4: Bronchoalveolar tumors fro
Page 115 and 116: Table 5: IARC groupings of PAHs, mi
Page 117 and 118: Table 6 (continued): IARC Group 3 P
Page 119 and 120: Potency Equivalency Factors (PEF) f
Page 121 and 122: This was rounded to a PEF of 0.1. 1
Page 123 and 124: experiment (Takayama et al., 1985)
Page 125 and 126: Deutsch-Wenzel RP, Brune H, Grimmer
Page 127 and 128: Krewski D, Thorslund T and Withey J
Page 129 and 130: U.S. Environmental Protection Agenc
Page 131 and 132: Sorahan et al. (1983) studied cance
Page 133 and 134: Lijinsky W. 1986. Chronic bioassay
Page 135 and 136: the drinking water (Schroeder and M
Page 137 and 138: Table II. Effective dose, upper-bou
Page 139 and 140: BIS(2-CHLOROETHYL)ETHER CAS No: 111
Page 141 and 142: IV. DERIVATION OF CANCER POTENCY Ba
Page 143 and 144: BIS(CHLOROMETHYL)ETHER CAS No: 542-
Page 145 and 146: Table 1. Bis(chloromethyl)ether-ind
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Drew RT, Laskin S, Kuschner M and N
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ates for the 1968 U.S. male populat
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Table 1: Incidence of primary tumor
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IV. DERIVATION OF CANCER POTENCY Ba
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National Institute of Occupational
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was less than 0.05 when controlling
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up period. The final cohort include
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If the cadmium-exposed workers incl
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on personnel records (20%); (3) eva
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were exposed to a continuous (23.5
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procedure (NLIN), the parameters we
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International Agency for Research o
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Two reports were published on cance
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Mendel rats, respectively), and sub
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Eschenbrenner A and Miller E. 1946.
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III. CARCINOGENIC EFFECTS Human Stu
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cancers, were less than expected. T
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and no cases of cancer (although cl
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There was a statistically significa
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NTP (1982a) also conducted an carci
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Several pathologists have independe
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hepatocellular adenoma/carcinoma tu
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carcinogenic potency may decline in
Page 193 and 194:
Cochrane W, Singh J and Miles W. 19
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North Atlantic Treaty Organization,
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CHLORINATED PARAFFINS (average chai
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ased on dose-response data for beni
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chloroform in drinking water with k
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Overall, the present epidemiologica
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female dogs received toothpaste bas
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Calculated q 1 * values from the ab
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Hogan MD, Chi Py, Hoel DG and Mitch
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Table 1. Study design summary for N
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V. REFERENCES California Environmen
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toluidine. Followup of this subcoho
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feeding studies on by NCI (1979) us
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CHROMIUM (HEXAVALENT) CAS No: 18540
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expected rate may be inflated becau
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Oral Borneff et al. (1968) exposed
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CREOSOTE (COAL TAR-DERIVED) CAS No:
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from an inhalation exposure study (
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U.S. Environmental Protection Agenc
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Table 1. Study design summary for N
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Table 1. Experimental design for ca
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Hazardous Substance Data Bank (HSDB
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Table 1: Tumor induction in Fischer
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Table 1. Experimental design of 2,4
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Additional analysis of these data b
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Jackson RJ, Greene CJ, Thomas JT, M
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Table 1. Tumor incidence in rats ex
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Girard R, Tolot F, Martin P and Bou
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exposed more than 16 years before t
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interpretation of dose extrapolatio
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1, 1-DICHLOROETHANE CAS No: 75-34-3
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Table 1b. Study design for carcinog
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National Cancer Institute (NCI) 197
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mice, hepatocellular carcinoma inci
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V. REFERENCES California Department
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DAB/day by gavage for the life of t
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2,4-DINITROTOLUENE CAS No: 121-14-2
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Ellis et al.(1979) (also reported b
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Final Statement of Reasons for OAL,
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to the small sample size and short
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In an inhalation study, Torkelson e
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V. REFERENCES American Conference o
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EPICHLOROHYDRIN CAS No: 106-89-8 I.
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espiratory tumors were noted in the
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Table 4. Epichlorohydrin-induced fo
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Konishi Y, Kawabata A, Denda A, Ike
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exposed to arsenicals for 20 months
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espectively (all statistically sign
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ETHYLENE DICHLORIDE CAS No: 107-06-
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Several factors have been suggested
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myelogenous leukemias (4 and 8 year
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statistically significant. CDHS not
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combined with the incidence in the
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incidence of primary brain tumors.
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Table 6 (continued): Organ/Sex Mali
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An Upper 95% Confidence Limit (UCL)
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ETHYLENE THIOUREA (ETU) CAS No: 96-
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male and female rats. Tumor inciden
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FORMALDEHYDE CAS No: 50-00-0 I. PHY
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presented an extension of a previou
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Methodology In developing a spectru
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Casanova M, Morgan KT, Steinhagen W
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Tobe M, Kaneko T, Uchida Y, Kamata
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Table 1. Hexachlorobenzene-induced
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50 pups (F 1 ) of each sex were ran
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Ertürk E, Lambrecht RW, Peters HA,
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Table 1. Liver hepatoma incidence i
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1988). An airborne unit risk factor
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HYDRAZINE CAS No: 302-01-2 I. PHYSI
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Methodology Inhalation A linearized
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LEAD AND LEAD COMPOUNDS (INORGANIC)
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and other occupational carcinogens
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y inhalation is similar for rats an
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Goyer RA. 1992. Nephrotoxicity and
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LINDANE (g-Hexachlorocyclohexane) C
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Using these relationships, a human
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METHYL TERT-BUTYL ETHER (MTBE) CAS
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Tumor incidences according to the r
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kidney changes indicative of chroni
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Interspecies scaling for oral doses
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Table 4 (continued): Dose Response
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Experimental Pathology Laboratories
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Animal Studies Male and female HaM/
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Gold L, Sawyer C, Magaw R, Backman
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Using the statistical tests (one-ta
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Table 1: Methylene chloride-induced
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Significant treatment-related incre
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National Toxicology Program (NTP) 1
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noted; however, the study duration
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Crump KS, Howe RB, Van Landingham C
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Table 1. Michler’s ketone-induced
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NICKEL AND NICKEL COMPOUNDS CAS No:
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the high exposure group was 14.0. A
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male and 121 female rats, was expos
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2.1 - 2.6 × 10 -4 (µg/m 3 ) -1 .
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The increased incidence of bladder
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A linearized multistage procedure w
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N-NITROSO-N-METHYLETHYLAMINE CAS No
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propylamine in drinking water at 0.
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N-NITROSODIETHYLAMINE CAS No: 55-18
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Table 2. Treatment groups, concentr
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California Department of Health Ser
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animals and the second generation t
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ationale for selection of the OEHHA
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A unit risk value based upon air co
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N-NITROSODIPHENYLAMINE CAS No: 86-3
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Methodology Dosage estimates of NDP
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Crump KS, Howe RB. 1984. The multis
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Table 1. P-Nitrosodiphenylamine-ind
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N-NITROSOMORPHOLINE CAS No: 59-89-2
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Page 429 and 430:
N-NITROSOPIPERIDINE CAS No: 100-75-
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Table 3. N-Nitrosopiperidine-induce
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Crump KS, Howe RB, Van Landingham C
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testicular tumors were noted in the
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PARTICULATE MATTER FROM DIESEL-FUEL
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etired railroad workers who had had
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employment (χ 2 test for trend: p
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elevated smoking-adjusted risk esti
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Table 1 (continued): Reference Miln
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Table 1 (continued): Reference Damb
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Table 1 (continued): Reference Burn
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Table 1 (continued): Reference Raff
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Table 1 (continued): Epidemiologica
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Table 1 (continued): Epidemiologica
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Table 1 (continued): Reference Wegm
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Animal Studies Section 6.1 (Animal
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The variability, or heterogeneity,
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estimate for those studies for whic
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Figure 1: Estimates of Relative Ris
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q 1 * = Excess relative risk × CA
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Table 3: Number of Workers in the E
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u nexposed workers at zero concentr
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for each µg/m 3 of diesel exhaust
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Table 4: Values from Unit Risk for
Page 477 and 478:
their findings that a reasonable es
Page 479 and 480:
Garshick E, Schenker M, Woskie S an
Page 481 and 482:
Lewis T, Green, FH MW, Burg J and L
Page 483 and 484:
Rothman K. 1986. Modern epidemiolog
Page 485 and 486:
PENTACHLOROPHENOL CAS No: 87-86-5 I
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The default lifespan for mice is 10
Page 489 and 490:
documented. An excess risk from ski
Page 491 and 492:
B6C3F 1 mice and F344/N rats were e
Page 493 and 494:
This model, rather than a time depe
Page 495 and 496:
POLYCHLORINATED BIPHENYLS (PCBs) CA
Page 497 and 498:
several benign adenomatous lesions
Page 499 and 500:
Ito et al. (1973) exposed groups of
Page 501 and 502:
could not be characterized by chlor
Page 503 and 504:
exposure (all pathways and mixtures
Page 505 and 506:
National Toxicology Program 1993. T
Page 507 and 508:
Table 1. Potassium bromate-induced
Page 509 and 510:
1,3-PROPANE SULTONE CAS No: 1120-71
Page 511 and 512:
Page 513 and 514:
PROPYLENE OXIDE CAS No: 75-56-9 I.
Page 515 and 516:
oxide. In the NTP carcinogenicity s
Page 517 and 518:
1,1,2,2-TETRACHLOROETHANE CAS No: 7
Page 519 and 520:
assumed a body weight of 70 kg and
Page 521 and 522:
total); an untreated control group
Page 523 and 524:
TOLUENE DIISOCYANATE CAS No: 26471-
Page 525 and 526:
Animal Studies The National Toxicol
Page 527 and 528:
Mortillaro PT and Schiavon M. 1982.
Page 529 and 530:
male or female rats. Increases in h
Page 531 and 532:
TRICHLOROETHYLENE CAS No: 79-01-6 I
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A mortality analysis of a cohort of
Page 535 and 536:
elative to that of the controls whi
Page 537 and 538:
applied or metabolized. The range o
Page 539 and 540:
Katz RM and Jowett D. 1981. Female
Page 541 and 542:
10,000 ppm 2,4,6-trichlorophenol in
Page 543 and 544:
Page 545 and 546:
Bionetics Research Laboratories. 19
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control; females: 6/10 exposed, 0/1
Page 549 and 550:
over controls (p < 0.04). Other tum
Page 551 and 552:
was increased (100/314 exposed vs.
Page 553 and 554:
Table 3. Cancer potency estimates f
Page 555 and 556:
Crouch E. 1983. Uncertainties in in
Page 557 and 558:
VINYL CHLORIDE CAS No: 75-01-4 I. P
Page 559 and 560:
Table 1 (continued): A Summary of E
Page 561 and 562:
al., 1983). Histopathology of all o
Page 563 and 564:
Table 3: Tumor incidences in 100 pp
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experiment, animals were exposed to
Page 567 and 568:
Experiment BT1 Most previous risk a
Page 569 and 570:
No statistical analyses of mortalit
Page 571 and 572:
Table 11 gives unit risk estimates
Page 573 and 574:
Bertazzi PA, Villa A, Foa V, Saia B
Page 575 and 576:
Nicholson WJ, Hammond EC, Seidman H
Page 577 and 578:
immunotoxicity, reproductive toxici
Page 579 and 580:
scheme. TEFs for two major noncance
Page 581 and 582:
NATO/CCMS (1988a) Pilot Study on In
Page 583 and 584:
Table 2 Toxicity Equivalency Factor
Page 585 and 586:
Table 4 A Comparison of CTEF- and I
Page 587 and 588:
Office of Environmental Health Haza
Page 589 and 590:
Group 4: The agent is probably not
Page 591 and 592:
TECHNICAL SUPPORT DOCUMENT FOR DESC
Page 593 and 594:
US EPA IRIS Inhalation Unit Risk an
Page 595 and 596:
TECHNICAL SUPPORT DOCUMENT FOR DESC
Page 597 and 598:
as appropriate, and revise IRIS fil
Page 599 and 600:
Chemical Exposure Route Study Type
Page 601 and 602:
Page 603 and 604:
Page 605 and 606:
Methyl tert-butyl ether p. 5: Added
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