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Hazardous Waste Conference 1993Hazard Assessment and Risk Estimation Advances in Estimating and Predicting Linda S. Birnbaum, Ph.D., D.A.B.T. Introduction Major Risk Assessment Issues Assessing health risks is a scientific process that can be described as analyzing the relationships among exposure, dose, and response. This paper will focus on these relationships. Approaches to be discussed include uses of methods, measurements, and models, best done in an highly integrated fashion. Exposure assessment, which describes pathways by which chemical or physical insults move from a source to the exterior of the body, is not included. One of the first questions to be asked when discussing "dose" is what the term means. Is it dose to the organism, or dose to the tissue? The level of refinement may be even more specific with target dose being the dose to a cell or even a specific macromolecule within the cell. Methods must be developed and measurements made that will allow predictive models to be formulated to estimate the appropriate dose metric. Lack of agreement between model predictions and experimental measures leads to development of improved methods, better measurements, and models with not only more validity but more predictive power as well. Once the appropriate dose metric has been defined, the question must be addressed whether "dose" to a target tissue (cell, macromolecule) means a response will occur. For example, does binding of a ligand to its cognate receptor necessarily result in signal transduction? Does formation of a DNA adduct mean a mutation has occurred? The answer to both of these questions is no. Interaction of a dose with a target allows the potential for a response. Additional steps are always necessary to actually bring about a biologic effect. The inherent sensitivity of the tissue plus the dose determines whether a response will occur. For example, if a given cell type does not have a necessary factor, a response cannot occur. If a chemical causes an anti-mitogenic signal that says "stop dividing," but the cell is already terminally differentiated, it cannot respond to the signal. Risk assessment involves two basic types of extrapolation: dose extrapolations and response extrapolations. Most experimental studies are usually conducted at high dose for short times by the oral route, when in reality, concern for environmental health usually involves low-dose exposure over long periods of time and often by inhalation or dermal exposure. Recent applications of techniques of physiologically based pharmacokinetic modeling have led to major advances in the area of dose extrapolations. This approach incorporates realistic physiologic and biochemical parameters into quantitative descriptions of what the body does to a chemical: absorption, distribution, metabolism, and elimination. By contrast, extrapolation of animal data to human response involves the development of biologically based, dose-response models. These models incorporate mechanistic information and understanding of inherent tissue sensitivity and involve quantitative descriptions of what the chemical in question does tothe body. Mechanistic studies may be conducted in vivo or in vitro and may involve animals or humans. The classic parallelogram approach is often applied. However, a three-dimensional array involving high-to-low dose, interspecies, and in vivo-in vitro studies is probably a better representation of the many relationships that need to be understood to incorporate mechanistic data into risk assessment processes. Incorporation of New Scientific Information on Risk Assessment The remainder of this paper will focus on how the incorporation of new scientific information is affecting the process and findings of risk assessment. Some major chemical classes found at hazardous waste sites include volatile organic hydrocarbons, heavy metals, and dioxins/PCBs. Examples of recent investigations into the pharmacokinetics and mechanisms of a representative chemical from each of these classes will be discussed. [Sections on Benzene and Arsenic removed.] Dioxins / PCBs The polyhalogenated dibenzo-p-dioxins (PHDDs), dibenzofurans (PHDFs), and biphenyls are widespread persistent environmental contaminants. The most toxic of these is the PHDD isomer, 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD or "dioxin." TCDD has a wide spectrum of effects, many of which are tissue-, species-, and developmental-stage specific (Birnbaum, In press). It is best considered as an environmental hormone because of the broad variety of its effects. At the highest doses, dioxin causes delayed lethality, with the time to death being species specific. Because the "high" dose for dioxin is extremely low compared with doses for most other chemicals, dioxin is often considered the most toxic synthetic compound. At doses just below those that cause lethality, dioxin causes a severe wasting syndrome in which animals may lose as much as half their body weight. Slightly lower doses result in atrophy of lymphoid tissues and of the testis. Liver toxicity occurs in many species as a correlate of dioxin toxicity. This involves liver enlargement, fatty deposits, and even necrosis. Hyperplasia may be observed in epithelial tissues lining the bile duct, urinary bladder, and gastrointestinal tract. Metaplasia occurs in the meibomian glands of the eyelids and ceruminous glands of the ear canal resulting in waxy deposits. Dermal effects result in chloracne, a severe form of cystic acne that has often been called the hallmark of dioxin toxicity. Dioxin also causes birth defects, immunosuppression, and tumors. Some of the best-studied biologic responses to dioxin involve biochemical alterations. Dioxin results in induction of many enzymes leading to alterations in metabolism. Effects on multiple growth factors and their receptors leads to altered differentiation and proliferation. Perturbation of multiple hormone systems disturbs the normal homeostatic controls of an organism. Some key issues in dioxin risk assessment involve understanding how dioxin causes its biologic effects. What is the mechanism of action of TCDD? Are humans a sensitive species to the biologic effects of dioxin? Do other chemicals act like TCDD? A specific cellular protein, known as the Ah receptor, binds dioxin and is essential for all its effects (Birnbaum 1994). However, although the Ah receptor is necessary, it is NOT sufficient to bring about responses to dioxin. Binding of dioxin is just the first step in a cascade of events that vary for different responses. The activated Ah-receptor/dioxin complex interacts with other proteins and regulatory factors to alter gene expression. Although functionally similar to members of the steroid receptor superfamily of nuclear receptors, the Ah receptor is a basic helix/loop/helix protein (Burbach et al. 1992, Ema et al. 1992). Clearly, however, interaction with the receptor is necessary but not sufficient for dioxin's effects. Although the dioxin/Ah receptor complex functions as a transcriptional enhancer for CYP1A1, the Ah receptor may have additional effects on signal transduction, such as direct activation of tyrosine kinases. Phosphorylation in response to dioxin has been demonstrated to be a rapid and sensitive response in human and mouse cells and tissues (Bombick et al. 1988, Clark et al. 1992, DeVito et al. 1994, Ma et al. 1992). The species specificity of dioxin is most evident in the varying oral doses that result in lethality. Although guinea pigs die following an exposure to approximately 1 µg TCDD/kg, hamsters require approximately 5000 times as much. However, most animals examined have oral LD50s in the range of 100mg/kg. In fact, for any biologic response, a given species may be an outlier. Overall, however, most species exhibit similar responses following comparable treatments. What about humans? The ability to induce drug-metabolizing enzymes is similar in humans and experimental animals. In fact, the body burdens associated with induction of cytochrome CYP1A1 in humans may be even lower than those required in animals (Lucier 1991). The body concentrations of dioxins and related chemicals associated with chloracne are similar in humans, hairless mice, rabbit ears, and monkeys (Ryan et al. 1990). Using cells in culture, suppression of the immune response in lymphocytes occurs at similar concentrations of TCDD with cells from mice, monkeys, and humans (Neubert et al. 1992, Wood et al. 1992). Organ cultures of embryonic palatal shelves from rats and humans fail to fuse when exposed to the same concentration of TCDD (Abbott and Birnbaum 1991). And dioxin appears to cause cancer in both animals and humans. At least 18 positive cancer studies have been conducted in both sexes of rats, mice, and hamsters. Tumors are produced at multiple sites in all species (Huff 1992). In addition, dioxin induces high incidence of tumors in fish (Johnson et al. 1992) with short latency and at multiple sites. Three recent epidemiologic studies (Fingerhut et al. 1991, Manz et al. 1991, Zober et al. 1990), all with the advantage of measuring serum dioxin levels to validate exposure matrices, have indicated that elevated risk from all cancers is observed in highly exposed occupational cohorts. Commonalities observed in mechanisms of dioxin effects between animals and humans support response information indicating similar sensitivities. Thus, the weight of evidence is compatible with the conclusion that exposure to high levels of dioxin may be associated with increased incidence of cancer in both animals and humans. Examination of dose-response relationships suggest that cancer may not be the most sensitive endpoint resulting from exposure to dioxin. Because all responses to dioxin require interaction with the Ah receptor, ligand binding occurs at the lowest exposure concentration. Biochemical responses such as induction of CYP1A1 and CYP1A2 can be detected at very low levels using molecular techniques such as quantitative PCR (Heuvel et al. 1992). At slightly higher doses, induction of enzymatic activity can be detected. These doses are similar to those at which immunotoxic and developmental effects have also been noted. Chloracne is a relatively high-dose response, and body burdens associated with detectable increase in tumors are still higher. As mentioned, 2,3,7,8-TCDD is but one member of a family of chemicals that causes the same spectrum of biologic responses via its interaction with the Ah receptor. Approximate stereoisomers include the laterally halogenated dibenzo-p-dioxins, furans, biphenyls, naphthalenes, and azo- and azoxybenzenes, among others. The structural similarity, common mechanism of action, and common responses have led to development of toxic equivalency factors (TEFs) (EPA 1989). The toxic equivalency approach is a relative- potency scheme in which 2,3,7,8-TCDD is assigned a value of 1.0, and the potency of related compounds is expressed as some fraction of the TCDD potency. The toxic equivalency of a mixture can be expressed as a sum of the relative toxicities of each component. This approach has been widely used to predict and to describe the toxicity of complex environmental mixtures of PCDDs and PCDFs. However, use of TEFs for PCBs is more complex because only a small subset of PCBs are dioxin-like in their activity (Barnes et al. 1991). Non-dioxin-like PCBs have inherent toxicity of their own. Some appear to have neurotoxic properties, while metabolites of others are reproductive toxicants. Several non-dioxin-like PCBs are potent tumor promoters. Even for dioxin-like PCBs, the appropriate TEFs have demonstrated a wide range of values, depending on the response and system used (Safe 1990, Walker and Peterson 1991, DeVito et al. 1993). Although differences in relative potency of dioxin-like PCBs are in part due to pharmacokinetic differences, such as differential rates of metabolism of various congeners, recent studies have provided increasing understanding of factors controlling the dosimetry of dioxin. In fact, several recent PBPK models have been developed to describe the behavior of TCDD and related compounds (Andersen et al. 1993, Kedderis et al. 1993, Kohn et al. 1993). In these models, disposition of dioxin is described as a diffusion-limited process, where tissue distribution is governed by its lipophilicity, metabolism, and induction of a hepatic-binding protein. These models have also linked kinetic behavior with the induction of a biochemical response, such as the increase in CYP1A1 and CYP1A2. Estimates of human serum concentrations suggest that the average TCDD level, on a lipid-adjusted basis, is approximately 6 parts per trillion (ppt) (Needham et al. 1991). Inclusion of other laterally substituted PCDDs and PCDFs raises the average toxic equivalency to approximately 30 ppt. If recent estimates of TEFs for dioxin-like PCBs are included, dioxin equivalency might be in the range of 50 ppt. Where does this body burden come from? The majority of general population exposure to dioxin and related compounds comes from food, especially meat, dairy products, and fish. Persons in the United States, Canada, and western Europe ingest an estimated 1-3 pg PCDD/PCDF equivalents/kg body weight/day (Furst et al. 1991). Inclusion of dioxin-like PCBs in this estimate would raise the level of daily exposure to approximately 5 pg/kg/day. Of course, occupationally exposed workers, subsistence fishermen, and nursing infants would receive higher exposures. Whether general population exposures or those of sensitive subpopulations are at the level where adverse effects would occur is unclear. However, some evidence exists that this background level is not far below that where effects have already been detected in the human population (Egeland 1992, Sweeney et al. 1992, Wolfe et al. 1992). Conclusions Scientific risk assessment requires integration of exposure information, hazard identification, and dose/response data. Incorporating new scientific data decreases uncertainties in the assessment. PBPK modeling of benzene has demonstrated nonlinearities in production of toxic metabolites that could lead to underestimation of risk. Disposition studies of arsenic indicate the existence of nonlinearities in the methylation of arsenic, generally a detoxification process, which could result in overestimation of risk. Better understanding of the mechanism of action of dioxin and related compounds is leading to improved characterization of potential risk from this ubiquitous contaminant. The better the science, the better the risk assessment. Integrated approaches that involve both experiments and modeling will work in an iterative fashion to advance knowledge most quickly and efficiently. Incorporating data from both in-vivo and in-vitro studies allows mechanistic information to greatly improve our ability to extrapolate, not only from one experimental situation to another, but ultimately from animals to humans. References Abbott BD, Birnbaum LS. (1991) TCDD exposure of human embryonic palatal shelves in organ culture alters the differentiation of medial epithelial cells. Teratology 43:119-32. Agency for Toxic Substances and Disease Registry (ATSDR). (1989). Toxicological profile for benzene. Atlanta: U.S. Department of Health and Human Services, Public Health Service. ATSDR/RP-88/03. Andersen ME, Mills JJ, Gargas ML, Kedderis L, Birnbaum LS, Neubert, D, Greenlee WF. (1993). Modeling receptor-mediated processes with dioxins: implications for pharmacokinetics and risk assessment. Risk Anal 13:25-36. Aposhian HV. (1989). Biochemical toxicology of arsenic. Review of Biochemical Toxicology 10:265-99. Barnes D, Stevens AA, Birnbaum LS, Kutz FW, Wood W, Patton D. (1991). Toxicity equivalency factors of PCBs? Quality assurance: good practice. Regulation and Law 1(1):70-81. Birnbaum LS. (In press). The mechanism of dioxin toxicity: relationship to risk assessment. Environ Health Perspect. Birnbaum LS. (1994). Evidence for the role of the Ah receptor in responses to dioxin. In: Spitzer H, Slaga T, Greenlee W, McClain M, eds. Receptor-mediated biological processes: Implications for evaluating carcinogenesis. Series: Progress in clinical and biological research. Somerset, New Jersey: John Wiley. pp 139- 54. Bois FY, Smith MT, Spear RC. (1991). Mechanisms of benzene carcinogenesis: application of a physiological model of benzene pharmacokinetics and metabolism. Toxicol Lett 56:283-98. Bombick DW, Jankun J, Tullis K, et al. (1988). 2,3,7,8- Tetrachlorodibenzo-p-dioxin causes increases in expression of c- erb-A and levels of protein-tyrosine kinases in selected tissues of responsive mouse strains. Proc National Acad Sci USA 85:4128. Brodfuehrer JI, Chapman DE, Wilke TJ, Powis G. (1989). Comparative studies of the in-vitro metabolism and covalent binding of 14C- benzene by liver slices and microsomal fraction of mouse, rat, and human. Drug Metab Dispos 18(1):20-7. Burbach KM, Poland A, Bradfield CA (1992). Cloning of the Ah- receptor CDNA reveals a distinctive ligand-activated transcription factor. Proc Natl Acad Sci USA 89:8185-9. Buchet JP, Lauwerys RR (1987). Study of factors influencing the in-vivo methylation of inorganic arsenic in rats. Toxicol Appl Pharmacol 91:65-74. Clark GC, Blank JA, Germolec DR, et al. (1992). 2,3,7,8- Tetrachlorodibenzo-p-dioxin stimulation of tyrosine phosphorylation in B lymphocytes: potential role in immunosuppression. Mol Pharmacol 189:59. Cooper KR, Snyder R (1988). Benzene metabolism. In: M Aksoy, ed. Benzene carcinogenicity. Boca Raton, Florida: CRC Press 33-58. Cullen WR, Reimer KJ (1989). Arsenic speciation in the environment. Chem Rev 89:713-64. Cuzick J, Sasieni P, Evans S. (1992). Ingested arsenic, keratoses and bladder cancer. Am J Epidemiol 136:417-21. Delnomdedieu M, Basti MM, Otvos JD, Thomas DJ (1994). Reduction and binding of arsenate and dimethylarsinate by glutathione: A magnetic resonance study. Chem Biol Interact 90:139-55. Delnomdedieu M, Basti MM, Otvos JD, Thomas DJ (1993). Transfer of arsenite from glutathione to dithiols: a model of interaction. Chem Res Toxicol 6(5):598-602. DeVito MJ, Maier WE, Diliberto JJ, Birnbaum LS (1993). Comparative ability of various PCBs, PCDFs, and TCDD to induce cytochrome P450 1A1 and 1A2 activity following 4 weeks of treatment. Fundam Appl Toxicol 20:125-30. DeVito MJ, Ma X, Babish JG, Menache M, Birnbaum LS (1994). Dose response relationships in mice following subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin: CYP1A1, CYP1A2, estrogen receptor and protein tyrosine phosphorylation. Toxicol Appl Pharmacol 124:82-90. Egeland GM, Sweeney MH, Fingerhut MA, Halperin WE, Wile KK, Schnorr TM (1992). Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin's (TCDD) effect on total serum testosterone and gonadotropins in occupationally exposed men. Minneapolis: Society of Epidemiological Research. Ema M, Sogawa K, Watanabe N, Chujoh Y, Matsushita N, Gotoh O, Funae Y, Gujii-Kuriyama Y (1992). CDNA cloning and structure of mouse putative Ah receptor. Biochem Biophys Res Commun 184(1):246-53. Environmental Protection Agency (EPA). (1962). 1942 Drinking water standards. References in drinking water standards, Title 42, Chapter 1, Part 72. Interstate Quantities. Fed. Reg. 2152 (March 6, 1962). Environmental Protection Agency (EPA). (1984a). Health effects assessment for benzene. Washington, D.C.: U.S. Environmental Protection Agency, Office of Health and Environmental Assessment. EPA/540/1-86-037. Environmental Protection Agency (EPA). (1984b). Health assessment document of inorganic arsenic. EPA/600/8-83/021F. Washington D.C.: U.S. Environmental Protection Agency, Office of Health and Environmental Assessment. Environmental Protection Agency (EPA). (1989). Interim procedures for estimating risks associated with exposure to mixtures of chlorinated dibenzo-p-dioxin and dibenzofurans and 1989 update. Risk Assessment Forum, EPA/625/3-89/016. Principal authors: Barnes D, Kutz F, and Bottimore D, National Technical Information Service, Springfield, VA. Fingerhut MA, Halperin WE, Marlow DA, Piacitelli LA, Honchar PA, Sweeney MH, Griefe AL, Dill PA, Steenland K, Suruda AH (1991). Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo- p-dioxin. N Engl J Med 324:212-8. Furst P, Furst C, Wilmers K (1991). Body burden with PCDD and PCDF from food. In: Gallo MA, Scheuplein RJ, VanDer Heijden KA, eds. Biological basis for risk assessment of dioxins and related compounds, Banbury Report 35. Cold Spring Harbor, Mass: Cold Spring Harbor Laboratory Press, 133-42. Harrington-Brock K, Smith TW, Doerr CL, Moore MM (1993). Mutagenicity of the human carcinogen arsenic and its methylated metabolites, monomethylarsonic and dimethylarsinic acids in L5178Y TK +/- mouse lymphoma cells. Environ Mol Mutagen 21 (Supplement 22). Henderson RF, Sabourin PJ, Medinsky MA, Birnbaum LS, Lucier GL. (1992). Benzene dosimetry in experimental animals: Relevance for risk assessment. In: D'Amato R, Slaga TJ, Farland WH, Henry C, eds. Relevance of animal studies to the evaluation of human cancer risk. New York: Wiley-Liss:93-105. Heuvel JPV, Lucier GW, Clark GC, Tritscher AM, Greenlee WF, Bell DA (1992). Use of reverse-transcription polymerase chain reaction to quantitate MRNA for dioxin-responsive genes in the low-dose region in rat liver. In: Dioxin 92, 12th International symposium on dioxins and related compounds. Tampere, Finland: 225-6. Huff J. (1992). 2,3,7,8-TCDD: A potent and complete carcinogen in experimental animals. Chemosphere 25:173-6. Hughes MF, Menache M, Thompson DJ (1994). Dose dependent disposition of sodium arsenate in mice following acute oral exposure. Fundam Appl Toxicol 22:80-9. Inoue O, Seiji K, Kasahara M, Nakatsuka H, Watanabe T, Yin SG, et al. (1988). Determination of catechol and quinol in the urine of workers exposed to benzene. Br J Ind Med 45:482-7. Inoue O, Seiji K, Kasahara M, Nakatsuka H, Watanabe T, Yin SG, et al. (1989). Urinary t,t-muconic acid as an indicator of exposure to benzene. Br J Ind Med 46:122-7. International Agency for Research on Cancer (IARC). (1987a). Benzene. In: IARC Monograph on the evaluation of carcinogenic risks to humans--Overall evaluations of carcinogenicity: An update of IARC monographs 1 to 42, Suppl 7. Lyon, France: IARC. Supplement 7:120-2. International Agency for Research on Cancer (IARC). (1987b). Arsenic and arsenic compounds. In: IARC Monograph on the evaluation of carcinogenic risks to humans--Overall evaluations of carcinogenicity: An update of IARC monographs 1 to 42, Suppl 7. Lyon, France: IARC: 100. International Agency for Research on Cancer (IARC). (1980). IARC Monographs on the evaluation of the carcinogenic risk of chemicals to man: some metals and metallic compounds. Lyon, France: IARC: 23:39-141. Johnson R, Tietge J, Botts S. (1992). Carcinogenicity of 2,3,7,8- TCDD to medaka. Toxicologist 12(1):476. Kedderis LB, Mills JJ, Andersen ME, Birnbaum LS. (1993). A physiologically-based pharmacokinetic model for 2,3,7,8- tetrabromodibenzo-p-dioxin (TBDD) in the rat: Tissue distribution and CYP1A induction. Toxicol Appl Pharmacol 121:87-98. Kohn MC, Lucier GW, Clark GC, Sewall C, Tritscher AM, Portier CJ. (1993). A mechanistic model of effects of dioxin on gene expression in the rat liver. Toxicol Appl Pharmacol 120:138-54. Koop DR, Laethem CL, Schnier GG. (1989). Identification of ethanol- inducible P-450 isozyme 3a (P450IIE1) as a benzene and phenol hydroxylase. Toxicol Appl Pharmacol 98:278-88. Lee T-C, Tanaka N, Lamb PW, Gilmer TM, Barrett CJ. (1988). Induction of gene amplification by arsenic. Science 241:79-81. Lucier GW. (1991). Humans are a sensitive species to some of the biochemical effects of structural analogs of dioxin. Environmental Toxicology and Chemistry 10:727-35. Ma X, Mufti NA, Babish JG. (1992). Protein tyrosine phosphorylation as an indicator of 2,3,7,8-tetrachloro-p-dioxin exposure in-vivo and in-vitro. Biochem Biophys Res Commun 189:59. Maltoni C, Ciliberti A, Cotty G, Conti B, Belpoggi F. (1989). Benzene, an experimental multipotential carcinogen: Results of the long-term bioassays performed at the Bologna Institute of Oncology. Environ Health Perspect 82:109-24. Manz A, Barger J, Dwyer JH. (1991). Cancer mortality among workers in chemical plant contaminated with dioxin. Lancet 338:959-64. Mass MJ. (1992). Human carcinogenesis by arsenic. Environmental Geochemistry and Health 14:49-54. McKinney JB. (1992). Metabolism and disposition of inorganic arsenic in laboratory animals and humans. Environmental Geochemistry and Health 14:43-8. Medinsky MA, Sabourin PJ, Lucier G, Birnbaum LS, Henderson RG. (1989). A physiological model for simulation of benzene metabolism by rats and mice. Toxicol Appl Pharmacol 99:193-206. National Toxicology Program (NTP). (1986). Toxicology and carcinogenesis studies of benzene in F344/N rats and B6C3F1 mice. Technical Report Series, No. 289. Washington D.C.: U.S. Department of Health and Human Services. Needham LL, Patterson DG Jr, Houk VN. (1991). Levels of TCDD in selected human populations and their relevance to human risk assessment. In: Gallo MA, Scheuplein RJ, Van Der Heijden KA, eds. Biological basis for risk assessment of dioxins and related compounds, Banbury Report 35. Cold Spring Harbor, Mass: Cold Spring Harbor Laboratory Press: 229-57. Neubert R, Golor G, Stahlmann R, et al. (1992). Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system. 2. in- vitro effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on lymphocytes of venous blood from man and a non-human primate (callithriz jacchus). Arch Toxicol 65:213-9. Pershagen G, Bjorklund NE. (1985). On the pulmonary tumorigenicity of arsenic trisulfide and calcium arsenate in hamsters. Cancer Lett. 27:99-104. Rogers EM, Chernoff N, Kavlock RJ. (1981). The teratogenic potential of cacodylic acid: the rat and mouse. Drug Chem Toxicol 4:49-61. Ryan JJ, Gasiewicz TA, Brown JF Jr. (1990). Human body burden of polychlorinated dibenzofurans associated with toxicity based on the Yusho and Yucheng incidents. Fundam Appl Pharmacol 15:722-31. Sabourin PJ, Chen BT, Lucier GW, Birnbaum LS, Fisher E, Henderson RF. (1987). Effect of dose on the absorption and excretion of [14C]benzene administered orally or by inhalation in rats and mice. Toxicol Appl Pharmacol 87:325-36. Sabourin PJ, Bechtold WE, Birnbaum LS, Lucier GW, Henderson RF. (1988). Differences in the metabolism and disposition of inhaled [14C]benzene by F344/N rats and B6C3F1 mice. Toxicol Appl Pharmacol 94:128-40. Sabourin PJ, Sun JD, MacGregor JT, Wehr CM, Birnbaum LS, Lucier GW, Henderson RF. (1990). Effect of repeated benzene inhalation exposures on benzene metabolism binding to hemoglobin, and induction of micronuclei. Toxicol Appl Pharmacol 103:453-62. Sabourin PJ, Bechtold WE, Griffith WC, Birnbaum LS, Lucier GW, Henderson RB. (1989). Effect of exposure concentration, exposure route, and rate of administration on metabolism of benzene by F344 rats and B6C3F1 mice. Toxicol Appl Pharmacol 99:421-44. Sabourin PJ, Muggenburg BA, Couch RC, Lefler D, Lucier GW, Birnbaum LS, Henderson RB, (1992). Metabolism of [14C]benzene by cynomolgus monkeys and chimpanzees. Toxicol Appl Pharmacol 114:277-84. Safe S. (1990). Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: Environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). Crit Rev Toxicol 21:219-38. Scott N, Hatlelid KM, MacKenzie NE, Carter DE. (1993). Reactions of arsenic (III) and arsenic (V) species with glutathione. Chem Res Toxicol 6:102-6. Smith AH, Hopenhayn-Rich C, Bates MN, Goeden HM, Hertz-Picciotto I, Duggan HM, et al. (1992). Cancer risks from arsenic in drinking water. Environ Health Perspect. 97:259-67. Squibb KS, Fowler BA. (1983). The toxicity of arsenic and its compounds. In: Fowler BA, ed. Biological and environmental effects of arsenic. Amsterdam: Elsevier Science 233-69. Stohrer G. (1991). Arsenic: Opportunity for risk assessment. Arch Toxicol 65:525-31. Subrahmanyam VV, Doane-Setzer P, Steinmetz L, Ross D, Smith MT. (1990). Phenol-induced stimulation of hydroquinone bioactivation in mouse bone marrow in-vivo: possible implications in benzene myelotoxicity. Toxicology 62:107-16. Sweeney MH, Hornung RW, Wall DK, et al. (1992). Prevalence of diabetes and elevated serum glucose levels in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In: Dioxin 92, 12th International symposium on dioxins and related compounds. Tampere, Finland: 225-6. Thompson DJ. (1993). A chemical hypothesis for arsenic methylation in mammals. Chem Biol Interact 88:89-114. Travis CC, Quillen JL, Arms AD. (1990). Pharmacokinetics of benzene. Toxicol Appl Pharmacol 102:400-20. Walker MK Peterson RE. (1991). Potencies of polychlorinated dibenzo-p-dioxin, dibenzofuran and biphenyl congeners, relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin for producing early life stage mortality in rainbow trout (oncorhynchus mykiss). Aquatic Toxicology 21:219-38. Wolfe W, Michalek J, Miner J, et al. (1992). Diabetes versus dioxin body burden in veterans of operation ranch hand. In: Dioxin 92, 12th International symposium on dioxins and related compounds. Tampere, Finland: 279-82. Wood SC, Karras JG, Holsapple MP. (1992). Integration of the human lymphocyte into immunotoxicological investigations. Fundam Appl Toxicol 18:450-9. Yarley NM, Thompson DJ, Adamovic JB, Hughes MF, Hall LL. (1993). Analysis of labeled arsenic metabolites in urine. The Toxicologist 13(1):40. Yin S-N, Li G-L, Tain F-D, Fu Z-I, Jin C, Chen YJ, et al. (1989). A retrospective cohort study of leukemia and other cancers in benzene workers. Environ Health Perspect 82:207-13. Zober A, Messerer P, Huber P. (1990). Thirty-four year mortality follow up of BASF employees exposed to 2,3,7,8-TCDD after the 1953 accident. Int Arch Occup Environ Health 62:139-57. |
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