TL: Comments on "A Cancer Risk-Specific Dose Estimate for 2,3,7,8-TCDD" and "Estimating Exposures to 2,3,7,8-TCDD" (GP) SO: Prepared and presented by Pat Costner Research Director National Toxics Campaign DT: 28-29 November 1988 Keywords: toxics dioxins greenpeace groups us gp / "Resist with care the spirit of innovation upon its principles, however specious the pretexts." -- George Washington Greenpeace has a contract with a firm to prepare a `fact sheet' on risk assessment/risk management -- something to explain what risk assessment/risk management means to someone who has a municipal incinerator or a chemical plant next door. To be blunt, we have always regarded risk assessment/risk management is so much `regulatory snake oil' -- a bogus `remedy' that hides the fact that, some time ago, the federal objective underwent a radical change. It shifted from minimizing public exposure to toxic chemicals to setting so-called `acceptable' levels of toxics exposure -- levels that are as high as the public will tolerate. This policy shift maximizes toxics exposures for the public and the environment and minimizes costs for toxics manufacturers and users. Anyway, now we can cancel the contract for the risk assessment fact sheet. With these two reports, EPA has shot more holes in risk assessment than Greenpeace or anyone else could possibly do. There are three conclusions that can be drawn from these two reports: * until scientists know a lot more than they know now, risk assessment is nothing more than `smoke and mirrors' -- assumptions and uncertainties stacked on top of more uncertainties and assumptions. * polychlorinated dioxins and furans are a very real and very immediate threat to public health and the environment. * EPA needs to make identifying and eliminating dioxin sources one of the Agency's highest priorities. The identification of dioxin sources must follow a `trace chemistries of chlorine' approach, beginning with the chloralkali industry and encompassing any and all processes and products that use or generate chlorine and/or organochlorines. The elimination of dioxin sources must proceed as rapidly and as universally as possible. EPA's "National Dioxin Study: Tiers 3,5,6, and 7" identified many `non-combustion' dioxin sources. Pulp and paper mills were pinpointed as one major source category -- dioxin-contaminated fish were found downstream from 53 percent of the pulp and paper mills checked. The industry is already shifting away from chlorine-based processes in Sweden, Canada and, in some cases, in the U.S. The National Dioxin Study also found dioxin-contaminated fish downstream from more than 60 percent of the organic chemical manufacturers studied (organic chemicals, plastics and synthetic fibers and pesticides) and 56 percent of the inorganic chemical manufacturers. Apparently, neither EPA nor any of these industries are responding to these dioxin releases which are even more prevalent than those of the pulp and paper industry. Scientists who conducted a study funded for the American Paper Institute have calculated an average body burden of 2,3,7,8-TCDD equivalents among U.S. citizens of 5.8 parts per trillion. It's a good thing we aren't cannibals ... eating fish containing 1 ppt of 2,3,7,8-TCDD has been estimatead to increase cancer risks to 1 in 100,000. Meanwhile, a Canadian scientist has found dioxins and furans in milk sold in paper containers. Calculations show that teenagers consuming this milk at the recommended 3 glass per day may be receiving 2,3,7,8-TCDD equivalents at levels that are more than twice the EPA's Acceptable Daily Intake for TCDD human reproductive effects, which is 1 pg/kg/day. EPA's 1985 "Work/Quality Assurance Project Plan for the Bioaccumulation Study" has a list of commercial chemical products that are known to be contaminated with polychlorinated dioxins and furans. The report includes producers, their locations and their production status as of 1985. EPA's 1980 "Dioxins" report carries lists of 77 commercial chemical products and 60 pesticides that are suspected to be accompanied by the formation of dioxins and furans during their manufacture. I'd like to quote from a memo an EPA scientist sent in response to being asked to review "A Cancer Risk-Specific Dose Estimate for 2,3,7,8-TCDD:" "We have a classic "can't see the forest through the trees" syndrome with our continued efforts to redefine the cancer potency of TCDD. This compound is 50 million times more potent a carcinogen than the regulated pollutant vinyl chloride, and manifests serious teratogenic and developmental effects in all animal species tested at doses at or near the cancer response. TCDD has no known benefit to society. TCDD and other CDDs as well as CDFs enter the environment as inadvertent contaminants in ... chemical processing. It is probable that most of the current input of CDDs and CDFs ... arise as continuous air emissions from a wide variety of combustion sources. ... Resources should be directed towards identifying the environmental pathways and likely sources of continued population exposures with the prospect of reducing such exposure." Following are some excerpts from the "...Risk-Specific Dose ..." document: "... the Workgroup ... agreed that (1) the 1984 assessment that associates a 0.006 pg/kg/day dose with a plausible upper-bound increased cancer risk of one in a million (10(-6)) should be reconsidered, and (2) a majority of the group agreed that a change to a 0.1 pg/kg/day dose as a plausible upper-bound ... is consistent with the available data and theories, and represents a reasonable science policy position for the Agency." Consider this ... "a majority of the group agreed that a change to a 0.1 pg/kg/day dose as a plausible upper-bound". What does "plausible" mean? plausible: 1. seemingly true, acceptable, etc.; often implying disbelief. 2. specious. specious: 1. resembling, simulating, or apparently corresponding with right or truth; appearing just, fair, or proper without really being so; plausible but not genuine; as, a specious argument; specious promises. -- Webster's New Universal Unabridged Dictionary, 1983 And what is "science policy?" And why is EPA's Science Advisory Board being asked to take a position on a "science policy?" "The scientific evidence is consistent with, and would support, a recommended science policy position that the RsD (10(-6)) for 2,3,7,8- TCDD be 0.1 pg/kg/day ... for the following reasons: * the scientific data indicate that the Agency's current upper bound for 2,3,7,8-TCDD may be an overestimate; * the scientific data do not permit an estimate of the extent of the overestimate; * all of the UCL LMS RsD estimates generated by the Federal agencies are arguably of equal scientific merit at this time; * for strictly policy purposes, there is great benefit in Federal agencies' adopting consistent positions in the absence of compelling scientific information; and * an order of magnitude estimate of the RsD (potency), as opposed to some more precise estimate of the risk-specific dose, helps to convey the notion that the numerical expression is only a rough estimate (the science permits no greater accuracy). "Laboratory studies conclusively establish a relationship between exposure to 2,3,7,8-TCDD and cancer in test animals." "There is ... considerable uncertainty and controversy about the mechanism by which 2,3,7,8-TCDD causes cancer, an uncertainty that can strongly influence both qualitative assessments and the mathematical methods used to assess cancer risk to humans." "... the actual sequence of cellular events leading to (1) initiation of a cell, (2) clonal expansion of the population of initiated cells, and (3) progression leading to malignant transformation is still unknown for even a single chemical." [footnote: "It should still be noted, that initiation, promotion, and transformation may also be made up of a series of steps."] "... the question of complete carcinogenicity versus promotion has little effect on identifying potential human cancer hazard associated with exposure to 2,3,7,8-TCDD. Differences, however, in mechanism of carcinogenesis may lead to differences in approaches to quantitative risk assessment, with resulting differences in numerical risk estimates." [from footnote] "* Does the choice of approach (and related assumptions) have any bearing on a discrepancy perceived by some between the observed human cancer experience and human risk estimates based on animal studies?" "This analysis identifies several reasonable approaches to estimating 2,3,7,8-TCDD cancer risk, but concludes that there do not appear to be compelling scientific reasons for regarding any one of them as a "most appropriate" approach." "... the Workgroup proposes that the Agency adopt a dose of 0.1 pg/kg/day as a plausible upper-bound increased lifetime risk of one in a million. The estimate is consistent with the available data and theories and represents a reasonable science policy position." "This explicit discussion of assumptions and policy choices highlights some of the uncertainties inherent in the risk assessment process generally, and in the analyses and assessments specific to the carcinogenicity of 2,3,7,8-TCDD ..." "The analysis shows that differences among the risk assessments for 2,3,7,8-TCDD developed by various regulatory agencies are not due to disagreements about the scientific data base per se, bur rather are due to the judgments, science policy positions, and methods used in estimating human risk." "While choice of model often reflects, in part, the historical or philosophical tradition of a particular agency, in the case of 2,3,7,8-TCDD, it also reflects important differences in the way different scientists interpret and weigh the scientific evidence and related uncertainties." "The analysis follows EPA's Guidelines for Carcinogen Risk Assessment which call for articulation of "major assumptions, scientific judgments and to the extent possible, estimates of the uncertainties embodied in the assessment ... distinguishing clearly between fact, assumption, and science policy" (U.S. EPA, 1986a)." "In every instance [of epidemiological studies], because of lack of empirical exposure data, some surrogate basis for estimating exposure has been used." "Two epidemiological studies ... have reported five- to sevenfold elevated risks of soft tissue sarcoma (STS) related to occupational exposure to phenoxy herbicides and/or chlorophenols, some of which were assumed to contain 2,3,7,8-TCDD. ... it appears that the elevated risks ... are real and should be considered in hazard evaluation." " ... other studies (including studies in certain U.S. populations) may give some support to the association between exposure to 2,3,7,8- TCDD and STS (see Appendix B) ..." "... Hardell et al. (1981) reported a statistically significant risk of non-Hodgkin's lymphoma (NHL) in agricultural, forestry, and woodworking employees exposed to phenoxy herbicides, chlorophenols, or both. The relative risk ratio ranged from 4.3 to 6.0 for both classes of compounds together as well as separately. In addition to NHL, results from these studies have raised questions about increased risks of stomach cancer, prostate cancer, Hodgkin's disease, and kidney cancer." "To date, most of these studies [of Vietnam veterans] have shown no statistically significant correlation between Vietnam service (and, therefore, possible exposure to 2,3,7,8-TCDD) and an increased risk of cancer." [Albanese, R.A., "United States Air Force Personnel and Exposure to Herbicide Orange," USAFSAM- TR-88-3, February 1988: this study shows the overall risk of cancer among the dioxin-exposed veterans to be increased by a factor of 1.97. The greatest risk increase is for skin cancers, where the risk is increased by a factor of 2.6, while the risk of "systemic cancers" is increased by a factor of 1.2.] "... a study of Massachusetts Vietnam veterans reports a significant excess of connective tissue sarcomas compared to non- Vietnam veterans ..." "... the high relative risks seen in the Swedish studies are noteworthy. While an association may exist between exposure to chemicals contaminated with 2,3,7,8-TCDD (e.g., phenoxy herbicides) and increased incidences of cancer, the data are still to uncertain to attribute the effects ... to 2,3,7,8-TCDD." " ... 2,3,7,8-TCDD is one of the most potent inducers studied. ... [the induction potential for TCDD is 30,000 greater than that of 3- methylcholanthrene ... which is used "routinely ... as an inducer of AHH.] ... the increased enzymatic activity elicited by 2,3,7,8-TCDD remains elevated, near peak level, for over 30 days while the enzymatic activity elicited by 3-methylcholanthrene returned to normal in 8 days, reflecting the influence of 2,3,7,8-TCDD's long half-life." "While this information [enzyme induction, increased cellular proliferation, antagonism of hormone-mediated responses, cytotoxicity, and in vitro transformation] is of interest and does signal qualitative concern for carcinogenicity in humans exposed to 2,3,7,8- TCDD, it is not possible at present to factor these observations into a quantitative risk assessment." "... it is often difficult (if not impossible) to separate carcinogens into discrete categories based on mechanism of action. This process is further complicated by the possibility of multiple carcinogenic mechanisms, direct and indirect, occurring as a result of exposure to a single compound." "... observations of an increased number of rare tumors, a decrease in the time-to-tumor, or a statistically significant increase of site- specific tumor incidence in multiple species and strains of animal bioassays have generally been taken to support the conclusion that the test chemical is a complete carcinogen." "A recent review comparing the results from short-term tests and long-term chronic bioassays for 76 chemicals ... showed that the concordance between short-term tests and a response in a chronic bioassay was only 60%. ... this review indicates that the lack of positive results in short-term tests is often not a predictor of the outcome of a chronic bioassay, and .. may not be a reliable predictor of direct, complete carcinogenicity. Also .. at least two chemicals that test negative in mutagenicity tests conducted by the NTP can activate oncogenes which may result in a specific irreversible cellular change. ... These kinds of observations suggest that as new approaches to investigating molecular events potentially involved in the carcinogenic process become available, our understanding of how particular chemicals exert their carcinogenic effect may change." " ... it is not possible, at this time to conclude definitely whether or not 2,3,7,8-TCDD is acting as a complete carcinogen in some tissues." " ... if the Agency considers 2,3,7,8-TCDD to be a direct-acting complete carcinogen, then, the use by EPA of a plausible upper bound derived from the LMS model is appropriate and consistent with Agency science policy." "At present, carcinogens are defined operationally because of a lack of understanding of the mechanisms by which chemicals cause cancer." "Like complete carcinogens, promoters are defined operationally .... as providing a certain pattern of results in initiation/promotion tests." "... a low incidence of tumors in animals given only 2,3,7,8- TCDD suggests that 2,3,7,8-TCDD may have some initiation potential or that the observed tumors are the result of potent promotion of background events or unidentified initiators found in the animals' environment (e.g., substances in food)." [given the array of xenobiotics now ubiquitous in the bodies of U.S. citizens, this is a moot point] "Some tumors observed in the lung, nasal turbinate, and hard palate may be the result of "complete carcinogenicity," although, as discussed previously, this is not uniformly accepted." "A "pure" promoter .. may be expected to demonstrate a threshold ..." "...[these] support the observation that there is an overall decrease in the carcinogenic response with some dose of 2,3,7,8- TCDD ..." "... chemicals have been shown to overcome background processes or their own effects at some doses to produce a net negative effect on the carcinogenic outcome of animal bioassays. Such responses could have a profound effect on expectations of the dose-response if anticarcinogenic effects were canceling out carcinogenic effects at a given dose in some tissues." "Scientific interest in interspecies and high- to low-dose extrapolation has led to the development of a variety of predictive models, including models for estimating the likelihood of human cancer based on data from animal studies. Selection of the appropriate model ... is difficult because of a lack of knowledge of concordant events across species and at low doses. Selection is further complicated by the possibility of multiple effects affecting the carcinogenic process." "Pleitropism, i.e., action through multiple pathways, is not an uncommon finding with molecules such as 2,3,7,8-TCDD." "The weight of evidence for the most prevalent 2,3,7,8-TCDD effects falls into the category of the receptor model." "Risk modeling for carcinogenic xenobiotics can be segregated into three classes or types of models: (1) physiologically based pharmacokinetic (PBPK) models in which the body is considered to be a small group of physiological compartments ...; (2) biologically motivated models of carcinogenesis (BMMC) in which the carcinogenic process is considered to occur through a series of linked reactions that result from two or more molecular events followed by a cellular amplification by "promoter" molecules ...; and (3) the LMS model of Armitage-Doll as modified by Crump and Howe (1984) in which it is assumed that a sequence of events occur within a single cell, some of which are irreversible, leading to the neoplastic change." "After considering all of the data, the Workgroup has concluded that thinking about 2,3,7,8-TCDD either solely as a "promoter" or as a "complete" carcinogen is an oversimplification. Rather, while it is clear that 2,3,7,8-TCDD acts as a potent promoter, it may also affect other important carcinogenic processes, some of which may result in a linear carcinogenic response in the low- dose region." "... at least three classes of mechanisms of carcinogenic action for 2,3,7,8-TCDD h ave been considered in this document. First, tumors found in long-term bioassays in which 2,3,7,8-TCDD is the only known agent suggest that this agent is .. a complete carcinogen. Second, data from in vivo studies for promoter activity demonstrate that 2,3,7,8-TCDD is a potent promoter of carcinogenesis with little or no demonstrated ability to act as a direct genotoxin. Finally, an indirect impact on carcinogenic processes is suggested by studies linking 2,3,7,8-TCDD to responses such as enhancement of initiation, increase cell proliferation, antagonism of hormone-mediated responses, cytotoxicity, and in vitro transformational activity." "Despite evidence supporting each potential mechanism, 2,3,7,8- TCDD does not exhibit certain properties generally expected for each of the first two mechanisms. ... [lack of genotoxicity or binding to DNA] suggests that 2,3,7,8-TCDD is not a "typical" complete carcinogen. Unlike many promoting agents, 2,3,7,8-TCDD acts at low doses (2,3,7,8- TCDD is active at doses 1000 times less than other known promoters.) Furthermore, reversibility, an oft-cited characteristic of promotion, has not and cannot easily be demonstrated because of the long half- life of 2,3,7,8-TCDD in biological systems." "It should be noted here that the 1985 estimate of the potency of 2,3,7,8-TCDD (U.S. EPA, 1985) has always been characterized as a plausible upper bound to the risk; the extent of this "overestimate" is unknown, but it may be higher than previously thought." "Although 2,3,7,8-TCDD is a strong promoter, biological data and statistical limitations to the power of bioassays suggest that a threshold cannot be adequately demonstrated and may not exist. This assessment is tempered somewhat by observations both in vivo and in vitro suggesting "anticarcinogenic" effects at low doses which could offset the other effects of 2,3,7,8-TCDD and possibly produce a threshold. An anticarcinogenic effect working in conjunction with a carcinogenic effect in the same tissue might result in a net response of zero over background and might be described as a threshold effect, in summary. "Until such time that some of these critical issues are resolved, the Workgroup concluded that it would not be prudent to adopt a threshold approach for estimating human cancer risk for 2,3,7,8-TCDD." "In summary, the Workgroup concludes that none of the available models adequately describe the carcinogenic behavior of 2,3,7,8- TCDD at low doses. " "* The available evidence suggest that reliance on the LMS model, as traditionally used by EPA, may be less appropriate for 2,3,7,8-TCDD than for many other chemicals, and that the Agency's 1985 assessment based on the LMS model may overestimate the upper bound on the risk by some unknown amount. However a rationale for a possible linear behavior at low doses has been developed in this report, and the LMS model provides a useful and familiar context which is widely used in the Federal government when discussing risk estimates. Therefore the Workgroup discusses its recommendation using the LMS model as a construct, that is, the plausible upper-bound estimate of risk and the risk-specific dose." "Application of the LMS model to estimate the carcinogenic potency of 2,3,7,8-TCDD results in a range of RsDs (10(-6)) from 0.001 pg/kg/day to 1.2 pg/kg/day depending on the data used as the basis for the analysis and the assumptions made in the assessment." "Incorporation of the factors used by the FDA for scaling from animals to humans, along with use of only the tumors of the lung, hard palate, and nasal turbinates observed in the Kociba et al. (1978) study results in a RsD (10(-6)) of 1.2 pg/kg/day, the highest RsD we have developed based on the LMS model. This analysis excludes the tumors observed in the liver because of the strong promoter activity shown by 2,3,7,8-TCDD in this organ. However, the Workgroup gives less weight to this point on the range because (1) it excludes 90% of the response observed in the bioassay, and (2) there is controversy whether the tumors of the lung, hard palate, and nasal turbinates should be considered at all .... "The lowest RsD in the range is based on differences in the relative half-lives of 2,3,7,8-TCDD in rats and humans. The Workgroup gives less weight to this point because of numerous uncertainties about the pharmacokinetics of 2,3,7,8-TCDD, particularly the absence of information on species differences and rates of incorporation and absorption of 2,3,7,8-TCDD in different tissues and species. Similarly, the rate of release of this chemical is likely to be different from tissue to tissue and species to species. Furthermore, it is not clear how 2,3,7,8-TCDD will behave in different species, particularly humans, under conditions of chronic exposure, incorporation, and release." "Using the same basic LMS model approach, EPA, CDC, and FDA have estimated carcinogenic RsDs (10(-6)) for 2,3,7,8-TCDD of 0.006, 0.03, and 0.06 pg/kg/day, respectively. Several different policy- based assumptions account for the differences. For example, EPA scales from animals to humans on the basis of relative body surface area, while FDA uses relative body weights. In addition, both EPA and FDA used the 2,3,7,8-TCDD concentration in rat food as a surrogate for dose, while CDC used the concentration of the chemical in rat liver as a measure of dose. There is no obvious scientific basis for excluding any of these values from the range." "... a majority of the Workgroup has concluded that the 1985 EPA estimate of the upper-bound potency (RsD) generated from the application of the UCL LMS model to the Kociba et al. (1978) data is likely to have led to an overestimate of risk (or underestimate of the risk-specific dose). The weight of evidence indicates that a more appropriate upper-bound estimate would be obtained by a reduction of the potency by some unquantifiable amount." "The Workgroup concluded that there is currently no definitive scientific basis for an answer to that question [How great a reduction in slope (or increase in RsD) [or reduction in potency] is appropriate?] APPENDICES A THROUGH F A. Steven P. Bayard, CAG "2,3,7,8-Tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) is the most potent animal carcinogen ever tested. It is 50 times more potent than aflatoxin B1 on a per mole basis and 50 million times more potent than vinyl chloride. ... 2,3,7,8-TCDD is also the most potent animal teratogen known and it causes other reproductive and immune system effects at extremely low doses as well." "Even with the use of the same model [the linearized multistage model] [by four U.S. agencies], however, the results varied over 10- fold due to the selection of different factors relating both to the animal data and to the procedure. Such factors are: * Choice of animal bioassay * Adjustment made for differential nontumor mortality among the animal treatment groups * Selection of tumor types for modeling * Animal-to-human dose equivalence * Dose used for curve fit" "... EPA, FDA, and CDC all used the cancer response data from ... Kociba et al. (1977, 1978)." [reference dose for upper-limit risk of 10(-6)); units of fg/kg-day: EPA = 6.4; FDA = 57.2; CDC = 27.6 (California used NTP mouse study and came up with a dose of 6.7] "In order to correct for high early mortality in the high-dose rats, EPA's analysis eliminated all animals that died during the first year of the study (before the appearance of the first tumor)." "Even assuming that the basic mechanism of the carcinogen stays the same from high- to low-doses, there are often large species differences both in tissue distribution and in metabolic pathways to form the active carcinogen. Almost never is there a good understanding of the mechanism." "... consideration of all the unknowns of actual mechanism and metabolism make it apparent that the species correction factor is only a rough approximation, meant to somehow convey the concept of increased sensitivity of the human compared to the smaller animals." ".. if total body burden ... only is considered, the very long half- life in the human [6-10 years] leads to risk estimates between 16 and 27 times that in EPA's HAD (1985)." "The limited evidence suggests that if liver tissue concentration- time species equivalence is correct, then the EPA HAD (1985) might underpredict the upper-limit risk by a factor of 1.6 to 6.8." "While EPA's cancer risk estimates were the highest of the agencies presented, other methodologies consistent with the data have yielded still higher estimates." "Of even greater uncertainty is the extremely long half-life of 2,3,7,8-TCDD in the human compared to the rat. If half-life is related to species sensitivity as implied by the cross-species extrapolation factor, then recent estimates of human half-life of 6 to 10 years implies that rat-to-human extrapolation estimates should be significantly higher, probably by a fctor of 2 to 7." F. B. R. Sonawane, R.J. Smialowicz and R.W. Luebe "It is not clear whether and how repeated doses might affect the immune system or whether short-term exposure could result in irreversible effects." "The effects following perinatal exposure have been reported to be more profound than those produced following adult exposure, although in some cases a high degree of fetal toxicity has been reported ..." "Laboratory studies have clearly demonstrated the immunotoxic effects of 2,3,7,8-TCDD in a variety of animal models. Extrapolation of these data to predict effects of human 2,3,7,8- TCDD exposure are complicated at best, since actual exposure levels, route of exposure, and even comparability of human and animal susceptibility to the toxic effects of 2,3,7,8-TCDD are unknown." "Human Health Aspects of Environmental Exposure to Polychlorinated Dibenzo-p-dioxin and Polychlorinated Dibenzofurans: Report of the Ad Hoc Panel on Health Aspects of Polychlorinated Dibenzo-p-dioxins and Polychlorinated Dibenzofurans," Universities Associated for Research and Education in Pathology, Inc., Bethesda, MD, June 1988. [supported by a grant from the American Paper Institute] "None of these selections [general approaches to risk assessment] can be justified on a purely scientific basis." "A growing body of evidence indicates that populations of modern industrialized nations including the United States are continually exposed to PCDDs/PCDFs with diet being the most important source. Thus, there exist background body burdens of these compounds in humans, and the average of these is close to calculated body burdens associated with adverse effect levels in experimental animals." "...because of inter-individual variability both in dietary exposure and susceptibility, ... some individuals are at risk of adverse health consequences from any additional exposure to these compounds." "These results [EPA National Human Adipose Tissue Survey data] confirm that humans are continually exposed to PCDDs/PCDFs in the environment and the health risks of additional expousres must be evaluated in the context of adding to an already existing body burden rather than as a de novo exposure." ".. the average body burden of 2,3,7,8-TCDD equivalents is 5.8 ng/kg of body weight [5,800 pg/kg of body weight]." EPA Memo: "2,3,7,8-TCDD in Aquatic Environments," February 4, 1987, from Philip M. Cook, Chief, Hazardous Waste Research Branch, to Jim Cummings, Office of the Assistant Administrator for Solid Waste and Emergency Response. "2,3,7,8-TCDD is so toxic to fish tht BCF [bioconcentration factor] determinations have not yet been made over long exposure periods without toxic effects and mortality occurring. No-effect levels are likely to be less than 10 ppq total 2,3,7,8-TCDD in water and possibly less than 1 ppq if only "dissolved" 2,3,7,8- TCDD is considered in the bioaccumulatable and toxic component." "2,3,7,8-TCDD was lethal to carp at an accumulated dose of 2 ug/kg. Rainbow trout appear to be a little more sensitive. This toxicity is comparable to the 1 ug/kg LD50 found for the guinea pig, the most sensitive mammalian species known." Birnbaum, et al.: "Subchronic Effectgs of Exposure to OCDD," Div. of Toxicol. Res. & Testing, Nat. Instit. of Enviro. Health Sciences, Research Triangle Park "Researchers from the National Institute of Environmental Health Sciences report that the liver is a "major depot" for OCDD, and that toxic effects on the liver induced by subchronic expousre to OCDD "can result in effects similar to that observed for TCDD." The researchers estimate that "OCDD has a potency between .01 and .001 that of TCDD." [EPA Toxic Equivalency Factor (TEF) for OCDD is 0.] "Given the opportunity for low dose chronic expousre to OCDD, serious consideration should be given to its potential toxicity." Miller, H. et al.: "Photolysis of OCDD in Soils: Production of 2,3,7,8-TCDD," Univ. Nevada, Enseco-Cal Lab, Sacramento, CA, Envir. Res. Lab., U.S. EPA OCDD in soils has been found to undergo photolysis and, through dechlorination, to create 2,3,7,8-TCDD. As you can see, I could go on and on with this ... in fact, I have. And I'll be glad to provide you with my favorite excerpts from both of these reports, excerpts from several other reports, including a study funded by the American Paper Institute, "Human Health Aspects of Environmental Exposure to Polychlorinated Dibenzo-p-dioxins and Polychlorinated Dibenzofurans," June 1988, in addition to several other appropriate documents: "No Margin of Safety" Memorandum: "Review of "A Cancer Risk-Specific Dose Estimate for 2,3,7,8-TCDD," from David H. Cleverly, Environmental Scientist, Pollutant Assessment Branch, to Peter W. Presuss, Director, Office of Technology Transfer and Regulatory Support, December 23, 1987 "The National Dioxin Study: Tiers 3,5,6, and 7," U.S. EPA, Washington, D.C. 20460, EPA 440/4-87-003, February 1987. Excerpts Memorandum: "Evaluation of Data Collected During U.S. EPA's 1984 Field Study of Midland, Michigan," from J. Milton Clark, Toxic Substances Section, to David Stringham, Deputy Director, Waste Management Division, February 28, 1985. Excerpts Report: "Reproductive risks from consumption of dioxin- and furan-contaminated milk packaged in paper containers," from Alder Hill Associates to Pat Costner, Greenpeace, November 22, 1988 Esposito, M.P., Tiernan, T.O. and Dryden, F.E., "Dioxins," EPA- 600/2-80-197, November 1980. Excerpts "Work/Quality Assurance Project Plan for the Bioaccumulation Study," USEPA, Monitoring and Data Support Division, Office of Water Regulations and Standards, September 1985. Excerpts [commercial chemicals known to be contaminated with polychlorinated dibenzodioxins and dibenzofurans] "This `nontoxic' dioxin isn't," Science News, Vol. 133, No. 17, April 23, 1988.